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Uribe-Noguez LA, Prieto-Torres ME, Uribe-Noguez LO, Mata-Marín JA, Arroyo-Anduiza CI, Paquentín-Jimenez R, Chaparro-Sanchez A, Vazquez-Gonzalez WG, Santos Coy-Arechavaleta A, Pompa-Mera EN, Gaytán-Martínez J, Alvarado-Yaah JE, Santacruz-Tinoco CE, Ocaña-Mondragón A. Prevalence and Risk Factors of Occult HCV Infection in the Adult Population of Mexico City. Viruses 2025; 17:236. [PMID: 40006991 PMCID: PMC11860181 DOI: 10.3390/v17020236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 01/31/2025] [Accepted: 02/03/2025] [Indexed: 02/27/2025] Open
Abstract
Occult HCV infection (OCI) is defined by the presence of HCV RNA in hepatocytes and/or peripheral blood mononuclear cells (PBMCs) without detectable HCV RNA or anti-HCV antibodies in plasma. OCI is underrecognized and may contribute to HCV transmission. This study estimated OCI prevalence and associated risk factors in adults from Mexico City. Methods: A retrospective cross-sectional study was conducted, analyzing 507 general population volunteers. Demographic data and potential risk factors were collected via questionnaire. Anti-HCV detection was performed using two techniques: immunochromatographic rapid test and chemiluminescent microparticle immunoassay (CMIA). Nested PCR was employed to detect HCV RNA in plasma and PBMCs. Positive samples were genotyped through sequencing and phylogenetic analysis of the Core/E1 region. Results: Of 507 participants, four were anti-HCV positive. HCV RNA was found in PBMCs of 27 individuals, while plasma samples tested negative, indicating a 5.3% OCI prevalence. OCI was significantly associated with blood donation (p = 0.015), drug use (p = 0.019), particularly cocaine (p = 0.001), and endoscopy (p = 0.043). Genotypes 1b, 1a, 2b, 3a, and 2j were detected in OCI cases. Conclusions: OCI prevalence in Mexico City's general population is notable, with significant links to blood donation, cocaine use, and endoscopy. Enhanced diagnostic strategies are crucial to detect OCI and mitigate HCV transmission.
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Affiliation(s)
- Luis Antonio Uribe-Noguez
- Laboratorio Central de Epidemiología, División de Laboratorios Especializados, Centro Médico Nacional (CMN) “La Raza”, IMSS, México City 02990, Mexico; (W.G.V.-G.); (A.S.C.-A.); (J.E.A.-Y.); (A.O.-M.)
| | - María Erandhi Prieto-Torres
- Coordinación de Información y Análisis Estratégico, Instituto Mexicano del Seguro Social (IMSS), Mexico City 77503, Mexico;
| | | | - José Antonio Mata-Marín
- Departamento de Enfermedades Infecciosas, Hospital de Infectología, CMN “La Raza”, IMSS, Mexico City 02990, Mexico; (J.A.M.-M.); (A.C.-S.); (J.G.-M.)
| | | | - Rebeca Paquentín-Jimenez
- Inflammatory Eye Disease Clinic, Asociación Para Evitar la Ceguera en México, Hospital “Dr. Luis Sánchez Bulnes”, México City 04030, Mexico;
| | - Alberto Chaparro-Sanchez
- Departamento de Enfermedades Infecciosas, Hospital de Infectología, CMN “La Raza”, IMSS, Mexico City 02990, Mexico; (J.A.M.-M.); (A.C.-S.); (J.G.-M.)
| | - Wendy Guadalupe Vazquez-Gonzalez
- Laboratorio Central de Epidemiología, División de Laboratorios Especializados, Centro Médico Nacional (CMN) “La Raza”, IMSS, México City 02990, Mexico; (W.G.V.-G.); (A.S.C.-A.); (J.E.A.-Y.); (A.O.-M.)
| | - Andrea Santos Coy-Arechavaleta
- Laboratorio Central de Epidemiología, División de Laboratorios Especializados, Centro Médico Nacional (CMN) “La Raza”, IMSS, México City 02990, Mexico; (W.G.V.-G.); (A.S.C.-A.); (J.E.A.-Y.); (A.O.-M.)
| | - Ericka Nelly Pompa-Mera
- Unidad de Investigación en Enfermedades Infecciosas y Parasitarias, Hospital de Pediatría, CMN “Siglo XXI”, IMSS, Mexico City 06720, Mexico;
| | - Jesus Gaytán-Martínez
- Departamento de Enfermedades Infecciosas, Hospital de Infectología, CMN “La Raza”, IMSS, Mexico City 02990, Mexico; (J.A.M.-M.); (A.C.-S.); (J.G.-M.)
| | - Julio Elias Alvarado-Yaah
- Laboratorio Central de Epidemiología, División de Laboratorios Especializados, Centro Médico Nacional (CMN) “La Raza”, IMSS, México City 02990, Mexico; (W.G.V.-G.); (A.S.C.-A.); (J.E.A.-Y.); (A.O.-M.)
| | | | - Alicia Ocaña-Mondragón
- Laboratorio Central de Epidemiología, División de Laboratorios Especializados, Centro Médico Nacional (CMN) “La Raza”, IMSS, México City 02990, Mexico; (W.G.V.-G.); (A.S.C.-A.); (J.E.A.-Y.); (A.O.-M.)
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Jurasz H, Bukowska-Ośko I, Rydzanicz M, Popiel M, Dzieciątkowski T, Bakuła-Grządka K, Paciorek M, Makowiecki M, Horban A, Laskus T, Radkowski M, Perlejewski K. Torque teno virus (TTV) Infection in Patients with Encephalitis. Int J Mol Sci 2024; 25:11177. [PMID: 39456958 PMCID: PMC11508335 DOI: 10.3390/ijms252011177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/13/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Torque teno virus (TTV) is a ssDNA orphan virus belonging to the Anelloviridae family, but some recent studies suggested its possible involvement in central nervous system (CNS) pathology. We analyzed serum and cerebrospinal fluid samples (CSF) from 109 patients with encephalitis for TTV infection using serological and molecular testing, virus quantitative measurement, and next-generation sequencing-based (NGS) phylogenetic analysis. TTV noncoding region (UTR) and/or open reading frame 1 (ORF-1) sequences were detected in serum of 86 (79%) patients and in nine (8%) patients in CSF. Five of the latter patients were coinfected with various entero- and herpesviruses. Anti-TTV-IgG were detected in 80 (73.4%) sera and in two (1.8%) CSF samples, while anti-TTV-IgM were present in three (2.8%) sera and in none of the CSFs. Phylogenic analysis of CSF-derived TTV ORF-1 sequences revealed the presence of three unique variants in one patient. TTV was quantified in five CSF-serum pairs: in two patients viral loads were similar, and in three serum TTV loads were approximately one log higher. Our results suggest at least an occasional replication of TTV in CNS. However, whether TTV could be the cause of encephalitis requires further studies.
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Affiliation(s)
- Henryk Jurasz
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawinskiego 3c, 02-106 Warsaw, Poland; (H.J.); (I.B.-O.); (M.P.); (M.R.)
| | - Iwona Bukowska-Ośko
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawinskiego 3c, 02-106 Warsaw, Poland; (H.J.); (I.B.-O.); (M.P.); (M.R.)
| | - Małgorzata Rydzanicz
- Department of the Medical Genetics, Medical University of Warsaw, Pawinskiego 3c, 02-106 Warsaw, Poland;
| | - Marta Popiel
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawinskiego 3c, 02-106 Warsaw, Poland; (H.J.); (I.B.-O.); (M.P.); (M.R.)
| | - Tomasz Dzieciątkowski
- Chair and Department of Medical Microbiology, Medical University of Warsaw, Chałubinskiego 5, 02-004 Warsaw, Poland;
| | - Karolina Bakuła-Grządka
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawinskiego 3c, 02-106 Warsaw, Poland; (H.J.); (I.B.-O.); (M.P.); (M.R.)
| | - Marcin Paciorek
- Department of Adults Infectious Diseases, Medical University of Warsaw, Wolska 37, 01-201 Warsaw, Poland; (M.P.); (M.M.); (A.H.)
| | - Michał Makowiecki
- Department of Adults Infectious Diseases, Medical University of Warsaw, Wolska 37, 01-201 Warsaw, Poland; (M.P.); (M.M.); (A.H.)
| | - Andrzej Horban
- Department of Adults Infectious Diseases, Medical University of Warsaw, Wolska 37, 01-201 Warsaw, Poland; (M.P.); (M.M.); (A.H.)
| | - Tomasz Laskus
- Department of Adults Infectious Diseases, Medical University of Warsaw, Wolska 37, 01-201 Warsaw, Poland; (M.P.); (M.M.); (A.H.)
| | - Marek Radkowski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawinskiego 3c, 02-106 Warsaw, Poland; (H.J.); (I.B.-O.); (M.P.); (M.R.)
| | - Karol Perlejewski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawinskiego 3c, 02-106 Warsaw, Poland; (H.J.); (I.B.-O.); (M.P.); (M.R.)
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Landa CR, Ariza-Mateos A, Briones C, Perales C, Wagner A, Domingo E, Gómez J. Adapting the rhizome concept to an extended definition of viral quasispecies and the implications for molecular evolution. Sci Rep 2024; 14:17914. [PMID: 39095425 PMCID: PMC11297277 DOI: 10.1038/s41598-024-68760-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 07/26/2024] [Indexed: 08/04/2024] Open
Abstract
The rhizome concept proposed by Gilles Deleuze and Félix Guattari offers a novel perspective on the organization and interdependence of complex constellations of heterogeneous entities, their mapping and their ruptures. The emphasis of the present study is placed on the dynamics of contacts and communication among such entities that arise from experimentation, without any favored hierarchy or origin. When applied to biological evolution, the rhizome concept integrates all types of heterogeneity resulting from "symbiotic" relationships among living beings (or their genomic material), horizontal genetic transfer, recombination and mutation, and breaks away from the approach that gives rise to the phylogenetic tree of life. It has already been applied to describe the dynamics and evolution of RNA viruses. Thus, here we introduce a novel framework for the interpretation the viral quasispecies concept, which explains the evolution of RNA virus populations as the result of dynamic interconnections and multifaceted interdependence between highly heterogeneous viral sequences and its inherently heterogeneous host cells. The rhizome network perspective underlines even further the medical implications of the broad mutant spectra of viruses that are in constant flow, given the multiple pathways they have available for fitness loss and gain.
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Affiliation(s)
- Carlos Raico Landa
- Laboratory of RNA Archaeology, Instituto de Parasitología y Biomedicina "López-Neyra" (CSIC), Avd. Conocimiento 17, 18016, Armilla, Granada, Spain
| | - Ascensión Ariza-Mateos
- Laboratory of RNA Archaeology, Instituto de Parasitología y Biomedicina "López-Neyra" (CSIC), Avd. Conocimiento 17, 18016, Armilla, Granada, Spain
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Campus de Cantoblanco, Madrid, Spain
| | - Carlos Briones
- Department of Molecular Evolution, Centro de Astrobiología (CSIC-INTA), Madrid, Spain
| | - Celia Perales
- Centro Nacional de Biotecnología (CNB-CSIC), Campus de Cantoblanco, Madrid, Spain
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain
| | | | - Esteban Domingo
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Campus de Cantoblanco, Madrid, Spain
| | - Jordi Gómez
- Laboratory of RNA Archaeology, Instituto de Parasitología y Biomedicina "López-Neyra" (CSIC), Avd. Conocimiento 17, 18016, Armilla, Granada, Spain.
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Stoenescu AF, Popescu CP, Florescu SA, Vancea G, Ceausu E, Calistru P. The Prevalence of Depression and Its Potential Link to Liver Fibrosis in Patients Diagnosed With Chronic Hepatitis C Virus Infection Prior to the Initiation of Direct-Acting Antiviral Treatment. Cureus 2024; 16:e62970. [PMID: 38912074 PMCID: PMC11194022 DOI: 10.7759/cureus.62970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2024] [Indexed: 06/25/2024] Open
Abstract
Introduction Chronic hepatitis C virus (HCV) infection is associated with various extrahepatic manifestations, including depression. This study aimed to determine the prevalence of depression in treatment-naive HCV patients and explore its potential association with liver fibrosis severity. Methodology A consecutive cohort of 50 treatment-naive HCV patients without coinfections was enrolled over six months. Depression was assessed using the Hamilton Depression Rating Scale (HAM-D), and the liver fibrosis stage was evaluated using Fibroscan elastography. Results The cohort comprised 62% females (n=31) and 38% males (n=19), with ages ranging from 27 to 76 years. HAM-D scores indicated mild depression in 78% (n=39) and moderate depression in 16% (n=8) of patients. Notably, patients with mild depression displayed varying degrees of liver fibrosis (F0, F1, and F2), while all patients with moderate depression had advanced fibrosis (F3). Based on the multiple regression model, fibrosis was a statistically significant independent predictor with an unstandardized regression coefficient (B) of 3.115 (p=0.007). Conclusions Our findings point to a high prevalence of depression in treatment-naive HCV patients. Interestingly, there might be a link between depression severity and the stage of liver fibrosis, with advanced fibrosis potentially associated with more severe depression.
