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Ali AA, Tabll AA. Unlocking potential: Virus-like particles as a promising strategy for effective HCV vaccine development. Virology 2025; 602:110307. [PMID: 39580887 DOI: 10.1016/j.virol.2024.110307] [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: 10/01/2024] [Revised: 11/01/2024] [Accepted: 11/14/2024] [Indexed: 11/26/2024]
Abstract
Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. The development of prophylactic vaccine is essential for HCV global eradication. Despite over three decades of research, no effective vaccine for HCV has been developed, primarily due to the virus's genetic diversity, immune evasion mechanisms, and incomplete understanding of protective immunity. However, Virus-Like Particles (VLPs) offer a promising approach to overcoming these challenges. VLPs mimic the structure of native virus but without the infectious genome, making them safe and non-infectious vaccines candidates. The capability of VLPs to incorporate neutralizing and conformational epitopes, and engage humoral and cellular immune responses, positions them as a promising tool for overcoming challenges associated with the HCV vaccine development. This review examines the challenges and immunological considerations for HCV vaccine development and provides an overview of the VLPs-based vaccines development. It also discusses future directions and public health implications of HCV vaccine development.
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Affiliation(s)
- Ahmed A Ali
- Molecular Biology Department, Biotechnology Research Institute, National Research Centre, (NRC), 12622, Cairo, Egypt.
| | - Ashraf A Tabll
- Microbial Biotechnology Department, Biotechnology Research Institute, National Research Centre, 12622, Cairo, Egypt; Egyptian Centre for Research and Regenerative Medicine (ECRRM), 11517, Cairo, Egypt.
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Zhang M, Li L, Wu L, Zhang J. Isarubrolone C Promotes Autophagic Degradation of Virus Proteins via Activating ATG10S in HepG2 Cells. JOURNAL OF NATURAL PRODUCTS 2022; 85:1018-1028. [PMID: 35201775 DOI: 10.1021/acs.jnatprod.1c01161] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Isarubrolone C is a bioactive polycyclic tropoloalkaloid from Streptomyces. Our previous study showed that isarubrolone C could trigger autophagy. Here, we report isarubrolone C potential in broad-spectrum antiviral effect and its antiviral mechanism in vitro. Our results show that isarubrolone C activated autophagy and reduced levels of viral proteins in the cells harboring HCV-CORE/NS5B, HBx, ZIKV-NS5, and HIV-RT, respectively. The role of isarubrolone C in suppression of the viral proteins was via an autophagic degradation pathway rather than a proteasome pathway. Co-immunoprecipitation assays revealed that isarubrolone C promoted both autophagy flux opening and the viral proteins being enwrapped in autolysosomes. PCR assays showed that isarubrolone C elevated the transcription levels of ATG10/ATG10S and IL28A. Further, ATG10S high expression could efficiently enhance IL28A expression and the ability of isarubrolone C to degrade the viral proteins by promoting the colocalization of viral proteins with autolysosomes. Additionally, knockdown of endogenous IL28A caused both losses of the isarubrolone C antiviral effect and autolysosome formation. These results indicate that the role of isarubrolone C antiviruses is achieved by triggering the autophagic mechanism, which is mediated by endogenous ATG10S and IL28A activation. This is the first report about isarubrolone C potential of in vitro broad-spectrum antiviruses.