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Affiliation(s)
- Andreea Florentina Stoenescu
- Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Dr. Victor Babes Hospital of Infectious and Tropical Diseases, Bucharest, ROU
| | - Corneliu Petru Popescu
- Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Dr. Victor Babes Hospital of Infectious and Tropical Diseases, Bucharest, ROU
| | - Simin Aysel Florescu
- Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Dr. Victor Babes Hospital of Infectious and Tropical Diseases, Bucharest, ROU
| | - Geta Vancea
- Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Dr. Victor Babes Hospital of Infectious and Tropical Diseases, Bucharest, ROU
| | - Emanoil Ceausu
- Infectious Diseases, Academy of Medical Sciences, Dr. Victor Babes Hospital of Infectious and Tropical Diseases, Bucharest, ROU
| | - Petre Calistru
- Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, ROU
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Echeverría N, Gámbaro F, Beaucourt S, Soñora M, Hernández N, Cristina J, Moratorio G, Moreno P. Mixed Infections Unravel Novel HCV Inter-Genotypic Recombinant Forms within the Conserved IRES Region. Viruses 2024; 16:560. [PMID: 38675902 PMCID: PMC11053413 DOI: 10.3390/v16040560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/12/2024] [Accepted: 03/16/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatitis C virus (HCV) remains a significant global health challenge, affecting millions of people worldwide, with chronic infection a persistent threat. Despite the advent of direct-acting antivirals (DAAs), challenges in diagnosis and treatment remain, compounded by the lack of an effective vaccine. The HCV genome, characterized by high genetic variability, consists of eight distinct genotypes and over ninety subtypes, underscoring the complex dynamics of the virus within infected individuals. This study delves into the intriguing realm of HCV genetic diversity, specifically exploring the phenomenon of mixed infections and the subsequent detection of recombinant forms within the conserved internal ribosome entry site (IRES) region. Previous studies have identified recombination as a rare event in HCV. However, our findings challenge this notion by providing the first evidence of 1a/3a (and vice versa) inter-genotypic recombination within the conserved IRES region. Utilizing advanced sequencing methods, such as deep sequencing and molecular cloning, our study reveals mixed infections involving genotypes 1a and 3a. This comprehensive approach not only confirmed the presence of mixed infections, but also identified the existence of recombinant forms not previously seen in the IRES region. The recombinant sequences, although present as low-frequency variants, open new avenues for understanding HCV evolution and adaptation.
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Affiliation(s)
- Natalia Echeverría
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (N.E.); (F.G.); (M.S.); (J.C.); (G.M.)
- Laboratorio de Evolución Experimental de Virus, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
| | - Fabiana Gámbaro
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (N.E.); (F.G.); (M.S.); (J.C.); (G.M.)
| | - Stéphanie Beaucourt
- Viral Populations and Pathogenesis Laboratory, Institut Pasteur, 75015 Paris, France;
| | - Martín Soñora
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (N.E.); (F.G.); (M.S.); (J.C.); (G.M.)
- Laboratorio de Simulaciones Biomoleculares, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
| | - Nelia Hernández
- Clínica de Gastroenterología, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo 11600, Uruguay;
| | - Juan Cristina
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (N.E.); (F.G.); (M.S.); (J.C.); (G.M.)
| | - Gonzalo Moratorio
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (N.E.); (F.G.); (M.S.); (J.C.); (G.M.)
- Laboratorio de Evolución Experimental de Virus, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
| | - Pilar Moreno
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (N.E.); (F.G.); (M.S.); (J.C.); (G.M.)
- Laboratorio de Evolución Experimental de Virus, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
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Radkowski M, Kryczka T, Szymańska-Kotwica B, Berak H, Horban A, Pawłowski T, Perlejewski K, Laskus T. Depression and Cognitive Dysfunction in Patients with Chronic Hepatitis C: Correlation with Viral Replication in the Peripheral Blood Mononuclear Cells and Cytokines in Serum. Int J Mol Sci 2023; 24:15351. [PMID: 37895030 PMCID: PMC10607636 DOI: 10.3390/ijms242015351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 10/13/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is commonly associated with depression and cognitive dysfunction, the cause of which could be related to the HCV neuroinvasion and/or state of chronic inflammation. Viral sequences and proteins were previously detected in the brain and since blood leukocytes can cross the blood-brain barrier, they could provide viral access to the CNS. Eighty chronic hepatitis C patients were tested for viral replication in PBMCs (detection of the HCV RNA-negative strand) and serum cytokines. Depression was assessed by the Beck Depression Inventory (BDI), neuroticism by the Eysenck Personality Inventory (N/EPO-R), and anxiety by the State-Trait Anxiety Inventory (STAI) while neurocognitive testing included the Wisconsin Card Sorting Test (WCST), Ruff Figural Fluency Test (RFFT), California Verbal Learning Test (CVLT), and Grooved Pegboard Test (GPT). The HCV RNA-negative strand was detected in PBMCs from 24 (30%) patients and these patients had significantly higher BDI scores (median 12.5 [IQR] 6.3-20.5 vs. median 8.00 [IQR] 3-12; p = 0.013). Both depression and anxiety correlated positively with IL-8 while cognitive flexibility, executive function, problem-solving skills, memory, and motor functioning correlated negatively with some proinflammatory cytokines. Our findings suggest that due to chronic HCV infection, the brain function is negatively affected by both viral replication in PBMCs and by the immune activation state.
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Affiliation(s)
- Marek Radkowski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 02-106 Warsaw, Poland; (M.R.); (K.P.)
| | - Tomasz Kryczka
- Department of Development of Nursing and Social and Medical Sciences, Medical University of Warsaw, 01-445 Warsaw, Poland;
| | - Bogna Szymańska-Kotwica
- Outpatient Clinic, Warsaw Hospital for Infectious Diseases, 01-201 Warsaw, Poland; (B.S.-K.); (H.B.)
| | - Hanna Berak
- Outpatient Clinic, Warsaw Hospital for Infectious Diseases, 01-201 Warsaw, Poland; (B.S.-K.); (H.B.)
| | - Andrzej Horban
- Department of Adult Infectious Diseases, Medical University of Warsaw, 01-201 Warsaw, Poland
| | - Tomasz Pawłowski
- Department of Psychiatry, Wroclaw Medical University, 50-367 Wroclaw, Poland;
| | - Karol Perlejewski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 02-106 Warsaw, Poland; (M.R.); (K.P.)
| | - Tomasz Laskus
- Department of Adult Infectious Diseases, Medical University of Warsaw, 01-201 Warsaw, Poland
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Shehata GA, Ahmed GK, Hassan EA, Rehim ASEDA, Mahmoud SZ, Masoud NA, Seifeldein GS, Hassan WA, Aboshaera KO. Impact of direct-acting antivirals on neuropsychiatric and neurocognitive dysfunction in chronic hepatitis C patients. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2022. [DOI: 10.1186/s41983-022-00568-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Abstract
Background
Hepatitis C virus (HCV) infection is associated with psychiatric and cognitive dysfunctions. We aimed to investigate depression, anxiety, and cognitive function of chronic hepatitis C (CHC) patients before and after treatment with direct-acting antivirals (DAAs). Forty CHC patients (20 non-cirrhotic and 20 cirrhotic) who had undergone DAA treatment in our outpatient clinic and ten controls. We administered the Hospital Anxiety and Depression questionnaires to measure the anxiety and depression symptoms and the Cognitive Abilities Screening Instruments (CASI) to measure the cognitive function at the beginning and 3 months after the end of the treatment.
Results
Sustained virological response (SVR) was achieved in all patients. Post-treatment anxiety and depression scores showed a significant improvement than pre-treatment ones in CHC patients. Regarding CASI, before and after the treatment, a statistical significance was found in short-term memory (P = 0.001), concentration (P = 0.033), abstract thinking and judgment (P = 0.024), total (P = 0.001) in non-cirrhotic, Also, an improvement was seen in long-term memory (P = 0.015), short-term memory (P < 0.001), concentration (P = 0.024) and total (P = 0.01) in cirrhotic. However, these changes were still impaired in post-treated cirrhotic compared to controls.
Conclusions
CHC patients' anxiety, depression, and cognitive function partially improved after DAA therapy. Besides, improving the status of CHC, reversibility of cognitive dysfunction in non-cirrhotic patients may indicate the importance of treatment in early stages of liver disease.
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Mbaga DS, Kenmoe S, Njiki Bikoï J, Takuissu GR, Amougou-Atsama M, Atenguena Okobalemba E, Ebogo-Belobo JT, Bowo-Ngandji A, Oyono MG, Magoudjou-Pekam JN, Kame-Ngasse GI, Nka AD, Feudjio AF, Zemnou-Tepap C, Adamou Velhima E, Ndzie Ondigui JL, Nayang-Mundo RA, Touangnou-Chamda SA, Kamtchueng Takeu Y, Taya-Fokou JB, Mbongue Mikangue CA, Kenfack-Momo R, Kengne-Ndé C, Sake CS, Esemu SN, Njouom R, Ndip L, Riwom Essama SH. Global prevalence of occult hepatitis C virus: A systematic review and meta-analysis. World J Methodol 2022; 12:179-190. [PMID: 35721241 PMCID: PMC9157636 DOI: 10.5662/wjm.v12.i3.179] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/03/2022] [Accepted: 04/30/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Occult hepatitis C infection (OCI) is characterized by the presence of hepatitis C virus (HCV) RNA in the liver, peripheral blood mononuclear cells (PBMC) and/or ultracentrifuged serum in the absence of detectable HCV-RNA in serum. OCI has been described in several categories of populations including hemodialysis patients, patients with a sustained virological response, immunocompromised individuals, patients with abnormal hepatic function, and apparently healthy subjects.
AIM To highlight the global prevalence of OCI.
METHODS We performed a systematic and comprehensive literature search in the following 4 electronic databases PubMed, EMBASE, Global Index Medicus, and Web of Science up to 6th May 2021 to retrieve relevant studies published in the field. Included studies were unrestricted population categories with known RNA status in serum, PBMC, liver tissue and/or ultracentrifuged serum. Data were extracted independently by each author and the Hoy et al tool was used to assess the quality of the included studies. We used the random-effect meta-analysis model to estimate the proportions of OCI and their 95% confidence intervals (95%CI). The Cochran's Q-test and the I2 test statistics were used to assess heterogeneity between studies. Funnel plot and Egger test were used to examine publication bias. R software version 4.1.0 was used for all analyses.
RESULTS The electronic search resulted in 3950 articles. We obtained 102 prevalence data from 85 included studies. The pooled prevalence of seronegative OCI was estimated to be 9.61% (95%CI: 6.84-12.73) with substantial heterogeneity [I² = 94.7% (95%CI: 93.8%-95.4%), P < 0.0001]. Seropositive OCI prevalence was estimated to be 13.39% (95%CI: 7.85-19.99) with substantial heterogeneity [I2 = 93.0% (90.8%-94.7%)]. Higher seronegative OCI prevalence was found in Southern Europe and Northern Africa, and in patients with abnormal liver function, hematological disorders, and kidney diseases. Higher seropositive OCI prevalence was found in Southern Europe, Northern America, and Northern Africa.
CONCLUSION In conclusion, in the present study, it appears that the burden of OCI is high and variable across the different regions and population categories. Further studies on OCI are needed to assess the transmissibility, clinical significance, long-term outcome, and need for treatment.
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Affiliation(s)
- Donatien Serge Mbaga
- Department of Microbiology, The University of Yaounde I, Yaounde 00237, Cameroon
| | - Sebastien Kenmoe
- Department of Microbiology and Parasitology, University of Buea, Buea 00237, Cameroon
- Department of Virology, Centre Pasteur of Cameroon, Yaounde 00237, Cameroon
| | - Jacky Njiki Bikoï
- Department of Microbiology, The University of Yaounde I, Yaounde 00237, Cameroon
| | - Guy Roussel Takuissu
- Centre of Research in Food, Food Security and Nutrition, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | - Marie Amougou-Atsama
- Centre de Recherche sur les Maladies Emergentes et Re-Emergentes, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | | | - Jean Thierry Ebogo-Belobo
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | - Arnol Bowo-Ngandji
- Department of Microbiology, The University of Yaounde I, Yaounde 00237, Cameroon
| | - Martin Gael Oyono
- Laboratory of Parasitology and Ecology, The University of Yaounde I, Yaounde 00237, Cameroon
| | | | - Ginette Irma Kame-Ngasse
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | - Alex Durand Nka
- Virology Laboratory, Chantal Biya International Reference Center for Research on HIV/AIDS Prevention and Management, Yaounde 00237, Cameroon
| | | | - Cromwel Zemnou-Tepap
- Department of Biochemistry, The University of Yaounde I, Yaounde 00237, Cameroon
| | - Elie Adamou Velhima
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | | | | | | | - Yrene Kamtchueng Takeu
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | | | | | - Raoul Kenfack-Momo
- Department of Biochemistry, The University of Yaounde I, Yaounde 00237, Cameroon
| | - Cyprien Kengne-Ndé
- Epidemiological Surveillance, Evaluation and Research Unit, National Aids Control Committee, Douala 00237, Cameroon
| | | | - Seraphine Nkie Esemu
- Department of Microbiology and Parasitology, University of Buea, Buea 00237, Cameroon
| | - Richard Njouom
- Department of Virology, Centre Pasteur of Cameroon, Yaounde 00237, Cameroon
| | - Lucy Ndip
- Department of Microbiology and Parasitology, University of Buea, Buea 00237, Cameroon
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9
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RNA-Binding Proteins as Regulators of Internal Initiation of Viral mRNA Translation. Viruses 2022; 14:v14020188. [PMID: 35215780 PMCID: PMC8879377 DOI: 10.3390/v14020188] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/03/2022] [Accepted: 01/14/2022] [Indexed: 12/17/2022] Open
Abstract
Viruses are obligate intracellular parasites that depend on the host’s protein synthesis machinery for translating their mRNAs. The viral mRNA (vRNA) competes with the host mRNA to recruit the translational machinery, including ribosomes, tRNAs, and the limited eukaryotic translation initiation factor (eIFs) pool. Many viruses utilize non-canonical strategies such as targeting host eIFs and RNA elements known as internal ribosome entry sites (IRESs) to reprogram cellular gene expression, ensuring preferential translation of vRNAs. In this review, we discuss vRNA IRES-mediated translation initiation, highlighting the role of RNA-binding proteins (RBPs), other than the canonical translation initiation factors, in regulating their activity.
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10
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Occult Infection with Hepatitis C Virus: Looking for Clear-Cut Boundaries and Methodological Consensus. J Clin Med 2021; 10:jcm10245874. [PMID: 34945170 PMCID: PMC8707082 DOI: 10.3390/jcm10245874] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/11/2021] [Accepted: 12/13/2021] [Indexed: 02/07/2023] Open
Abstract
The sustained virologic response and elimination of HCV is widely viewed as a true cure of chronic hepatitis C as it associates with amelioration of histological liver damage and improved clinical outcomes. Therefore, the existence and clinical burden of occult HCV infection (OCI) has been a controversial issue for many years. In this review, we summarize recently published data that adds new information on the molecular and clinical background of OCI and its epidemiological significance. We also identify and discuss the most important methodological pitfalls, which can be a source of inconsistency between studies. Data that have accumulated so far, strongly support the existence of extrahepatic HCV replication in individuals negative for serum HCV-RNA by conventional clinical tests. OCI emerges as a condition where the immune system is unable to fully resolve infection but it is continuously stimulated by low levels of HCV antigens, leading to progression of liver pathology and extrahepatic HCV-related complications. Moreover, the development of monitoring strategies or management guidelines for OCI is still hampered by the lack of clear definition and the confusion regarding its clinical significance. Careful study design and the introduction of uniform protocols for the detection of low-level HCV-RNA are crucial for obtaining reliable data on OCI.
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11
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Moretti R, Giuffrè M, Merli N, Caruso P, Di Bella S, Tiribelli C, Crocè LS. Hepatitis C Virus-Related Central and Peripheral Nervous System Disorders. Brain Sci 2021; 11:1569. [PMID: 34942871 PMCID: PMC8699483 DOI: 10.3390/brainsci11121569] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatitis C Virus (HCV), despite being a hepatotropic virus, is the causative agent of many systemic disorders, such as vasculitis, autoimmune diseases, lymphoproliferative disorders, and a broad spectrum of neurological and psychiatric manifestations. Although symptoms have been misdiagnosed or underdiagnosed, only recently, evidence of direct (inflammatory) or indirect (immune-mediated) HCV-dependent cerebral effects has been established. HCV infection can promote acute inflammatory response, pro-coagulative status and ischemic disorders, and neurodegeneration. These effects rely on cerebral HCV replication, possibly mediated by blood-brain barrier alterations. Further study is needed to better understand the HCV-related mechanisms of brain damage.
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Affiliation(s)
- Rita Moretti
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Mauro Giuffrè
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Nicola Merli
- Department Neurological Sciences, University of Ferrara, 44121 Ferrara, Italy;
| | - Paola Caruso
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Stefano Di Bella
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | | | - Lory Saveria Crocè
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
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12
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Lotfi AA, Mohamed AE, Shalaby NA, Eissa DS, El-Dabaa E, Sallam AM, Kamel MM, Abdelaziz H, El-Afifi AM, Abdel-Moneim AS. Occult hepatitis C virus infection in patients with malignant lymphoproliferative disorders. Int J Immunopathol Pharmacol 2021; 34:2058738420961202. [PMID: 33045856 PMCID: PMC7557643 DOI: 10.1177/2058738420961202] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Despite the link between HCV and malignant lymphoproliferative disorders has been established, the association between occult hepatitis C virus infection and malignant lymphoproliferative disorders remains obscure. The present study intended to identify the possible association between occult HCV infection and malignant lymphoproliferative disorders. Newly diagnosed patients with LPDs were screened for the presence of HCV-RNA in both plasma and PBMCs. PBMCs of the subjects were also, examined by transmission and immuno-electron microscopy. LPD patients showed a high percentage of HCV infection (71.9%): OCI-HCV (37.5%) and HCV (34.38%). Meanwhile, 28.13% of LPD patients did not show any evidence of HCV infection. Ultrastructural examination of PBMCs revealed the presence of intracytoplasmic vacuoles enclosing viral like particles, which were less prominent in occult HCV patients. The possibility of occult HCV should be considered in patients with LPDs which can be helpful in the management of the treatment protocol in order to set up a balance between the control of the tumor progression and minimizing post chemotherapy complications related to HCV infection.
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Affiliation(s)
- Abeya A Lotfi
- Clinical and Chemical Pathology Department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Asmaa E Mohamed
- Clinical and Chemical Pathology Department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Nahela A Shalaby
- Clinical and Chemical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Deena S Eissa
- Clinical and Chemical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ehab El-Dabaa
- Biochemistry and Molecular biology department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Ayman M Sallam
- Biochemistry and Molecular biology department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Mahmoud M Kamel
- Clinical Pathology Department, National Cancer Institute, Cairo University, Giza, Egypt
| | - Hisham Abdelaziz
- Clinical Pathology Department, National Cancer Institute, Cairo University, Giza, Egypt
| | - Amal M El-Afifi
- Department of Clinical hematology and transplantation, Ain shams University, Cairo, Egypt
| | - Ahmed S Abdel-Moneim
- Microbiology Department, College of Medicine, Taif University, Taif, Saudi Arabia.,Virology Department, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt
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13
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van den Akker GGH, Zacchini F, Housmans BAC, van der Vloet L, Caron MMJ, Montanaro L, Welting TJM. Current Practice in Bicistronic IRES Reporter Use: A Systematic Review. Int J Mol Sci 2021; 22:5193. [PMID: 34068921 PMCID: PMC8156625 DOI: 10.3390/ijms22105193] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/05/2021] [Accepted: 05/12/2021] [Indexed: 12/26/2022] Open
Abstract
Bicistronic reporter assays have been instrumental for transgene expression, understanding of internal ribosomal entry site (IRES) translation, and identification of novel cap-independent translational elements (CITE). We observed a large methodological variability in the use of bicistronic reporter assays and data presentation or normalization procedures. Therefore, we systematically searched the literature for bicistronic IRES reporter studies and analyzed methodological details, data visualization, and normalization procedures. Two hundred fifty-seven publications were identified using our search strategy (published 1994-2020). Experimental studies on eukaryotic adherent cell systems and the cell-free translation assay were included for further analysis. We evaluated the following methodological details for 176 full text articles: the bicistronic reporter design, the cell line or type, transfection methods, and time point of analyses post-transfection. For the cell-free translation assay, we focused on methods of in vitro transcription, type of translation lysate, and incubation times and assay temperature. Data can be presented in multiple ways: raw data from individual cistrons, a ratio of the two, or fold changes thereof. In addition, many different control experiments have been suggested when studying IRES-mediated translation. In addition, many different normalization and control experiments have been suggested when studying IRES-mediated translation. Therefore, we also categorized and summarized their use. Our unbiased analyses provide a representative overview of bicistronic IRES reporter use. We identified parameters that were reported inconsistently or incompletely, which could hamper data reproduction and interpretation. On the basis of our analyses, we encourage adhering to a number of practices that should improve transparency of bicistronic reporter data presentation and improve methodological descriptions to facilitate data replication.
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Affiliation(s)
- Guus Gijsbertus Hubert van den Akker
- Department of Orthopedic Surgery, Maastricht University, Medical Center+, 6229 ER Maastricht, The Netherlands; (G.G.H.v.d.A.); (B.A.C.H.); (L.v.d.V.); (M.M.J.C.)
| | - Federico Zacchini
- Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, I-40138 Bologna, Italy; (F.Z.); (L.M.)
- Centro di Ricerca Biomedica Applicata—CRBA, Bologna University, Policlinico di Sant’Orsola, I-40138 Bologna, Italy
| | - Bas Adrianus Catharina Housmans
- Department of Orthopedic Surgery, Maastricht University, Medical Center+, 6229 ER Maastricht, The Netherlands; (G.G.H.v.d.A.); (B.A.C.H.); (L.v.d.V.); (M.M.J.C.)
| | - Laura van der Vloet
- Department of Orthopedic Surgery, Maastricht University, Medical Center+, 6229 ER Maastricht, The Netherlands; (G.G.H.v.d.A.); (B.A.C.H.); (L.v.d.V.); (M.M.J.C.)
| | - Marjolein Maria Johanna Caron
- Department of Orthopedic Surgery, Maastricht University, Medical Center+, 6229 ER Maastricht, The Netherlands; (G.G.H.v.d.A.); (B.A.C.H.); (L.v.d.V.); (M.M.J.C.)
| | - Lorenzo Montanaro
- Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, I-40138 Bologna, Italy; (F.Z.); (L.M.)
- Centro di Ricerca Biomedica Applicata—CRBA, Bologna University, Policlinico di Sant’Orsola, I-40138 Bologna, Italy
- Programma Dipartimentale in Medicina di Laboratorio, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, I-40138 Bologna, Italy
| | - Tim Johannes Maria Welting
- Department of Orthopedic Surgery, Maastricht University, Medical Center+, 6229 ER Maastricht, The Netherlands; (G.G.H.v.d.A.); (B.A.C.H.); (L.v.d.V.); (M.M.J.C.)
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14
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Nath A, Johnson TP. Mechanisms of viral persistence in the brain and therapeutic approaches. FEBS J 2021; 289:2145-2161. [PMID: 33844441 DOI: 10.1111/febs.15871] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 03/31/2021] [Accepted: 04/09/2021] [Indexed: 12/16/2022]
Abstract
There is growing recognition of the diversity of viruses that can infect the cells of the central nervous system (CNS). While the majority of CNS infections are successfully cleared by the immune response, some viral infections persist in the CNS. As opposed to resolved infections, persistent viruses can contribute to ongoing tissue damage and neuroinflammatory processes. In this manuscript, we provide an overview of the current understanding of factors that lead to viral persistence in the CNS including how viruses enter the brain, how these pathogens evade antiviral immune system responses, and how viruses survive and transmit within the CNS. Further, as the CNS may serve as a unique viral reservoir, we examine the ways in which persistent viruses in the CNS are being targeted therapeutically.
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Affiliation(s)
- Avindra Nath
- Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Tory P Johnson
- Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.,Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
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15
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Tsai PC, Chen CY, Kuo HT, Hung CH, Tseng KC, Lai HC, Peng CY, Wang JH, Chen JJ, Lee PL, Chien RN, Yang CC, Lo GH, Kao JH, Liu CJ, Liu CH, Yan SL, Bair MJ, Lin CY, Su WW, Chu CH, Chen CJ, Tung SY, Tai CM, Lin CW, Lo CC, Cheng PN, Chiu YC, Wang CC, Cheng JS, Tsai WL, Lin HC, Huang YH, Yeh ML, Huang CF, Hsieh MH, Huang JF, Dai CY, Chung WL, Ke CLK, Yu ML. Successful Antiviral Therapy Reduces Risk of Schizophrenia Among Chronic Hepatitis C Patients: A Nationwide Real-World Taiwanese Cohort (T-COACH). Open Forum Infect Dis 2020; 7:ofaa397. [PMID: 33376753 PMCID: PMC7751132 DOI: 10.1093/ofid/ofaa397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/27/2020] [Indexed: 01/12/2023] Open
Abstract
Background Chronic hepatitis C (CHC) has been associated with major psychoses, and interferon (IFN)-based therapy may cause psychiatric sequelae. We aimed to evaluate the effects of sustained virological response (SVR) on the incidence of major psychoses in a nationwide Taiwanese CHC cohort. Methods Fifteen thousand eight hundred thirty-six CHC Taiwanese who received IFN-based therapy were enrolled between 2003 and 2015. Of those, 12 723 patients were linked to the National Health Insurance Research Databases for the incidence of major psychoses. Death before major psychoses was considered a competing risk. Results Twenty-four patients developed new-onset major psychoses during 67 554 person-years (3.6 per 10 000 person-years), including 16 affective psychoses, 7 schizophrenia, and 1 organic psychotic condition. The incidence of major psychoses and affective psychoses did not differ between the SVR and non-SVR groups. The 10-year cumulative incidence of schizophrenia were significantly higher in the non-SVR than in SVR patients (0.14% vs 0.04%, P = .036). Cox subdistribution hazards showed that SVR and older age were associated with a significantly lower risk of schizophrenia (hazard ratio = 0.18 and 0.17). Sustained virological response was associated with decreased incidence of schizophrenia and majorly observed among patients with age <45 (P = .02). Conclusions Successful IFN-based therapy might reduce the incidence of schizophrenia among CHC patients, especially among younger patients.
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Affiliation(s)
- Pei-Chien Tsai
- Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chi-Yi Chen
- Department of Internal Medicine, Chiayi Christian Hospital, Chiayi, Taiwan
| | - Hsing-Tao Kuo
- Division of Hepatogastroenterology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Kuo-Chih Tseng
- Department of Gastroenterology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Hsueh-Chou Lai
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Yuan Peng
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jyh-Jou Chen
- Division of Gastroenterology and Hepatology, Chi-Mei Medical Center, Liouying, Tainan, Taiwan
| | - Pei-Lun Lee
- Division of Gastroenterology and Hepatology, Chi-Mei Medical Center, Liouying, Tainan, Taiwan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Chi-Chieh Yang
- Division of Gastroenterology, Department of Internal Medicine, Show Chwan Memorial Hospital, Changhua, Taiwan
| | - Gin-Ho Lo
- Division of Gastroenterology and Hepatology, Department of Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chen-Hua Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan
| | - Sheng-Lei Yan
- Division of Gastroenterology, Department of Internal Medicine, Chang Bing Show-Chwan Memorial Hospital, Changhua, Taiwan
| | - Ming-Jong Bair
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
| | - Chun-Yen Lin
- Division of Hepatology, Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Wei-Wen Su
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Cheng-Hsin Chu
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
| | - Chih-Jen Chen
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
| | - Shui-Yi Tung
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chi-Ming Tai
- Division of Gastroenterology and Hepatology, Department of Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Chih-Wen Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Ching-Chu Lo
- Department of Internal Medicine, St. Martin De Porres Hospital - Daya, Chiayi, Taiwan
| | - Pin-Nan Cheng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yen-Cheng Chiu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Chi Wang
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, New Taipei, Taiwan
| | - Jin-Shiung Cheng
- Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Wei-Lun Tsai
- Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Veterans General Hospital, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Meng-Hsuan Hsieh
- Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chung
- Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chiao-Li Khale Ke
- Department of Psychiatry, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
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16
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Peculiarities of the Expression of Immunohistochemical Marker HCV nS3 in the Autopsy Brain of the Patients Died in the Outcome of Chronic Infection, Caused by Hepatitis C Virus. ACTA BIOMEDICA SCIENTIFICA 2020. [DOI: 10.29413/abs.2020-5.2.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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17
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Yañez O, Chávez-Galarza J, Tellgren-Roth C, Pinto MA, Neumann P, de Miranda JR. The honeybee (Apis mellifera) developmental state shapes the genetic composition of the deformed wing virus-A quasispecies during serial transmission. Sci Rep 2020; 10:5956. [PMID: 32249797 PMCID: PMC7136270 DOI: 10.1038/s41598-020-62673-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 03/17/2020] [Indexed: 11/23/2022] Open
Abstract
The main biological threat to the western honeybee (Apis mellifera) is the parasitic mite Varroa destructor, largely because it vectors lethal epidemics of honeybee viruses that, in the absence of this mite, are relatively innocuous. The severe pathology is a direct consequence of excessive virus titres caused by this novel transmission route. However, little is known about how the virus adapts genetically during transmission and whether this influences the pathology. Here, we show that upon injection into honeybee pupae, the deformed wing virus type-A (DWV-A) quasispecies undergoes a rapid, extensive expansion of its sequence space, followed by strong negative selection towards a uniform, common shape by the time the pupae have completed their development, with no difference between symptomatic and asymptomatic adults in either DWV titre or genetic composition. This suggests that the physiological and molecular environment during pupal development has a strong, conservative influence on shaping the DWV-A quasispecies in emerging adults. There was furthermore no evidence of any progressive adaptation of the DWV-A quasispecies to serial intra-abdominal injection, simulating mite transmission, despite the generation of ample variation immediately following each transmission, suggesting that the virus either had already adapted to transmission by injection, or was unaffected by it.