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Affiliation(s)
- Miaoqing Zhang
- Key Laboratory of Biotechnology of Antibiotics, the National Health Commission (NHC), Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Linli Li
- Key Laboratory of Biotechnology of Antibiotics, the National Health Commission (NHC), Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Linzhuan Wu
- Key Laboratory of Biotechnology of Antibiotics, the National Health Commission (NHC), Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Jingpu Zhang
- Key Laboratory of Biotechnology of Antibiotics, the National Health Commission (NHC), Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
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Association of HLA Class II Alleles with Outcome of Hepatitis C Virus Infection: A Systematic Review and Meta-analysis. HEPATITIS MONTHLY 2021. [DOI: 10.5812/hepatmon.109493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Context: Hepatitis C Virus (HCV) infection is a major cause of chronic cirrhosis and hepatocellular carcinoma. Approximately 30% of infected persons with HCV spontaneously clear the viral infection; but, some of the remaining patients develop chronic HCV. Studies show that HLA molecules play an important role in the outcome of HCV infection by influencing the efficiency of the antiviral immune response to HCV infection. It is now known that polymorphisms in HLA loci are associated with HCV susceptibility or clearance. The purpose of the present study was to systematically review the studies that reported the association of HLA class II alleles (HLA-DQ and HLA-DR) with the outcome of HCV infection. Evidence Acquisition: Studies were identified by searching electronic databases, including PubMed and Scopus. A total of 12,265 relevant studies were identified by the electronic search, of which a total of 19 eligible papers were identified that were meta-analyzed for the association between HLA class II alleles and the outcome of HCV infection. Results: Subjects carrying HLA-DQB1*0301, HLA-DQB1*0501, HLA-DRB1*1303, HLA-DRB1*1201, HLA-DRB1*0401, HLA-DRB1*0101, and HLA-DRB1*1101 alleles were significantly associated with higher spontaneous clearance of HCV infection. Conclusions: The data from the current study confirm that several polymorphisms in HLA-DQ and HLA-DR loci are correlated with the clearance of HCV infection. Identifying these polymorphisms may contribute to a better understanding of immune mechanisms of HCV clearance or persistence.
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Ahovègbé LY, Ogwang PE, Peter EL, Mtewa AG, Kasali FM, Tolo CU, Gbenoudon J, Weisheit A, Pakoyo KF. Therapeutic potentials of Vachellia nilotica (L.) extracts in Hepatitis C infection: A review. SCIENTIFIC AFRICAN 2021. [DOI: 10.1016/j.sciaf.2021.e00918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Mishin DV, Isaeva EI, Grigorian SS, Balakina AA, Ilyichev AV, Deryabin PG, Maldov DG. The Mechanism of Suppression of Chronic Hepatitis C Infection by the Medicine Stimforte. BIOL BULL+ 2020. [DOI: 10.1134/s1062359020050076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Hepatitis C Virus Translation Regulation. Int J Mol Sci 2020; 21:ijms21072328. [PMID: 32230899 PMCID: PMC7178104 DOI: 10.3390/ijms21072328] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 03/18/2020] [Accepted: 03/25/2020] [Indexed: 12/12/2022] Open
Abstract
Translation of the hepatitis C virus (HCV) RNA genome is regulated by the internal ribosome entry site (IRES), located in the 5’-untranslated region (5′UTR) and part of the core protein coding sequence, and by the 3′UTR. The 5′UTR has some highly conserved structural regions, while others can assume different conformations. The IRES can bind to the ribosomal 40S subunit with high affinity without any other factors. Nevertheless, IRES activity is modulated by additional cis sequences in the viral genome, including the 3′UTR and the cis-acting replication element (CRE). Canonical translation initiation factors (eIFs) are involved in HCV translation initiation, including eIF3, eIF2, eIF1A, eIF5, and eIF5B. Alternatively, under stress conditions and limited eIF2-Met-tRNAiMet availability, alternative initiation factors such as eIF2D, eIF2A, and eIF5B can substitute for eIF2 to allow HCV translation even when cellular mRNA translation is downregulated. In addition, several IRES trans-acting factors (ITAFs) modulate IRES activity by building large networks of RNA-protein and protein–protein interactions, also connecting 5′- and 3′-ends of the viral RNA. Moreover, some ITAFs can act as RNA chaperones that help to position the viral AUG start codon in the ribosomal 40S subunit entry channel. Finally, the liver-specific microRNA-122 (miR-122) stimulates HCV IRES-dependent translation, most likely by stabilizing a certain structure of the IRES that is required for initiation.