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Affiliation(s)
- Orlando Yañez
- Institute of Bee Health, Vetsuisse Faculty, University of Bern, Bern, CH-3000, Switzerland
| | - Julio Chávez-Galarza
- Centro de Investigação de Montanha (CIMO), Instituto Politécnico de Bragança, Campus de Sta. Apolónia, 5300-253, Bragança, Portugal
- Instituto Nacional de Innovación Agraria (INIA), Av. La Molina, 1981, Lima, Perú
| | | | - M Alice Pinto
- Centro de Investigação de Montanha (CIMO), Instituto Politécnico de Bragança, Campus de Sta. Apolónia, 5300-253, Bragança, Portugal
| | - Peter Neumann
- Institute of Bee Health, Vetsuisse Faculty, University of Bern, Bern, CH-3000, Switzerland
| | - Joachim R de Miranda
- Department of Ecology, Swedish University of Agricultural Sciences, Uppsala, 750 07, Sweden.
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18
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Koirala D, Lewicka A, Koldobskaya Y, Huang H, Piccirilli JA. Synthetic Antibody Binding to a Preorganized RNA Domain of Hepatitis C Virus Internal Ribosome Entry Site Inhibits Translation. ACS Chem Biol 2020; 15:205-216. [PMID: 31765566 DOI: 10.1021/acschembio.9b00785] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Structured RNA elements within the internal ribosome entry site (IRES) of hepatitis C virus (HCV) genome hijack host cell machinery for translation initiation through a cap-independent mechanism. Here, using a phage display selection, we obtained two antibody fragments (Fabs), HCV2 and HCV3, against HCV IRES that bind the RNA with dissociation constants of 32 ± 7 nM and 37 ± 8 nM respectively, specifically recognizing the so-called junction IIIabc (JIIIabc). We used these Fabs as crystallization chaperones and determined the high-resolution crystal structures of JIIIabc-HCV2 and -HCV3 complexes at 1.81 Å and 2.75 Å resolution respectively, revealing an antiparallel four-way junction with the IIIa and IIIc subdomains brought together through tertiary interactions. The RNA conformation observed in the structures supports the structural model for this region derived from cryo-EM data for the HCV IRES-40S ribosome complex, suggesting that the tertiary fold of the RNA preorganizes the domain for interactions with the 40S ribosome. Strikingly, both Fabs and the ribosomal protein eS27 not only interact with a common subset of nucleotides within the JIIIabc but also use physiochemically similar sets of protein residues to do so, suggesting that the RNA surface is well-suited for interactions with proteins, perhaps analogous to the "hot spot" concept elaborated for protein-protein interactions. Using a rabbit reticulocyte lysate-based translation assay with a bicistronic reporter construct, we further demonstrated that Fabs HCV2 and HCV3 specifically inhibit the HCV IRES-directed translation, implicating disruption of the JIIIabc-ribosome interaction as a potential therapeutic strategy against HCV.
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Affiliation(s)
- Deepak Koirala
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, United States
| | - Anna Lewicka
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, United States
| | - Yelena Koldobskaya
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, United States
| | - Hao Huang
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, United States
| | - Joseph A. Piccirilli
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, United States
- Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States
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Hassaan SH, Darwish AM, Khalifa H, Ramadan HKA, Hassany SM, Ahmed GK, Moustafa EF. Assessment of cognitive functions and psychiatric symptoms in hepatitis C patients receiving pegylated interferon alpha and ribavirin: A prospective cohort study. Int J Psychiatry Med 2019; 54:424-440. [PMID: 31219366 DOI: 10.1177/0091217419858277] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Objective This study aimed to prospectively evaluate cognitive functioning in hepatitis C virus patients before, during, and after interferon alpha and to assess the psychiatric side effects of interferon alpha such as depression and anxiety. Methods A total of 100 chronic hepatitis C virus patients eligible for interferon therapy from the hepatitis outpatient clinic of Assiut University Hospital were included. A full medical and psychiatric assessment was done using the Hamilton Depression Rating Scale (HAM-D) and Hamilton Anxiety Rating Scale (HAM-A). Cognitive assessment was done using The Mini-Mental State Examination (MMSE), Memory Assessment Scales (MAS), and Wechsler Adult Intelligence Scale (WAIS). Medical, cognitive, and psychiatric assessments were conducted at the start of the study and after starting the treatment at two, four, and six months. Results There was a significant increase in the mean scores of HAM-D (t = 7.739, p < 0.001; t = 5.707, p < 0.001; t = 5.115, p < 0.001) and HAM-A (t = 6.237, p < 0.001; t = 4.154, p < 0.001; t = 3.955, p < 0.001) scales at the two, four, and six month follow-ups, respectively, in comparison to the baseline measurements. As regards to the MAS, repeated assessments after two, four, and six months showed no statistically significant difference from the baseline apart from deterioration in the verbal memory performance after six months in comparison to the baseline (t = −2.605, p = 0.011). As regards to MMSE, the verbal intelligence quotient (IQ), performance IQ, and total IQ, there was a significant improvement in the patients’ cognitive performance, in comparison to the baseline, after two months (t = 2.144, p = 0.035), four months (t = 2.868, p = 0.002), and six months (t = 3.505, p = 0.001), respectively. There was also a significant negative correlation between HAM-D mean scores and the MAS verbal mean scores of the patients (r = −.219, p = 0.039). Conclusion There were increases in symptoms of depression and anxiety during interferon alpha and ribavirin treatment, which do not correlate with the patients’ cognitive performance. There was a significant improvement in cognitive performance except in verbal memory with the progress of interferon alpha treatment. Years of education, socioeconomic status, and lower quantitative polymerase chain reaction are predictors for better cognitive performance.
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Affiliation(s)
- Shehab H Hassaan
- Department of Neurology and Psychiatry, Assiut University, Egypt
| | - Alaa M Darwish
- Department of Neurology and Psychiatry, Assiut University, Egypt
| | - Hossam Khalifa
- Department of Neurology and Psychiatry, Assiut University, Egypt
| | | | - Sahar M Hassany
- Tropical Medicine and Gastroenterlogy, Assiut University, Egypt
| | - Gellan K Ahmed
- Department of Neurology and Psychiatry, Assiut University, Egypt
| | - Ehab F Moustafa
- Tropical Medicine and Gastroenterlogy, Assiut University, Egypt
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Colitti B, Nogarol C, Giacobini M, Capucchio MT, Biasato I, Rosati S, Bertolotti L. Compartmentalized evolution of Bovine Viral Diarrhoea Virus type 2 in an immunotolerant persistently infected cow. Sci Rep 2019; 9:15460. [PMID: 31664116 PMCID: PMC6827220 DOI: 10.1038/s41598-019-52023-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 10/13/2019] [Indexed: 12/11/2022] Open
Abstract
Bovine viral diarrhea virus (BVDV) is one of the most important pathogens of cattle worldwide. BVDV-1 is widely distributed in Italy, while BVDV-2 has been detected occasionally. BVDV can be classified in two biotypes, cytopathic (CP) or noncytopathic (NCP). The characteristic of the virus is linked with the infection of a pregnant dam with a NCP strain: due to viral establishment before maturation of the fetal immune system the calf remains persistently infected (PI) and immunotolerant to the infecting BVDV strain. Thanks to their immunotolerance, PI animals represent a unique model to study the viral distribution and compartmentalization in absence of immunoresponse in vivo. In the present study, NGS sequencing was used to characterize the BVDV2 viral strain infecting a PI calf and to describe the viral quasispecies in tissues. Even if the consensus sequences obtained by all the samples were highly similar, quasispecies was described evaluating the presence and the frequency of variants among all the sequencing reads in each tissue. The results suggest a high heterogeneity of the infecting viral strain suggesting viral compartmentalization. The quasispecies analysis highlights the complex dynamics of viral population structure and can increase the knowledge about viral evolution in BVDV-2 persistently infected animals.
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Affiliation(s)
- Barbara Colitti
- Department of Veterinary Science, University of Torino, Largo Paolo Braccini 2, 10095, Grugliasco, Torino, Italy
| | - Chiara Nogarol
- Department of Veterinary Science, University of Torino, Largo Paolo Braccini 2, 10095, Grugliasco, Torino, Italy
| | - Mario Giacobini
- Department of Veterinary Science, University of Torino, Largo Paolo Braccini 2, 10095, Grugliasco, Torino, Italy
| | - Maria Teresa Capucchio
- Department of Veterinary Science, University of Torino, Largo Paolo Braccini 2, 10095, Grugliasco, Torino, Italy
| | - Ilaria Biasato
- Department of Agricultural, Forestry and Food Sciences, University of Torino, Largo Paolo Braccini 2, 10095, Grugliasco, Torino, Italy
| | - Sergio Rosati
- Department of Veterinary Science, University of Torino, Largo Paolo Braccini 2, 10095, Grugliasco, Torino, Italy
| | - Luigi Bertolotti
- Department of Veterinary Science, University of Torino, Largo Paolo Braccini 2, 10095, Grugliasco, Torino, Italy.
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Efficacy and safety of sofosbuvir-based, interferon-free therapy : The Management of rheumatologic extrahepatic manifestations associated with chronic hepatitis C virus infection. Z Rheumatol 2019; 77:621-628. [PMID: 28795238 DOI: 10.1007/s00393-017-0356-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND The use of pegylated interferon alpha (IFN) has been of concern in chronic hepatitis C virus (HCV) patients with rheumatologic extrahepatic manifestations (EHM) due to the immunostimulatory effects of IFN. AIM To study the efficacy and safety of sofosbuvir-based, IFN-free antiviral therapy in chronic HCV patients with rheumatologic EHM. MATERIAL AND METHODS Group A included 24 patients with arthropathy (arthralgia or arthritis, n = 15) or vasculitis (n = 9) who received sofosbuvir and ribavirin (n = 17) or sofosbuvir and simeprevir (n = 7). Group B comprised 15 historical controls suffering from arthropathy who had received IFN and ribavirin. All patients were clinically evaluated and by detection of HCV viremia at baseline (V0), at the end of treatment (V1), 12 weeks after end of treatment (V2) and 24 weeks after end of treatment (V3). RESULTS Sustained viral response was obtained in all patients of group A (100%) versus 12 out of 15 of group B (80%). In group A, the tender joint count (TJC) and visual analogue scale for pain (VAS) improved (p = 0.001 for both) while the swollen joint count (SJC) decreased at V1 (p = 0.001) but returned to baseline values at V3. All vasculitis patients improved. Purpura, arthralgia and leg ulcers disappeared, but peripheral neuropathy persisted. In group B, TJC, SJC and VAS increased from baseline values (p = 0.034, 0.03 and 0.001, respectively). Side effects in group A were generally mild, but one patient developed deterioration of arthralgia. CONCLUSION The use of IFN-free regimens is safe and effective in the treatment of most HCV-related rheumatologic EHM.
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Bukowska-Ośko I, Perlejewski K, Pawełczyk A, Rydzanicz M, Pollak A, Popiel M, Cortés KC, Paciorek M, Horban A, Dzieciątkowski T, Radkowski M, Laskus T. Human Pegivirus in Patients with Encephalitis of Unclear Etiology, Poland. Emerg Infect Dis 2019; 24:1785-1794. [PMID: 30226156 PMCID: PMC6154136 DOI: 10.3201/eid2410.180161] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Sequence analysis of human pegivirus from 3 patients indicates that the central nervous system constitutes a separate viral compartment from serum. Human pegivirus (HPgV), previously called hepatitis G virus or GB virus C, is a lymphotropic virus with undefined pathology. Because many viruses from the family Flaviviridae, to which HPgV belongs, are neurotropic, we studied whether HPgV could infect the central nervous system. We tested serum and cerebrospinal fluid samples from 96 patients with a diagnosis of encephalitis for a variety of pathogens by molecular methods and serology; we also tested for autoantibodies against neuronal antigens. We found HPgV in serum and cerebrospinal fluid from 3 patients who had encephalitis of unclear origin; that is, all the markers that had been tested were negative. Single-strand confirmation polymorphism and next-generation sequencing analysis revealed differences between the serum and cerebrospinal fluid–derived viral sequences, which is compatible with the presence of a separate HPgV compartment in the central nervous system. It is unclear whether HPgV was directly responsible for encephalitis in these patients.
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23
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Cerebral patterns of neuropsychological disturbances in hepatitis C patients. J Neurovirol 2019; 25:229-238. [PMID: 30610739 DOI: 10.1007/s13365-018-0709-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 09/01/2018] [Accepted: 11/20/2018] [Indexed: 12/20/2022]
Abstract
Neuropsychiatric symptoms and cognitive impairment have been consistently reported in patients with hepatitis C virus (HCV) infection. Since the mechanisms behind remain to be established, the present study attempted to assess whether neuropsychological impairments in HCV-infected patients are accompanied by structural alterations in the brain. Therefore, 19 anti-HCV-antibody-positive women with mild liver disease and 16 healthy controls underwent extensive neuropsychological testing and cranial magnetic resonance imaging (MRI) examination. Nine of the patients and five controls were followed up after 6-7 years. Voxel-based morphometry and magnetization transfer imaging were utilized to study HCV-associated structural gray and white matter changes. The HCV-infected patients had significantly worse fatigue and depression scores and significantly poorer performance on attention and memory tests than controls. The patients displayed gray matter (GM) atrophy in the bilateral insula and thalamus and a profound GM volume increases in the cerebellum. Microstructural GM changes in the insula were also evident by a reduced magnetization transfer ratio. Structural white matter changes were observed along several descending and crossing fiber tracts. Follow-up at 7 years revealed increased GM atrophy in the left amygdala and left parahippocampal regions over time. We conclude that our data provide evidence for structural alterations in the brains of patients with chronic HCV infection. Disturbances of cerebellothalamocortical regions and circuits, linking cerebellar projections to the prefrontal cortex through the thalamus, underpin the emotional and cognitive dysfunction characteristically observed in these patients.
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Mercuri L, Thomson EC, Hughes J, Karayiannis P. Quasispecies Changes with Distinctive Point Mutations in the Hepatitis C Virus Internal Ribosome Entry Site (IRES) Derived from PBMCs and Plasma. Adv Virol 2018; 2018:4835252. [PMID: 30581467 PMCID: PMC6276526 DOI: 10.1155/2018/4835252] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 11/11/2018] [Indexed: 12/12/2022] Open
Abstract
The 5' untranslated region (UTR) of the hepatitis C virus (HCV) genome contains the internal ribosome entry site (IRES), a highly conserved RNA structure essential for cap-independent translation of the viral polyprotein. HCV, apart from the liver, is thought to be associated with lymphocyte subpopulations of peripheral blood mononuclear cells (PBMCs), in lymph nodes and brain tissue. In this study, RT-PCR, cloning, and sequence analysis were employed to investigate the quasispecies nature of the 5'UTR following extraction of viral RNA from PBMCs and plasma of HCV infected individuals. The nucleotide variation between IRES-derived sequences from PBMCs and plasma indicated the existence of polymorphic sites within the IRES. HCV isolates had divergent variants with unique mutations particularly at positions 107, 204, and 243 of the IRES. Most of the PBMC-derived sequences contained an A-A-A variant at these positions. The mutations associated with the IRESes suggested the presence of unique quasispecies populations in PBMCs compared with plasma.
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Affiliation(s)
- Luca Mercuri
- Hepatology Section, Division of Medicine, Faculty of Medicine, Imperial College, London, UK
| | - Emma C. Thomson
- University of Glasgow MRC Centre for Virus Research, Glasgow, UK
| | - Joseph Hughes
- University of Glasgow MRC Centre for Virus Research, Glasgow, UK
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25
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Romano C, Cuomo G, Ferrara R, Del Mastro A, Esposito S, Sellitto A, Adinolfi LE. Uncommon immune-mediated extrahepatic manifestations of HCV infection. Expert Rev Clin Immunol 2018; 14:1089-1099. [PMID: 30338718 DOI: 10.1080/1744666x.2018.1538790] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Chronic hepatitis C virus (HCV) infection has been associated with myriad extrahepatic manifestations, often resulting from aberrant immune responses. Among the most common immune-mediated manifestations of HCV infection, mixed cryoglobulinemia is the best known extra-hepatic complication. Areas covered: Here we review less common extrahepatic manifestations of HCV infection, with ascertained or presumed immune pathogenesis and the role of the new all oral direct-acting antiviral agents. Rheumatologic, dermatologic, ophthalmologic, renal, pulmonary, hematologic, cardiovascular, and neuropsychiatric manifestations of HCV infection have been considered. Expert commentary: Pathogenesis of HCV-induced aberrant immune responses resulting in peculiar clinical manifestations is not restricted to a single mechanism. A sound approach would therefore consider implementation of an etiologic treatment, through use of antiviral medications, to stop upstream in the pathogenic process all the immune mechanisms leading to hepatic and extrahepatic abnormalities. With the recent introduction of interferon-free, direct antiviral agents, capable of warranting cure for nearly all HCV-infected patients subjected to therapy, both common and uncommon extrahepatic manifestations of chronic hepatitis C are expected to no longer constitute a matter of comorbidity in the course of HCV infection.
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Affiliation(s)
- Ciro Romano
- a Division of Internal Medicine, Department of Medical and Surgical Sciences , "Luigi Vanvitelli" University of Campania , Naples , Italy
| | - Giovanna Cuomo
- a Division of Internal Medicine, Department of Medical and Surgical Sciences , "Luigi Vanvitelli" University of Campania , Naples , Italy
| | - Roberta Ferrara
- a Division of Internal Medicine, Department of Medical and Surgical Sciences , "Luigi Vanvitelli" University of Campania , Naples , Italy
| | - Andrea Del Mastro
- a Division of Internal Medicine, Department of Medical and Surgical Sciences , "Luigi Vanvitelli" University of Campania , Naples , Italy.,b Department of Emergency and Admittance , Cardarelli Hospital , Naples , Italy
| | - Sergio Esposito
- a Division of Internal Medicine, Department of Medical and Surgical Sciences , "Luigi Vanvitelli" University of Campania , Naples , Italy
| | - Ausilia Sellitto
- a Division of Internal Medicine, Department of Medical and Surgical Sciences , "Luigi Vanvitelli" University of Campania , Naples , Italy.,c Department of Emergency and Admittance , "San Giuseppe Moscati" Hospital , Avellino , Italy
| | - Luigi Elio Adinolfi
- a Division of Internal Medicine, Department of Medical and Surgical Sciences , "Luigi Vanvitelli" University of Campania , Naples , Italy
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26
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Mechanisms of neuropathogenesis in HIV and HCV: similarities, differences, and unknowns. J Neurovirol 2018; 24:670-678. [PMID: 30291565 DOI: 10.1007/s13365-018-0678-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 08/20/2018] [Accepted: 09/07/2018] [Indexed: 12/17/2022]
Abstract
HIV and hepatitis C virus (HCV) have both been associated with cognitive impairment. Combination antiretroviral therapy (cART) has dramatically changed the nature of cognitive impairment in HIV-infected persons, while the role of direct-acting antivirals (DAA) in neurocognition of HCV-infected individuals remains unclear. Also, whether HIV and HCV interact to promote neurocognitive decline or whether they each contribute an individual effect continues to be an open question. In this work, we review the virally mediated mechanisms of HIV- and HCV-mediated neuropathogenesis, with an emphasis on the role of dual infection, and discuss observed changes with HIV viral suppression and HCV functional cure on neurocognitive impairments.
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27
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Dello Russo C, Cappoli N, Coletta I, Mezzogori D, Paciello F, Pozzoli G, Navarra P, Battaglia A. The human microglial HMC3 cell line: where do we stand? A systematic literature review. J Neuroinflammation 2018; 15:259. [PMID: 30200996 PMCID: PMC6131758 DOI: 10.1186/s12974-018-1288-0] [Citation(s) in RCA: 155] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 08/21/2018] [Indexed: 02/08/2023] Open
Abstract
Microglia, unique myeloid cells residing in the brain parenchyma, represent the first line of immune defense within the central nervous system. In addition to their immune functions, microglial cells play an important role in other cerebral processes, including the regulation of synaptic architecture and neurogenesis. Chronic microglial activation is regarded as detrimental, and it is considered a pathogenic mechanism common to several neurological disorders. Microglial activation and function have been extensively studied in rodent experimental models, whereas the characterization of human cells has been limited due to the restricted availability of primary sources of human microglia. To overcome this problem, human immortalized microglial cell lines have been developed. The human microglial clone 3 cell line, HMC3, was established in 1995, through SV40-dependent immortalization of human embryonic microglial cells. It has been recently authenticated by the American Type Culture Collection (ATCC®) and distributed under the name of HMC3 (ATCC®CRL-3304). The HMC3 cells have been used in six research studies, two of which also indicated by ATCC® as reference articles. However, a more accurate literature revision suggests that clone 3 was initially distributed under the name of CHME3. In this regard, several studies have been published, thus contributing to a more extensive characterization of this cell line. Remarkably, the same cell line has been used in different laboratories with other denominations, i.e., CHME-5 cells and C13-NJ cells. In view of the fact that "being now authenticated by ATCC®" may imply a wider distribution of the cells, we aimed at reviewing data obtained with the human microglia cell line clone 3, making the readers aware of this complicated nomenclature. In addition, we also included original data, generated in our laboratory with the HMC3 (ATCC®CRL-3304) cells, providing information on the current state of the culture together with supplementary details on the culturing procedures to obtain and maintain viable cells.
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Affiliation(s)
- Cinzia Dello Russo
- Institute of Pharmacology, Università Cattolica del S. Cuore, L.go F Vito 1, 00168, Rome, Italy. .,Pharmacology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
| | - Natalia Cappoli
- Institute of Pharmacology, Università Cattolica del S. Cuore, L.go F Vito 1, 00168, Rome, Italy
| | - Isabella Coletta
- Angelini RR&D (Research, Regulatory & Development) - Angelini S.p.A., Rome, Italy
| | - Daniele Mezzogori
- Institute of Human Physiology, Università Cattolica del S. Cuore, Rome, Italy
| | - Fabiola Paciello
- Institute of Otolaryngology, Università Cattolica del S. Cuore, Rome, Italy
| | - Giacomo Pozzoli
- Institute of Pharmacology, Università Cattolica del S. Cuore, L.go F Vito 1, 00168, Rome, Italy.,Pharmacology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Pierluigi Navarra
- Institute of Pharmacology, Università Cattolica del S. Cuore, L.go F Vito 1, 00168, Rome, Italy.,Pharmacology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Alessandra Battaglia
- Immunology Laboratory, Department of Oncological Gynecology, Università Cattolica del S. Cuore, Rome, Italy
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Loftis JM, Valerio J, Taylor J, Huang E, Hudson R, Taylor-Young P, Chang M, Ho SB, Dieperink E, Miranda JL, Hauser P. S100B and Inflammatory Cytokine Levels in Blood as Potential Markers of Blood-Brain Barrier Damage and Psychiatric Impairment in Comorbid Hepatitis C Viral Infection and Alcohol Use Disorder. Alcohol Clin Exp Res 2018; 42:10.1111/acer.13796. [PMID: 29953169 PMCID: PMC6310679 DOI: 10.1111/acer.13796] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 05/15/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection and alcohol use disorder (AUD) both adversely affect the immune system resulting in alterations in immune cell signaling and inflammatory processes. The aim of this study was to investigate how comorbid AUD contributes to abnormalities in inflammatory mediators and psychiatric impairments in adults with HCV. METHODS Alcohol use, mood, and inflammatory factors were evaluated at 3 time points (baseline, week 4, and week 12) in Veterans with HCV, with (n = 42) and without (n = 13) comorbid AUD. Peripheral indices of immune activation, blood-brain barrier (BBB) damage (S100 calcium-binding protein B [S100B]), liver function, and viral load were measured using immunoassays and polymerase chain reaction assays. RESULTS Comorbid AUD was associated with increased symptoms of depression and anxiety, elevated levels of liver enzymes, and altered expression of inflammatory factors. Alcohol consumption was positively correlated with the severity of psychiatric symptoms. Univariate analysis identified significant group differences in interleukin (IL)-8 (p = 0.006), IL-10 (p = 0.03), and S100B (p = 0.048), with increased levels in participants with AUD, which persisted over time despite reductions in alcohol use and no significant change in HCV viral load. Statistically significant effects of study group or time were not found for the other immune factors assessed. Exploratory receiver operating characteristic curve analysis evaluated the ability of IL-8, IL-10, and S100B to differentiate between levels of alcohol consumption and generated biomarker cutoff values used to identify low risk and unhealthy alcohol use groups. CONCLUSIONS These results demonstrate that HCV and comorbid AUD are associated with greater psychiatric impairments, potentially resulting from increased inflammation, dysregulated cytokine expression, and compromised BBB function. Alcohol-induced BBB damage may increase the risk of neuropathological consequences within the context of chronic HCV infection.
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Affiliation(s)
- Jennifer M. Loftis
- Research & Development Service, VA Portland Health Care System, Portland, OR, USA
- Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA
| | - Juno Valerio
- Research & Development Service, VA Portland Health Care System, Portland, OR, USA
| | - Jonathan Taylor
- Research & Development Service, VA Portland Health Care System, Portland, OR, USA
- Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA
| | - Elaine Huang
- Research & Development Service, VA Portland Health Care System, Portland, OR, USA
- Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA
| | - Rebekah Hudson
- Research & Development Service, VA Portland Health Care System, Portland, OR, USA
| | - Patricia Taylor-Young
- Nursing Research Department, VA Portland Health Care System, Portland, OR, USA
- School of Nursing, Oregon Health & Science University, Portland, OR, USA
| | - Michael Chang
- Gastroenterology, VA Portland Health Care System, Portland, OR, USA
- Internal Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Samuel B. Ho
- VA San Diego Healthcare System, San Diego, CA, USA
- Department of Medicine, University of California San Diego, San Diego, CA, USA
| | - Eric Dieperink
- Minneapolis VA Healthcare System, Minneapolis, MN, USA
- Department of Psychiatry, University of Minnesota School of Medicine, Minneapolis, MN, USA
| | - Juan Luis Miranda
- VA Long Beach Health Care System, 5901 E 7th St, Long Beach, CA, USA
| | - Peter Hauser
- VA Long Beach Health Care System, 5901 E 7th St, Long Beach, CA, USA
- Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA
- Department of Psychiatry, University of California San Diego, San Diego, CA, USA
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Yeoh SW, Holmes ACN, Saling MM, Everall IP, Nicoll AJ. Depression, fatigue and neurocognitive deficits in chronic hepatitis C. Hepatol Int 2018; 12:294-304. [PMID: 29931590 DOI: 10.1007/s12072-018-9879-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Accepted: 06/05/2018] [Indexed: 12/11/2022]
Abstract
Patients with chronic hepatitis C virus (HCV) infection experience a range of symptoms including depression, fatigue and neurocognitive deficits, impairing quality of life. Depression, in particular, may be reactive to increased psychosocial stress, and the physical symptoms of advanced HCV or associated comorbidities. However, even patients at an early stage of HCV infection, with minimal hepatic inflammation or comorbidities, report more depressive symptoms and fatigue than the general population. Similarly, specific neurocognitive deficits occur in early stage HCV infection and are independent of the presence of depression or encephalopathy. Therefore, intracerebral neurobiological changes associated with HCV may potentially explain these symptoms. These changes may arise from infiltration of the brain by peripherally induced cytokines, as well as direct neuropathic effects of HCV viral particles penetrating the blood-brain barrier. These phenomena parallel those reported in human immunodeficiency virus (HIV) infection. HCV-associated intracerebral changes include upregulated inflammatory responses, altered neurotransmitter levels, hormonal dysregulation, and release of neurotoxic substances. These may subsequently lead to abnormal neuronal conduction and function in areas of the brain governing affective responses, emotional processing, motivation, attention and concentration. Although direct-acting antiviral medications lead to high rates of HCV clearance, intracerebral changes may not be subsequently reversed and symptoms of depression, fatigue and neurocognitive deficits may persist. There is an ongoing role for multidisciplinary care and pharmacotherapy to manage these symptoms in HCV patients. Furthermore, there may be opportunities for future therapies to specifically target and ameliorate HCV-associated intracerebral changes.