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Hepatitis C Virus Downregulates Core Subunits of Oxidative Phosphorylation, Reminiscent of the Warburg Effect in Cancer Cells. Cells 2019; 8:cells8111410. [PMID: 31717433 PMCID: PMC6912740 DOI: 10.3390/cells8111410] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 02/08/2023] Open
Abstract
Hepatitis C Virus (HCV) mainly infects liver hepatocytes and replicates its single-stranded plus strand RNA genome exclusively in the cytoplasm. Viral proteins and RNA interfere with the host cell immune response, allowing the virus to continue replication. Therefore, in about 70% of cases, the viral infection cannot be cleared by the immune system, but a chronic infection is established, often resulting in liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Induction of cancer in the host cells can be regarded to provide further advantages for ongoing virus replication. One adaptation in cancer cells is the enhancement of cellular carbohydrate flux in glycolysis with a reduction of the activity of the citric acid cycle and aerobic oxidative phosphorylation. To this end, HCV downregulates the expression of mitochondrial oxidative phosphorylation complex core subunits quite early after infection. This so-called aerobic glycolysis is known as the “Warburg Effect” and serves to provide more anabolic metabolites upstream of the citric acid cycle, such as amino acids, pentoses and NADPH for cancer cell growth. In addition, HCV deregulates signaling pathways like those of TNF-β and MAPK by direct and indirect mechanisms, which can lead to fibrosis and HCC.
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Kida T, Umemura A, Kaneshita S, Sagawa R, Inoue T, Toyama S, Wada M, Kohno M, Oda R, Inaba T, Itoh Y, Kawahito Y. Effectiveness and safety of chronic hepatitis C treatment with direct-acting antivirals in patients with rheumatic diseases: A case-series. Mod Rheumatol 2019; 30:1009-1015. [PMID: 31625432 DOI: 10.1080/14397595.2019.1682787] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Objectives: To assess the effectiveness and safety of interferon-free direct-acting antiviral (DAA) therapy for patients with concomitant hepatitis C virus (HCV) infection and rheumatic diseases (RDs), including rheumatoid arthritis (RA).Methods: This was a single-center observational case-series study conducted in Japan from 2014 to 2018. The primary endpoint was the sustained virological response (SVR) rate 24 weeks after the end of therapy (EoT24). We also evaluated hepatological and rheumatological outcomes and adverse events.Results: Of the 2314 patients with RDs, 18 received DAA therapy (RA = 11, other RDs = 7). The SVR rate for the initial DAA therapy was 89% (16/18). The remaining two achieved SVR with secondary DAA therapy. Along with HCV elimination, hepatological parameters improved significantly from baseline to EoT24. During the study period, no patients newly developed cirrhosis or HCC after HCV elimination. Several patients showed improvement in RDs activity. In RA patients, the simplified disease activity index decreased significantly from baseline to EoT24 (median [interquartile range]: 11.53 [5.14-14.89] vs. 4.06 [2.08-9.05], respectively). On-treatment adverse events were minimal, while two patients experienced tuberculosis reactivation after EoT.Conclusion: DAA therapy was effective and safe, providing hepatological and rheumatological benefits in HCV-infected patients with RDs. Immune reconstitution following HCV elimination should be noted.
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Affiliation(s)
- Takashi Kida
- Department of Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Atsushi Umemura
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shunya Kaneshita
- Department of Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Risa Sagawa
- Department of Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takuya Inoue
- Department of Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shogo Toyama
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Makoto Wada
- Department of Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masataka Kohno
- Department of Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ryo Oda
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tohru Inaba
- Department of Infection Control and Laboratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yutaka Kawahito
- Department of Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Alizadeh S, Irani S, Bolhassani A, Sadat SM. Simultaneous use of natural adjuvants and cell penetrating peptides improves HCV NS3 antigen-specific immune responses. Immunol Lett 2019; 212:70-80. [PMID: 31254535 DOI: 10.1016/j.imlet.2019.06.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 06/11/2019] [Accepted: 06/25/2019] [Indexed: 02/07/2023]