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Affiliation(s)
- Sern Wei Yeoh
- Department of Gastroenterology, Eastern Health, 3 West, Building B, 8 Arnold St, Box Hill, VIC, 3128, Australia.
| | - Alex C N Holmes
- Department of Psychiatry, University of Melbourne, Level 1 North, Main Block, Royal Melbourne Hospital, 300 Grattan St, Parkville, VIC, 3050, Australia
| | - Michael M Saling
- Melbourne School of Psychological Sciences, 12th Floor, Redmond Barry Building, Parkville Campus, University of Melbourne, Parkville, VIC, Australia, 3010.,Department of Clinical Neuropsychology, Austin Health, Heidelberg Repatriation Hospital, 300 Waterdale Rd, Ivanhoe, VIC, 3079, Australia.,Florey Institute for Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia
| | - Ian P Everall
- Department of Psychiatry, University of Melbourne, Level 1 North, Main Block, Royal Melbourne Hospital, 300 Grattan St, Parkville, VIC, 3050, Australia.,Institute of Psychiatry, Psychology and Neuroscience, Kings College London, 16 De Crespigny Park, London, SE5 8AF, UK.,South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Monks Orchard Road, Beckenham, BR3 3BX, UK
| | - Amanda J Nicoll
- Department of Gastroenterology, Eastern Health, 3 West, Building B, 8 Arnold St, Box Hill, VIC, 3128, Australia.,Department of Gastroenterology and Hepatology, Royal Melbourne Hospital, 300 Grattan St, Parkville, VIC, 3050, Australia
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30
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Forton D, Weissenborn K, Bondin M, Cacoub P. Expert opinion on managing chronic HCV in patients with neuropsychiatric manifestations. Antivir Ther 2018; 23:47-55. [PMID: 30451150 DOI: 10.3851/imp3245] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2018] [Indexed: 10/27/2022]
Abstract
Neurological manifestations of HCV infection appear to be under-recognized in clinical practice despite the majority of HCV-infected patients experiencing symptoms such as fatigue, depression and cognitive dysfunction. There is also growing evidence for a link between HCV infection and an increased risk of Parkinson's disease. The mechanism underpinning the association between HCV and these neuropsychiatric syndromes still requires further investigation. Here we review the pre-clinical and clinical evidence for a link between HCV and effects on the central nervous system leading to neuropsychiatric syndromes. Lastly, we describe how improvements in neuropsychiatric manifestations of HCV following treatment have been observed, which is subsequently reflected in an overall improvement in health-related quality of life.
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Affiliation(s)
- Daniel Forton
- Department of Gastroenterology and Hepatology, St George's Hospital London, London, UK
- St George's University of London, London, UK
| | | | | | - Patrice Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France
- INSERM, UMR_S 959, Paris, France
- CNRS, FRE3632, F-75005, Paris, France
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
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31
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Cabezas J, Llerena S, Puente Á, Fábrega E, Crespo J. Causes of treatment failure for hepatitis C in the era of direct-acting antiviral therapy. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2017; 108:421-30. [PMID: 26666379 DOI: 10.17235/reed.2015.3894/2015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Hepatitis C therapy in the era of the newer direct-acting antiviral agents has radically changed our treatment schemes by achieving very high rates of sustained virological response. However, treatment with direct antiviral agents fails in a subgroup of patients. This group of so-called difficult-to-treat individuals is the subject of this paper, which reviews the causes of virological failure, their clinical implications, and some final recommendations.
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Affiliation(s)
- Joaquín Cabezas
- Aparato Digestivo/Unidad de Hepatología, Hospital Universitario Marqués de Valdecilla, España
| | - Susana Llerena
- Aparato Digestivo/ Unidad de Hepatologia, Hospital Universitario Marqués de Valdecilla, España
| | - Ángela Puente
- Aparato Digestivo/Unidad de Hepatología, Hospital Universitario Marqués de Valdecilla, España
| | | | - Javier Crespo
- Servicio Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, 39002
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32
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Adinolfi LE, Nevola R, Rinaldi L, Romano C, Giordano M. Chronic Hepatitis C Virus Infection and Depression. Clin Liver Dis 2017; 21:517-534. [PMID: 28689590 DOI: 10.1016/j.cld.2017.03.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection is a systemic disease with hepatic and extrahepatic manifestations, including neuropsychiatric conditions. Depression is a frequent disorder, which has been reported in one-third of patients with HCV infection and has an estimated prevalence of 1.5 to 4.0 times higher than that observed in patients with chronic hepatitis B virus infection or the general population. HCV seems to play a direct and indirect role in the development of depression. Impaired quality of life and increasing health care costs have been reported for patients with HCV infection with depression. Treatment-induced HCV clearance has been associated with improvement of depression and quality of life.
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Affiliation(s)
- Luigi Elio Adinolfi
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy.
| | - Riccardo Nevola
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy
| | - Luca Rinaldi
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy
| | - Ciro Romano
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy
| | - Mauro Giordano
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy
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Abstract
The extrahepatic manifestations of hepatitis C include effects on the central nervous system, which have been associated with the ability of hepatitis C virus (HCV) to replicate in microglial and endothelial cells and the chronic inflammation induced by HCV. HCV can induce impaired neurocognition, which is clinically manifested by impaired quality of life, fatigue, and brain fog. These cognitive defects can be present even in patients with mild histologic HCV and have been confirmed by neurocognitive testing and brain imaging by magnetic resonance spectroscopy. Neurocognitive defects include loss of functioning memory and subtle changes in attention and processing speed.
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Affiliation(s)
- Sentia Iriana
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, 110 Francis Street, Boston, MA 02125, USA
| | - Michael P Curry
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, 110 Francis Street, Boston, MA 02125, USA
| | - Nezam H Afdhal
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, 110 Francis Street, Boston, MA 02125, USA.
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Dirks M, Pflugrad H, Haag K, Tillmann HL, Wedemeyer H, Arvanitis D, Hecker H, Tountopoulou A, Goldbecker A, Worthmann H, Weissenborn K. Persistent neuropsychiatric impairment in HCV patients despite clearance of the virus?! J Viral Hepat 2017; 24:541-550. [PMID: 28117537 DOI: 10.1111/jvh.12674] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 12/14/2016] [Indexed: 12/30/2022]
Abstract
One of the most disabling symptoms of hepatitis C virus (HCV) infection is chronic fatigue. While this is accepted for HCV polymerase chain reaction (PCR)-positive patients, a relationship between HCV infection and chronic fatigue is questioned after successful virus eradication. As fatigue is a subjective criterion, we aimed to evaluate in addition mood alterations and cognitive function in HCV-exposed patients with only mild liver disease and to assess a) possible interrelationships between these factors and health-related quality of life and b) the impact of viremia and former interferon treatment. One hundred and fifty-nine anti-HCV-positive individuals without advanced liver disease answered health-related quality of life (HRQoL), fatigue and depression questionnaires and underwent a battery of attention and memory tests. Accompanying diseases which could distort the results of the study such as HIV co-infection or drug addiction were exclusion criteria. The patients were subdivided into four groups according to their viremia status and interferon treatment history. Patients' data were evaluated with respect to norms given in the respective test manuals and in addition compared to those of 33 age-matched healthy controls. Eighty-five per cent of the patients had chronic fatigue, 50-60% mild depression or anxiety, 45% memory deficits and 30% attention deficits, irrespective of their HCV viremia status or treatment history. HRQoL correlated negatively with chronic fatigue (P<.001), while cognitive deficits-especially memory function-were independent from fatigue and depression. HCV infection may cause long-standing cerebral dysfunction that significantly impairs HRQoL and may even persist after clearance of the virus.
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Affiliation(s)
- M Dirks
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - H Pflugrad
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - K Haag
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - H L Tillmann
- Division of Gastroenterology, Hepatology & Nutrition, East Carolina University, Greenville, NC, USA
| | - H Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - D Arvanitis
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - H Hecker
- Department of Biometrics, Hannover Medical School, Hannover, Germany
| | - A Tountopoulou
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - A Goldbecker
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - H Worthmann
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - K Weissenborn
- Department of Neurology, Hannover Medical School, Hannover, Germany
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Lin HC, Xirasagar S, Lee HC, Huang CC, Chen CH. Association of Alzhemier's disease with hepatitis C among patients with bipolar disorder. PLoS One 2017. [PMID: 28622343 PMCID: PMC5473552 DOI: 10.1371/journal.pone.0179312] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Associations of hepatitis C virus infection with Alzheimer’s disease have not been studied among higher risk, bipolar disorder patients. This population-based case-control study investigated the risks of hepatitis C virus infection among Alzheimer’s disease patients with bipolar disorder in the years preceding their Alzheimer’s disease diagnosis. We used 2000–2013 data from the Longitudinal Health Insurance Database in Taiwan. Among patients with bipolar disorder, 73 were diagnosed with Alzheimer’s disease (cases), who were compared with 365 individuals with bipolar disorder but without Alzheimer’s disease (randomly selected controls matched on sex, age, and index year with cases). Prior claims (before the diagnosis year/index year for controls) were screened for a diagnosis of hepatitis C virus infection. Conditional logistic regression models were used for analysis. We found that 23 (31.51%) and 60 (16.44%) patients with bipolar disease were identified with a hepatitis C diagnosis among those with and without Alzheimer’s disease, respectively. Compared to controls, patients with Alzheimer’s disease showed 2.31-fold (95% confidence interval = 1.28–4.16) increased risk of hepatitis C infections adjusted for demographics and socio-economic status. Findings suggest an association of Alzheimer’s disease with a preceding diagnosis of hepatitis C infection among patients with bipolar disorder. Findings may suggest a need for increased awareness of and appropriate surveillance for Alzheimer’s disease in patients with bipolar disorder diagnosed with hepatitis C infection.
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Affiliation(s)
- Herng-Ching Lin
- School of Health Care Administration, Taipei Medical University, Taipei, Taiwan
- Sleep Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Sudha Xirasagar
- Department of Health Services Policy and Management, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, United States of America
| | - Hsin-Chien Lee
- Department of Psychiatry, Taipei Medical University-Shuang-Ho Hospital, Taipei, Taiwan
- Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chung-Chien Huang
- School of Health Care Administration, Taipei Medical University, Taipei, Taiwan
| | - Chao-Hung Chen
- Department & Institute of Physiology, National Yang-Ming University, Taipei, Taiwan
- Department of Cosmetic Applications and Management, Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
- Department of Thoracic Surgery, MacKay Memorial Hospital, Taipei, Taiwan
- Research Center of Sleep Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- * E-mail:
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36
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Improvements in brain and behavior following eradication of hepatitis C. J Neurovirol 2017; 23:593-602. [PMID: 28560632 DOI: 10.1007/s13365-017-0533-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 04/19/2017] [Accepted: 05/02/2017] [Indexed: 01/18/2023]
Abstract
Despite recent advances in treatment, hepatitis C remains a significant public health problem. The hepatitis C virus (HCV) is known to infiltrate the brain, yet findings from studies on associated neurocognitive and neuropathological changes are mixed. Furthermore, it remains unclear if HCV eradication improves HCV-associated neurological compromise. This study examined the longitudinal relationship between neurocognitive and neurophysiologic markers among healthy HCV- controls and HCV+ adults following successful HCV eradication. We hypothesized that neurocognitive outcomes following treatment would be related to both improved cognition and white matter integrity. Participants included 57 HCV+ participants who successfully cleared the virus at the end of treatment (sustained virologic responders [SVRs]) and 22 HCV- controls. Participants underwent neuropsychological testing and, for a nested subset of participants, neuroimaging (diffusion tensor imaging) at baseline and 12 weeks following completion of HCV therapy. Contrary to expectation, group-level longitudinal analyses did not reveal significant improvement in neurocognitive performance in the SVRs compared to the control group. However, a subgroup of SVRs demonstrated a significant improvement in cognition relative to controls, which was related to improved white matter integrity. Indeed, neuroimaging data revealed beneficial effects associated with clearing the virus, particularly in the posterior corona radiata and the superior longitudinal fasciculus. Findings suggest that a subgroup of HCV+ patients experienced improvements in cognitive functioning following eradication of HCV, which appears related to positive changes in white matter integrity. Future research should examine whether any additional improvements in neurocognition and white matter integrity among SVRs occur with longer follow-up periods.
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37
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Affiliation(s)
- Daniel M Forton
- Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, UK
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38
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Tully DC, Hjerrild S, Leutscher PD, Renvillard SG, Ogilvie CB, Bean DJ, Videbech P, Allen TM, McKeating JA, Fletcher NF. Deep sequencing of hepatitis C virus reveals genetic compartmentalization in cerebrospinal fluid from cognitively impaired patients. Liver Int 2016; 36:1418-24. [PMID: 27045383 PMCID: PMC5553127 DOI: 10.1111/liv.13134] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 03/22/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) causes neuropsychiatric impairment and fatigue with recent studies suggesting HCV invasion of the central nervous system (CNS). Our previous finding that endothelial cells from the blood-brain barrier support HCV infection warrants further investigation to elucidate whether the CNS can serve as a reservoir for independent HCV evolution. METHODS Cerebrospinal fluid (CSF) and plasma from six HCV-infected patients without liver disease or co-morbidities together with plasma from six healthy subjects were profiled for markers of immune activation and viral quasispecies measured by deep sequencing. Unsupervised data analyses were used to identify any associations between cytokine activation markers and clinical outcomes. RESULTS Four of six HCV-infected patients showed significant evidence of cognitive dysfunction and fatigue. Deep sequencing revealed independent viral evolution within the CNS of two cognitively impaired patients. Principal component analysis of peripheral cytokines demonstrated that individuals without cognitive impairment clustered together while a distinct cytokine pattern emerged with patients exhibiting cognitive dysfunction and fatigue. CONCLUSIONS Deep sequencing demonstrated unique viral variants in the CSF of two cognitively impaired patients consistent with CNS replication or sequestration. Meanwhile, compartmentalization was absent in infected patients with no neurocognitive impairment. Examination of cytokine profiles in HCV-infected patients with cognitive dysfunction revealed elevated peripheral cytokine levels resulting in a distinct cytokine profile that may be related to cognitive impairment or viral penetration into the CNS. Further studies to determine the significance of unique HCV variants within the CNS are warranted.
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Affiliation(s)
| | - Simon Hjerrild
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark,Department of Affective Disorders, Aarhus University Hospital, Aarhus, Denmark
| | - Peter D. Leutscher
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Signe G. Renvillard
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | | | - David J. Bean
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Poul Videbech
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark,Department of Affective Disorders, Aarhus University Hospital, Aarhus, Denmark
| | - Todd M. Allen
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | | | - Nicola F. Fletcher
- Centre for Human Virology, University of Birmingham, Birmingham, UK,Veterinary Sciences Centre, University College Dublin, Dublin 4, Ireland
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39
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Yarlott L, Heald E, Forton D. Hepatitis C virus infection, and neurological and psychiatric disorders - A review. J Adv Res 2016; 8:139-148. [PMID: 28149649 PMCID: PMC5272938 DOI: 10.1016/j.jare.2016.09.005] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 09/09/2016] [Accepted: 09/09/2016] [Indexed: 02/06/2023] Open
Abstract
An association between hepatitis C virus infection and neuropsychiatric symptoms has been proposed for some years. A variety of studies have been undertaken to assess the nature and severity of these symptoms, which range from fatigue and depression to defects in attention and verbal reasoning. There is evidence of mild neurocognitive impairment in some patients with HCV infection, which is not fully attributable to liver dysfunction or psychosocial factors. Further evidence of a biological cerebral effect has arisen from studies using magnetic resonance spectroscopy; metabolic abnormalities correlate with cognitive dysfunction and resemble the patterns of neuroinflammation that have been described in HIV infection. Recent research has suggested that, in common with HIV infection, HCV may cross the blood brain barrier leading to neuroinflammation. Brain microvascular endothelial cells, astrocytes and microglia may be minor replication sites for HCV. Importantly, patient reported outcomes improve following successful antiviral therapy. Further research is required to elucidate the molecular basis for HCV entry and replication in the brain, and to clarify implications and recommendations for treatment.
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Affiliation(s)
- Lydia Yarlott
- Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, Blackshaw Rd, London SW17 0QT, United Kingdom
| | - Eleanor Heald
- Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, Blackshaw Rd, London SW17 0QT, United Kingdom
| | - Daniel Forton
- Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, Blackshaw Rd, London SW17 0QT, United Kingdom; St George's, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom
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40
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Raghwani J, Rose R, Sheridan I, Lemey P, Suchard MA, Santantonio T, Farci P, Klenerman P, Pybus OG. Exceptional Heterogeneity in Viral Evolutionary Dynamics Characterises Chronic Hepatitis C Virus Infection. PLoS Pathog 2016; 12:e1005894. [PMID: 27631086 PMCID: PMC5025083 DOI: 10.1371/journal.ppat.1005894] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 08/24/2016] [Indexed: 12/14/2022] Open
Abstract
The treatment of HCV infection has seen significant progress, particularly since the approval of new direct-acting antiviral drugs. However these clinical achievements have been made despite an incomplete understanding of HCV replication and within-host evolution, especially compared with HIV-1. Here, we undertake a comprehensive analysis of HCV within-host evolution during chronic infection by investigating over 4000 viral sequences sampled longitudinally from 15 HCV-infected patients. We compare our HCV results to those from a well-studied HIV-1 cohort, revealing key differences in the evolutionary behaviour of these two chronic-infecting pathogens. Notably, we find an exceptional level of heterogeneity in the molecular evolution of HCV, both within and among infected individuals. Furthermore, these patterns are associated with the long-term maintenance of viral lineages within patients, which fluctuate in relative frequency in peripheral blood. Together, our findings demonstrate that HCV replication behavior is complex and likely comprises multiple viral subpopulations with distinct evolutionary dynamics. The presence of a structured viral population can explain apparent paradoxes in chronic HCV infection, such as rapid fluctuations in viral diversity and the reappearance of viral strains years after their initial detection. Our knowledge of HCV within-host evolution is substantially limited, which is surprising given that highly successful therapies against the virus have been developed. Key aspects of HCV infection, such as rapid fluctuations in viral diversity and the reappearance of viral strains years after their initial detection, remain unexplained. To better understand this problem, we analyse viral sequences from HCV-infected patients sampled over several years. Our findings suggest that the replication dynamics during chronic HCV infection are distinct from those of HIV-1, and dominated by the co-circulation of multiple viral strains. Although a major difference between the two chronic-infecting viruses is the level of recombination, our results indicate that HCV within-host evolution is most likely to be shaped by a structured viral population. Crucially, our study shows that HCV sampled from blood does not fully represent the within-host viral population at that time. This may have important implications for HCV treatment, especially in patients that have seemingly cleared the virus, as well as for molecular epidemiology studies investigating HCV transmission.
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Affiliation(s)
- Jayna Raghwani
- Department of Zoology, University of Oxford, Oxford, United Kingdom
- * E-mail: (JR); (OGP)
| | - Rebecca Rose
- BioInfoExperts, Thibodaux, Los Angeles, California, United States of America
| | - Isabelle Sheridan
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom
| | - Philippe Lemey
- Department of Microbiology and Immunology, Rega Institute, KU Leuven–University of Leuven, Leuven, Belgium
| | - Marc A. Suchard
- Departments of Biomathematics, Biostatistics, Human Genetics, University of California, Los Angeles, California, United States of America
| | | | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom
| | - Oliver G. Pybus
- Department of Zoology, University of Oxford, Oxford, United Kingdom
- * E-mail: (JR); (OGP)
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41
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Floden EW, Khawaja A, Vopálenský V, Pospíšek M. HCVIVdb: The hepatitis-C IRES variation database. BMC Microbiol 2016; 16:187. [PMID: 27527702 PMCID: PMC4986321 DOI: 10.1186/s12866-016-0804-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 08/04/2016] [Indexed: 01/22/2023] Open
Abstract
Background Sequence variability in the hepatitis C virus (HCV) genome has led to the development and classification of six genotypes and a number of subtypes. The HCV 5′ untranslated region mainly comprises an internal ribosomal entry site (IRES) responsible for cap-independent synthesis of the viral polyprotein and is conserved among all HCV genotypes. Description Considering the possible high impact of variations in HCV IRES on viral protein production and thus virus replication, we decided to collect the available data on known nucleotide variants in the HCV IRES and their impact on IRES function in translation initiation. The HCV IRES variation database (HCVIVdb) is a collection of naturally occurring and engineered mutation entries for the HCV IRES. Each entry contains contextual information pertaining to the entry such as the HCV genotypic background and links to the original publication. Where available, quantitative data on the IRES efficiency in translation have been collated along with details on the reporter system used to generate the data. Data are displayed both in a tabular and graphical formats and allow direct comparison of results from different experiments. Together the data provide a central resource for researchers in the IRES and hepatitis C-oriented fields. Conclusion The collation of over 1900 mutations enables systematic analysis of the HCV IRES. The database is mainly dedicated to detailed comparative and functional analysis of all the HCV IRES domains, which can further lead to the development of site-specific drug designs and provide a guide for future experiments. HCVIVdb is available at http://www.hcvivdb.org. Electronic supplementary material The online version of this article (doi:10.1186/s12866-016-0804-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Evan W Floden
- Department of Genetics & Microbiology, Faculty of Science, Charles University in Prague, Viničná 5, 128 44, Prague 2, Czech Republic.,Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Anas Khawaja
- Department of Genetics & Microbiology, Faculty of Science, Charles University in Prague, Viničná 5, 128 44, Prague 2, Czech Republic
| | - Václav Vopálenský
- Department of Genetics & Microbiology, Faculty of Science, Charles University in Prague, Viničná 5, 128 44, Prague 2, Czech Republic
| | - Martin Pospíšek
- Department of Genetics & Microbiology, Faculty of Science, Charles University in Prague, Viničná 5, 128 44, Prague 2, Czech Republic
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42
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Weissenborn K, Tillmann HL. HCV encephalopathy - an artefact due to medical care? J Viral Hepat 2016; 23:580-3. [PMID: 27225063 DOI: 10.1111/jvh.12547] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 04/26/2016] [Indexed: 12/14/2022]
Abstract
Anti-HCV positive individuals frequently complain about chronic disabling fatigue, mood alterations and deficits in concentration and memory. Several data provide evidence that such alterations are unrelated to hepatitis C virus (HCV) viremia. Thus, merely being exposed to HCV in the past may be sufficient to trigger, but the HCV exposure itself. This commentary reviews the available data upon this topic with special reference to the paper by Lowry and colleagues published in this issue of the Journal of Viral hepatitis. We will carefully discuss scientific reasons, why HCV may be directly involved in the development of neuropsychiatric symptoms independent from ongoing detectable viremia, as suggested by epidemiological data.
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Affiliation(s)
- K Weissenborn
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - H L Tillmann
- Division of Gastroenterology Hepatology & Nutrition, East Carolina University, Greenville, NC, USA
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Lowry D, Burke T, Galvin Z, Ryan JD, Russell J, Murphy A, Hegarty J, Stewart S, Crowe J. Is psychosocial and cognitive dysfunction misattributed to the virus in hepatitis C infection? Select psychosocial contributors identified. J Viral Hepat 2016; 23:584-95. [PMID: 27167497 DOI: 10.1111/jvh.12544] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 03/29/2016] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C is associated with health-related quality of life and cognitive impairments, even in mild disease. Recent evidence demonstrating hepatitis C virus (HCV) neurotropism has strengthened a neuropathophysiological hypothesis. However, sample heterogeneity confounds study outcomes. A uniquely homogeneous cohort of Irish women, following an iatrogenic HCV outbreak, offers a rare opportunity to control for HCV chronicity and the virus' purported impact on quality of life and cognition. A multi site, three-group, cross-sectional design was employed. Noncirrhotic, iatrogenically infected women, developing either acute or chronic infection, were recruited from prospective tertiary-care liver clinics and the community. Well-matched healthy controls were also recruited. All participants completed a psychosocial survey and were invited to undergo a comprehensive neuropsychological test battery. Significantly distressed psychosocial symptom profiles were observed in those with an iatrogenic HCV exposure history, which was independent of viral chronicity. Chronic and cleared HCV cohorts were not differentiated from each other. Two distinct subgroups, demarcated along 'impaired' vs 'nonimpaired' quality-of-life reports, were clearly identified and logistic regression analysis identified depressed mood and cognitive fatigue, rather than viral status, as statistically significant predictors of group membership. Compared with matched controls, significant cognitive impairments were not observed in either HCV cohort. Our findings provide strong evidence of nonviral factors accounting for quality of life impairment in chronic HCV and they also appear to question existing reports of cognitive dysfunction in mild disease. Depressed mood and cognitive fatigue appear to be critical psychosocial mediators of reduced quality-of-life and we hypothesize that metabolite abnormalities reported in HCV samples may also be confounded by these factors, given the associated literature.
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Affiliation(s)
- D Lowry
- Liver Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland.,Cognitive and Behavioural Neuroscience Research Group, School of Psychology, University College Dublin, Belfield, Dublin 4, Ireland
| | - T Burke
- Cognitive and Behavioural Neuroscience Research Group, School of Psychology, University College Dublin, Belfield, Dublin 4, Ireland.,School of Nursing and Human Sciences, Dublin City University, Dublin 9, Ireland
| | - Z Galvin
- Liver Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - J D Ryan
- Liver Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - J Russell
- Liver Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - A Murphy
- Liver Unit, St. Vincent's University Hospital, Dublin 4, Ireland
| | - J Hegarty
- Liver Unit, St. Vincent's University Hospital, Dublin 4, Ireland
| | - S Stewart
- Liver Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - J Crowe
- Liver Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland
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Klebl BM, Kurtenbach A, Salassidis K, Daub H, Herget T. Host Cell Targets in HCV Therapy: Novel Strategy or Proven Practice? ACTA ACUST UNITED AC 2016; 16:69-90. [PMID: 15889531 DOI: 10.1177/095632020501600201] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The development of novel antiviral drugs against hepatitis C is a challenging and competitive area of research. Progress of this research has been hampered due to the quasispecies nature of the hepatitis C virus, the absence of cellular infection models and the lack of easily accessible and highly representative animal models. The current combination therapy consisting of interferon-α and ribavirin mainly acts by supporting host cell defence. These therapeutics are the prototypic representatives of indirect antiviral agents as they act on cellular targets. However, the therapy is not a cure, when considered from the long-term perspective, for almost half of the chronically infected patients. This draws attention to the urgent need for more efficient treatments. Novel anti-hepatitis C treatments under study are directed against a number of so-called direct antiviral targets such as polymerases and proteases, which are encoded by the virus. Although such direct antiviral approaches have proven to be successful in several viral indications, there is a risk of resistant viruses developing. In order to avoid resistance, the development of indirect antiviral compounds has to be intensified. These act on host cell targets either by boosting the immune response or by blocking the virus host cell interaction. A particularly interesting approach is the development of inhibitors that interfere with signal transduction, such as protein kinase inhibitors. The purpose of this review is to stress the importance of developing indirect antiviral agents that act on host cell targets. In doing so, a large source of potential targets and mechanisms can be exploited, thus increasing the likelihood of success. Ultimately, combination therapies consisting of drugs against direct and indirect viral targets will most probably provide the solution to fighting and eradicating hepatitis C virus in patients.