Abstract
To improve an effective hepatitis C virus (HCV) therapeutic vaccine, induction of a strong and long term HCV antigen-specific immune response is an important parameter. HCV non-structural protein 3 (NS3) has antigenic properties and plays a major role in viral clearance. In this study, DNA constructs encoding HCV NS3 and heat shock protein 27 (Hsp27)-NS3 genes, and the recombinant (r) NS3 and rHsp27-NS3 proteins complexed with HR9 and Cady-2 cell penetrating peptides (CPPs) were utilized to evaluate antibody, cytokine and Granzyme B secretion in mice. Herein, the formation of NS3 and Hsp27-NS3 DNA/ HR9 CPP complexes were revealed by gel retardation assay and protection against DNase and protease. Cady-2 peptide was used to form the nanoparticles with rNS3 and rHsp27-NS3 proteins. The size and charge of the nanoparticles were confirmed by SEM and Zetasizer instruments. Next, in vitro transfection of the nanoparticles was assessed by flow cytometry and western blotting. Finally, humoral and cellular immune responses were evaluated using different modalities in mice. Our data showed that HR9 and Cady-2 could form stable nanoparticles with DNA and proteins, respectively and enhance their delivery into HEK-293 T cells in a non-covalent approach. Furthermore, the heterologous Hsp27-NS3 DNA + HR9 prime/rHsp27-NS3+Cady-2 protein boost elicited a higher Th1 cellular immune response with a predominant IgG2a, IgG2b, IFN-γ profile and strong Granzyme B secretion than those induced by other groups. Briefly, the combination of a natural adjuvant (Hsp27) and CPPs (HR9 and Cady-2) could significantly stimulate effective immune responses as a promising approach for development of HCV therapeutic vaccines.
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Affiliation(s)
- Sina Alizadeh
- Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Shiva Irani
- Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Azam Bolhassani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran.
| | - Seyed Mehdi Sadat
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
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Hu P, Wilhelm J, Gerresheim GK, Shalamova LA, Niepmann M. Lnc-ITM2C-1 and GPR55 Are Proviral Host Factors for Hepatitis C Virus. Viruses 2019; 11:v11060549. [PMID: 31200545 PMCID: PMC6631246 DOI: 10.3390/v11060549] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 06/01/2019] [Accepted: 06/12/2019] [Indexed: 02/07/2023] Open
Abstract
Multiple host factors are known to play important roles in hepatitis C virus (HCV) replication, in immune responses induced by HCV infection, or in processes that facilitate virus escape from immune clearance, while yet only few studies examined the contribution of long non-coding RNAs (lncRNAs/lncRs). Using microarrays, we identified lncRNAs with altered expression levels in HCV replicating Huh-7.5 hepatoma cells. Of these, lncR 8(Lnc-ITM2C-1/LOC151484) was confirmed by quantitative real-time PCR (qRT-PCR) to be upregulated early after HCV infection. After suppressing the expression of lncR 8, HCV RNA and protein were downregulated, confirming a positive correlation between lncR 8 expression and HCV replication. lncR 8 knockdown in Huh-7.5 cells reduced expression of the neighboring gene G protein-coupled receptor 55 (GPR55) mRNA level at early times, and leads to increased levels of several Interferon stimulated genes (ISGs) including ISG15, Mx1 and IFITM1. Importantly, the effect of lncR 8 on ISGs and GPR55 precedes its effect on HCV replication. Furthermore, knockdown of GPR55 mRNA induces ISG expression, providing a possible link between lncR 8 and ISGs. We conclude that HCV induces lncR 8 expression, while lncR 8 indirectly favors HCV replication by stimulating expression of its neighboring gene GPR55, which in turn downregulates expression of ISGs. The latter fact is also consistent with an anti-inflammatory role of GPR55. These events may contribute to the failure to eliminate ongoing HCV infection.
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Affiliation(s)
- Pan Hu
- Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Friedrichstrasse 24, 35392 Giessen, Germany.
| | - Jochen Wilhelm
- Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), 35392 Giessen, Germany.
| | - Gesche K Gerresheim
- Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Friedrichstrasse 24, 35392 Giessen, Germany.
| | - Lyudmila A Shalamova
- Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Friedrichstrasse 24, 35392 Giessen, Germany.
| | - Michael Niepmann
- Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Friedrichstrasse 24, 35392 Giessen, Germany.
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Sato K, Yamazaki Y, Kobayashi T, Takakusagi S, Horiguchi N, Kakizaki S, Andou M, Matsuda Y, Uraoka T, Ohnishi H, Okamoto H. Sofosbuvir/Ribavirin therapy for patients experiencing failure of ombitasvir/paritaprevir/ritonavir + ribavirin therapy: Two cases report and review of literature. World J Clin Cases 2019; 7:1043-1052. [PMID: 31123677 PMCID: PMC6511930 DOI: 10.12998/wjcc.v7.i9.1043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 02/23/2019] [Accepted: 03/16/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The effectiveness of sofosbuvir/ribavirin (SOF/RBV) combination therapy, which is one of the 1st-choice therapeutic options for patients with hepatitis C virus (HCV) genotype 2 (HCV-G2) in Japan according to the most recent version of the Japan Society of Hepatology guideline, for patients who experienced failure of the ombitasvir/paritaprevir/ritonavir plus ribavirin (OBV/PTV/r+RBV) combination therapy, which was another option for patients with HCV-G2, is unknown. CASE SUMMARY We evaluated the effects of SOF/RBV combination therapy in two patients with genotype 2a who could not achieve a sustained virological response (SVR) by OBV/PTV/r+RBV combination therapy. One patient was complicated with Vogt-Koyanagi-Harada (VKH) disease. Resistance-associated variations before SOF/RBV combination therapy were not detected in two patients. Both patients had an SVR at 12 wk after the treatment (SVR12). Regarding adverse events (AEs), itching, chill, a dull feeling in the throat and cough as well as increase of alanine transaminase level were shown in one patient, while a headache and deterioration of light aversion probably due to the recurrence of VKH disease were shown in the other patients. In addition, the latter patient developed arthralgia and morning stiffness approximately 7 wk after the therapy and turned out to be diagnosed with rheumatoid arthralgia. CONCLUSION SOF/RBV therapy might be effective for patients experiencing failure of OBV/PTV/r+RBV therapy, but caution should be taken regarding the AEs.
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Affiliation(s)
- Ken Sato
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Yuichi Yamazaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Takeshi Kobayashi
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Satoshi Takakusagi
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Norio Horiguchi
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Masayasu Andou
- Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Yoshihiro Matsuda
- Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Hiroshi Ohnishi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329-0498, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329-0498, Japan
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Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling. Int J Mol Sci 2019; 20:ijms20061321. [PMID: 30875926 PMCID: PMC6470931 DOI: 10.3390/ijms20061321] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/06/2019] [Accepted: 03/12/2019] [Indexed: 12/14/2022] Open
Abstract
Background: Hepatitis C virus (HCV) infects human liver hepatocytes, often leading to liver cirrhosis and hepatocellular carcinoma (HCC). It is believed that chronic infection alters host gene expression and favors HCC development. In particular, HCV replication in Endoplasmic Reticulum (ER) derived membranes induces chronic ER stress. How HCV replication affects host mRNA translation and transcription at a genome wide level is not yet known. Methods: We used Riboseq (Ribosome Profiling) to analyze transcriptome and translatome changes in the Huh-7.5 hepatocarcinoma cell line replicating HCV for 6 days. Results: Established viral replication does not cause global changes in host gene expression—only around 30 genes are significantly differentially expressed. Upregulated genes are related to ER stress and HCV replication, and several regulated genes are known to be involved in HCC development. Some mRNAs (PPP1R15A/GADD34, DDIT3/CHOP, and TRIB3) may be subject to upstream open reading frame (uORF) mediated translation control. Transcriptional downregulation mainly affects mitochondrial respiratory chain complex core subunit genes. Conclusion: After establishing HCV replication, the lack of global changes in cellular gene expression indicates an adaptation to chronic infection, while the downregulation of mitochondrial respiratory chain genes indicates how a virus may further contribute to cancer cell-like metabolic reprogramming (“Warburg effect”) even in the hepatocellular carcinoma cells used here.