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Gill K, Ghazinian H, Manch R, Gish R. Hepatitis C virus as a systemic disease: reaching beyond the liver. Hepatol Int 2016; 10:415-23. [PMID: 26660706 PMCID: PMC4819925 DOI: 10.1007/s12072-015-9684-3] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 11/03/2015] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C (CHC) is associated with multiple extrahepatic manifestations that may impact infected patients. The mechanisms through which these develop include those which are immunological, in which the chronic persistence of virus leads to the circulation of immune complexes (mixed cryoglobulinemia) and other autoimmune phenomena, and those which are virological and related to the extrahepatic tropism of the virus to other tissues. It is estimated that 40-74 % of patients with CHC may develop at least one extrahepatic manifestation during the course of the disease. Extrahepatic syndromes may represent the first signal of hepatitis C infection in some patients. CHC is associated with a four-fold increased risk of insulin resistance and type 2 diabetes mellitus; with cardiovascular disease in 17-37 % of patients; and with increased risk for cerebrovascular deaths, with a biological gradient of cerebrovascular mortality correlating with an increasing serum viral load. CHC is also associated with lymphoproliferative disorders, particularly non-Hodgkin B-cell lymphoma. The kidney is involved in 35-60 % of patients with CHC-associated mixed cryoglobulinemia. The prevalent type of glomerulonephritis associated with mixed cryoglobulinemia is membranoproliferative glomerulonephritis. In 30 % of cases, renal involvement begins with a nephritis syndrome and acute renal failure, while in 55 % there is only mild hematuria, microalbuminuria, proteinuria and renal insufficiency. CHC is also associated with cognitive impairment, especially in memory and concentration. Thus, extrahepatic CHC manifestations involve multiple organ systems outside the liver linked to a variety of comorbidities which may lead to significantly increased mortality from non-liver-related events.
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Affiliation(s)
- Kirat Gill
- />Department of Internal Medicine, St. Joseph’s Hospital and Medical Center, Phoenix, AZ USA
| | - Hasmik Ghazinian
- />Hepatology Department, Nork-Marash Medical Center, 13 Armenak Armenakyan Street, 0047 Yerevan, Armenia
- />Department of Infectious Disease, Nork-Marash Medical Center, 13 Armenak Armenakyan Street, 0047 Yerevan, Armenia
| | - Richard Manch
- />Department of Internal Medicine, St. Joseph’s Hospital and Medical Center, Phoenix, AZ USA
| | - Robert Gish
- />Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA USA
- />National Viral Hepatitis Roundtable, San Francisco, CA USA
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46
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Mathew S, Faheem M, Ibrahim SM, Iqbal W, Rauff B, Fatima K, Qadri I. Hepatitis C virus and neurological damage. World J Hepatol 2016; 8:545-556. [PMID: 27134702 PMCID: PMC4840160 DOI: 10.4254/wjh.v8.i12.545] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 11/16/2015] [Accepted: 04/11/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection exhibits a wide range of extrahepatic complications, affecting various organs in the human body. Numerous HCV patients suffer neurological manifestations, ranging from cognitive impairment to peripheral neuropathy. Overexpression of the host immune response leads to the production of immune complexes, cryoglobulins, as well as autoantibodies, which is a major pathogenic mechanism responsible for nervous system dysfunction. Alternatively circulating inflammatory cytokines and chemokines and HCV replication in neurons is another factor that severely affects the nervous system. Furthermore, HCV infection causes both sensory and motor peripheral neuropathy in the mixed cryoglobulinemia as well as known as an important risk aspect for stroke. These extrahepatic manifestations are the reason behind underlying hepatic encephalopathy and chronic liver disease. The brain is an apt location for HCV replication, where the HCV virus may directly wield neurotoxicity. Other mechanisms that takes place by chronic HCV infection due the pathogenesis of neuropsychiatric disorders includes derangement of metabolic pathways of infected cells, autoimmune disorders, systemic or cerebral inflammation and alterations in neurotransmitter circuits. HCV and its pathogenic role is suggested by enhancement of psychiatric and neurological symptoms in patients attaining a sustained virologic response followed by treatment with interferon; however, further studies are required to fully assess the impact of HCV infection and its specific antiviral targets associated with neuropsychiatric disorders.
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Hjerrild S, Renvillard SG, Leutscher P, Sørensen LH, Østergaard L, Eskildsen SF, Videbech P. Reduced cerebral cortical thickness in Non-cirrhotic patients with hepatitis C. Metab Brain Dis 2016; 31:311-9. [PMID: 26530221 DOI: 10.1007/s11011-015-9752-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 10/21/2015] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection is associated with fatigue, depression, and cognitive impairment even in the absence of severe liver fibrosis or cirrhosis. HCV has been hypothesised to cause neurodegenerative changes through low-grade neuroinflammation. Our aim was to examine whether cortical thickness (CTh) differs between chronic HCV patients and healthy controls, suggestive of cortical atrophy. In this case-control study 43 HCV patients without severe liver fibrosis, substance abuse, or comorbid HIV or hepatitis B virus infection, and 43 age and sex matched controls underwent MRI. Cortical thickness was measured using a surface based approach. Participants underwent semi-structured psychiatric interview and fatigue was assessed using the fatigue severity scale. HCV was associated with higher fatigue scores, and 58 % of HCV patients suffered from significant fatigue (p < 0.0001). Depression was observed in 16 % of patients. Areas of significantly reduced CTh were found in both left and right occipital cortex and in the left frontal lobe after correction for multiple comparisons (p < 0.05). No association between fatigue, former substance abuse, or psychotropic medication and CTh was found. No overall difference in cerebral white and grey matter volume was found. The findings support the hypothesis that HCV is associated with neurodegenerative changes.
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Affiliation(s)
- Simon Hjerrild
- Department for Affective Disorders, Aarhus University Hospital, Skovagervej 2, 8240, Risskov, Denmark.
- Center of Functionally Integrative Neuroscience (CFIN), Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - Signe Groth Renvillard
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
- Department for Affective Disorders, Aarhus University Hospital, Skovagervej 2, 8240, Risskov, Denmark
| | - Peter Leutscher
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | | | - Leif Østergaard
- Center of Functionally Integrative Neuroscience (CFIN), Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Simon Fristed Eskildsen
- Center of Functionally Integrative Neuroscience (CFIN), Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Poul Videbech
- Department for Affective Disorders, Aarhus University Hospital, Skovagervej 2, 8240, Risskov, Denmark
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Wozniak MA, Lugo Iparraguirre LM, Dirks M, Deb-Chatterji M, Pflugrad H, Goldbecker A, Tryc AB, Worthmann H, Gess M, Crossey MME, Forton DM, Taylor-Robinson SD, Itzhaki RF, Weissenborn K. Apolipoprotein E-ε4 deficiency and cognitive function in hepatitis C virus-infected patients. J Viral Hepat 2016; 23:39-46. [PMID: 26306786 DOI: 10.1111/jvh.12443] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 07/16/2015] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) causes not only liver damage in certain patients but can also lead to neuropsychiatric symptoms. Previous studies have shown that the type 4 allele of the gene for apolipoprotein E (APOE) is strongly protective against HCV-induced damage in liver. In this study, we have investigated the possibility that APOE genotype is involved in the action of HCV in brain. One hundred HCV-infected patients with mild liver disease underwent a neurological examination and a comprehensive psychometric testing of attention and memory function. In addition, patients completed questionnaires for the assessment of fatigue, health-related quality of life and mood disturbances. Apolipoprotein E gene genotyping was carried out on saliva using buccal swabs. The APOE-ε4 allele frequency was significantly lower in patients with an impairment of working memory, compared to those with a normal working memory test result (P = 0.003). A lower APOE-ε4 allele frequency was also observed in patients with definitely altered attention ability (P = 0.008), but here, the P-value missed the level of significance after application of the Bonferroni correction. Our data suggest that the APOE-ε4 allele is protective against attention deficit and especially against poor working memory in HCV-infected subjects with mild liver disease. Considering the role of apolipoprotein E in the life cycle of the virus, the findings shed interesting new light upon possible pathomechanisms behind the development of neuropsychiatric symptoms in hepatitis C infection.
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Affiliation(s)
- M A Wozniak
- Faculty of Life Sciences, University of Manchester, Manchester, UK
| | | | - M Dirks
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - M Deb-Chatterji
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - H Pflugrad
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - A Goldbecker
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - A B Tryc
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - H Worthmann
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - M Gess
- Department of Gastroenterology and Hepatology, St George's Hospital and Medical School, London, UK
| | - M M E Crossey
- Department of Medicine, St Mary's Hospital Campus, Imperial College London, London, UK
| | - D M Forton
- Department of Gastroenterology and Hepatology, St George's Hospital and Medical School, London, UK
| | - S D Taylor-Robinson
- Department of Medicine, St Mary's Hospital Campus, Imperial College London, London, UK
| | - R F Itzhaki
- Faculty of Life Sciences, University of Manchester, Manchester, UK
| | - K Weissenborn
- Department of Neurology, Hannover Medical School, Hannover, Germany
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Negro F, Forton D, Craxì A, Sulkowski MS, Feld JJ, Manns MP. Extrahepatic morbidity and mortality of chronic hepatitis C. Gastroenterology 2015; 149:1345-60. [PMID: 26319013 DOI: 10.1053/j.gastro.2015.08.035] [Citation(s) in RCA: 271] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Revised: 08/14/2015] [Accepted: 08/17/2015] [Indexed: 12/17/2022]
Abstract
Chronic hepatitis C virus (HCV) infection is associated with several extrahepatic manifestations. Patients with HCV may develop mixed cryoglobulinemia and its sequelae, ranging from cutaneous and visceral vasculitis to glomerulonephritis and B-cell non-Hodgkin lymphoma. HCV-infected patients have increased rates of insulin resistance, diabetes, and atherosclerosis, which may lead to increased cardiovascular morbidity and mortality. Neurological manifestations of HCV infection include fatigue and cognitive impairment. The mechanisms causing the extrahepatic effects of HCV infection are likely multifactorial and may include endocrine effects, HCV replication in extrahepatic cells, or a heightened immune reaction with systemic effects. Successful eradication of HCV with interferon alfa and ribavirin was shown to improve some of these extrahepatic effects; sustained virological response is associated with resolution of complications of cryoglobulinemia, reduced levels of insulin resistance, reduced incidence of diabetes and stroke, and improved fatigue and cognitive functioning. The availability of new interferon-free, well-tolerated anti-HCV treatment regimens is broadening the spectrum of patients available for therapy, including those in whom interferon was contraindicated, and will likely result in greater improvements in the extrahepatic manifestations of HCV. If these regimens are shown to confer significant benefit in the metabolic, cardiovascular, or neuropsychiatric conditions associated with HCV infection, extrahepatic manifestations of HCV may become a major indication for treatment even in the absence of liver disease.
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Affiliation(s)
- Francesco Negro
- Division of Gastroenterology and Hepatology and Division of Clinical Pathology, University Hospital, Geneva, Switzerland
| | - Daniel Forton
- Department of Gastroenterology and Hepatology, St George's Hospital, London, England
| | - Antonio Craxì
- Gastroenterology and Internal Medicine, University of Palermo, Palermo, Italy
| | - Mark S Sulkowski
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Ontario, Canada
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover, Germany.
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Vigneswaran S, Rojas JHV, Garvey L, Taylor-Robinson S, Winston A. Differences in the variability of cerebral proton magnetic resonance spectroscopy (1H-MRS) measurements within three HIV-infected cohorts. Neuroradiol J 2015; 28:545-54. [PMID: 26493269 DOI: 10.1177/1971400915609867] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
INTRODUCTION Cerebral functional impairment remains prevalent in effectively treated HIV-infected subjects. As the results of formal cognitive testing are highly variable, surrogate markers to accurately measure cerebral function parameters are needed. Such markers include measurement of cerebral metabolite ratios (CMR) using proton magnetic resonance spectroscopy (1H-MRS). However, data on the inter-subject variability of CMR are sparse. Our aim was to assess inter-subject variability in CMRs within three different HIV-infected cohorts. METHODS Cerebral 1H-MRS was performed using a Phillips Achieva™ 1.5 Tesla magnetic resonance scanner in HIV-infected subjects as follows: 12 subjects before (group 1) and after intensification of antiretroviral therapy with maraviroc (group 2) and 13 subjects with acute viral hepatitis C (HCV) co-infection (group 3). The coefficients of variation (CV) for CMRs in each group were determined and compared using non-parametric tests to determine whether the inter-subject variability differed significantly. All baseline characteristics between the groups were similar. RESULTS Overall CVs for all CMRs in groups 1, 2 and 3 were 32.3%, 33.2% and 23.4%, respectively (group 1 vs. 2, p=0.863; group 1 vs. 3, p=0.076). On testing for differences in variability between individual CMRs, two metabolites in the right basal ganglia (RBG) had statistically significantly different CVs when comparing group 1 with group 3: N-acetyl aspartate/creatine (NAA/Cr), p=0.029 and myo-Inositol/creatine (mI/Cr), p=0.016. CONCLUSION The variability of 1H MRS-measurable CMRs in HIV-infected individuals was lower in those with acute HCV co-infection (group 3).We can conclude that the use of these CMRs in 1H MRS imaging in patients with HIV/acute HCV co-infection is more reliable to assess cerebral function than in patients with HIV infection alone. This has implications for future sample size estimations.
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Affiliation(s)
| | - Jaime H Vera Rojas
- Division of medicine, Brighton and Sussex Medical School Department of HIV and GU Medicine, Imperial College Healthcare NHS Trust, London, UK
| | - Lucy Garvey
- Department of HIV and GU Medicine, Imperial College Healthcare NHS Trust, London, UK
| | - Simon Taylor-Robinson
- Department of Medicine, Faculty of Medicine, Imperial College London, St Mary's Hospital Campus, London, UK
| | - Alan Winston
- Department of HIV and GU Medicine, Imperial College Healthcare NHS Trust, London, UK
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