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Unique Type I Interferon, Expansion/Survival Cytokines, and JAK/STAT Gene Signatures of Multifunctional Herpes Simplex Virus-Specific Effector Memory CD8 + T EM Cells Are Associated with Asymptomatic Herpes in Humans. J Virol 2019; 93:JVI.01882-18. [PMID: 30487281 DOI: 10.1128/jvi.01882-18] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 11/22/2018] [Indexed: 01/23/2023] Open
Abstract
A large proportion of the world population harbors herpes simplex virus 1 (HSV-1), a major cause of infectious corneal blindness. HSV-specific CD8+ T cells protect from herpesvirus infection and disease. However, the genomic, phenotypic, and functional characteristics of CD8+ T cells associated with the protection seen in asymptomatic (ASYMP) individuals, who, despite being infected, never experienced any recurrent herpetic disease, remains to be fully elucidated. In this investigation, we compared the phenotype, function, and level of expression of a comprehensive panel of 579 immune genes of memory CD8+ T cells, sharing the same HSV-1 epitope specificities, and freshly isolated peripheral blood from well-characterized cohorts of protected ASYMP and nonprotected symptomatic (SYMP) individuals, with a history of numerous episodes of recurrent herpetic disease, using the high-throughput digital NanoString nCounter system and flow cytometry. Interestingly, our results demonstrated that memory CD8+ T cells from ASYMP individuals expressed a unique set of genes involved in expansion and survival, type I interferon (IFN-I), and JAK/STAT pathways. Frequent multifunctional HSV-specific effector memory CD62Llow CD44high CD8+ TEM cells were detected in ASYMP individuals compared to more of monofunctional central memory CD62Lhigh CD44high CD8+ TCM cells in SYMP individuals. Shedding light on the genotype, phenotype, and function of antiviral CD8+ T cells from "naturally protected" ASYMP individuals will help design future T-cell-based ocular herpes immunotherapeutic vaccines.IMPORTANCE A staggering number of the world population harbors herpes simplex virus 1 (HSV-1) potentially leading to blinding recurrent herpetic disease. While the majority are asymptomatic (ASYMP) individuals who never experienced any recurrent herpetic disease, symptomatic (SYMP) individuals have a history of numerous episodes of recurrent ocular herpetic disease. This study elucidates the phenotype, the effector function, and the gene signatures of memory CD8+ T-cell populations associated with protection seen in ASYMP individuals. Frequent multifunctional HSV-specific effector memory CD8+ TEM cells were detected in ASYMP individuals. In contrast, nonprotected SYMP individuals had more central memory CD8+ TCM cells. The memory CD8+ TEM cells from ASYMP individuals expressed unique gene signatures characterized by higher levels of type I interferon (IFN), expansion and expansion/survival cytokines, and JAK/STAT pathways. Future studies on the genotype, phenotype, and function of antiviral CD8+ T cells from "naturally protected" ASYMP individuals will help in the potential design of T-cell-based ocular herpes vaccines.
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Huynh T, Zhang J, Hu KQ. Hepatitis C Virus Clearance by Direct-acting Antiviral Results in Rapid Resolution of Hepatocytic Injury as Indicated by Both Alanine Aminotransferase and Aspartate Aminotransferase Normalization. J Clin Transl Hepatol 2018; 6:258-263. [PMID: 30271737 PMCID: PMC6160300 DOI: 10.14218/jcth.2018.00014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 07/01/2018] [Accepted: 08/23/2018] [Indexed: 12/20/2022] Open
Abstract
Background and Aims: Hepatitis C virus (HCV) infection results in hepatocytic injury with elevation of both alanine aminotransferase (ALT) and aspartate aminotransferase (AST). It remains to be determined if direct-acting antiviral treatment can terminate hepatocytic injury following virologic response. To this end, we evaluated the pattern and predicting factors of ALT and AST normalization during and after direct-acting antiviral treatment with sustained virologic response at 12 weeks (SVR12). Methods: Single-center retrospective study on 115 HCV-infected patients who achieved SVR12 was performed. Results: At treatment week 2, 100% and 45.9% showed decline in HCV RNA to <700 IU/mL and undetectable levels, respectively, and this was associated with 85.5%, 83.9% and 77.4% ALT normalization, AST normalization and ALT and AST normalization. At end of treatment, 85.6% of patients with baseline elevation of both ALT and AST had normalization of both ALT and AST. At posttreatment weeks 12 and 24, 90.8% and 94.8% had normalization of both ALT and AST. HCV clearance also resulted in further decline of both ALT and AST in those with baseline <40 IU. Univariate analysis showed baseline Child-Pugh score of <6, model for end-stage liver disease score of <10, HCV genotype 1, and HCV RNA of <500 IU/mL at treatment week 2 were associated with sustained normalization of both ALT and AST at posttreatment week 12. On multivariate analysis, baseline model for end-stage liver disease score of <10 was significantly associated with normalization of both ALT and AST at posttreatment week 12, independent of baseline Child-Pugh score <6, HCV genotype 1, and HCV RNA of <500 IU/mL at treatment week 2. Conclusions: During direct-acting antiviral therapy, 85.5% and 83.9% had normalization of both ALT and AST as early as in week 2, providing biochemical evidence of hepatocytic injury resolution. Sustained normalization of both ALT and AST was seen in 90.8% at posttreatment weeks 12, and was independently associated with baseline model for end-stage liver disease score of <10.
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Affiliation(s)
- Tung Huynh
- Division of Gastroenterology and Hepatology, School of Medicine, University of California, Orange, CA, USA
| | - Johnathan Zhang
- Division of Gastroenterology and Hepatology, School of Medicine, University of California, Orange, CA, USA
| | - Ke-Qin Hu
- Division of Gastroenterology and Hepatology, School of Medicine, University of California, Orange, CA, USA
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15
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A Biomolecular Network Driven Proteinic Interaction in HCV Clearance. Cell Biochem Biophys 2018; 76:161-172. [PMID: 29313175 DOI: 10.1007/s12013-017-0837-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 12/26/2017] [Indexed: 12/20/2022]
Abstract
Hepatitis C virus infection causes chronic liver disease that leads to cancer-related mortality. Presently around 30% of the HCV (infected) affected population get rid of the infection through spontaneous disease clearance. This phenomenon is conducted by a set of reported immune candidate genes. Hence, this study focuses only on these immune-response related genes with aid of network approach, where the idea is to disseminate the network for better understanding of key functional genes and their transcription control activity. Based on the network analysis the IFNG, TNF, IFNB1, STAT1, NFKB1, STAT3, SOCS1, and MYD88 genes are prioritized as hub genes along with their common transcription factors (TFs), IRF9, NFKB1, and STAT1. The dinucleotide frequency of TF binding elements indicated GG-rich motifs in these regulatory elements. On the other hand, gene enrichment report suggests the regulation of response to interferon gamma signaling pathway, which plays central role in the spontaneous HCV clearance. Therefore, our study tends to prioritize the genes, TFs, and their regulatory pathway towards HCV clearance. Even so, the resultant hub genes and their TFs and TF binding elements could be crucial in underscoring the clearance activity in specific populations.
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16
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Maldov DG, Andronova VL, Grigorian SS, Isaeva EI, Deryabin PG, Mishin DV, Balakina AA, Ilyichev AV, Terentyev AA, Galegov GA. Different effects of the immunostimulatory drug Stimforte on infections of hepatitis C virus and herpes simplex virus type 1. DOKLADY BIOLOGICAL SCIENCES : PROCEEDINGS OF THE ACADEMY OF SCIENCES OF THE USSR, BIOLOGICAL SCIENCES SECTIONS 2018; 477:219-222. [PMID: 29299800 DOI: 10.1134/s0012496617060035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Indexed: 11/23/2022]
Abstract
Stimforte, an immune response-stimulating preparation, is active with respect to hepatitis C virus (HCV) and herpes simplex virus type I (HSV-1). The effects of Stimforte in animals infected with either HCV or HSV-1 are fundamentally different. In mice with acute herpes virus infection, Stimforte administration leads to a higher activity of natural killer cells and cytotoxic lymphocytes, and the amount of interferon (IFN) λ grows. In mice infected with HCV, Stimforte administration results in a significant increase in IFN-β but not IFN-λ in blood and affected organs. Stimforte has been found to affect directly HCV reproduction that causes the infected cell death, but it does not affect HSV-1 reproduction in the Vero cells (V).
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Affiliation(s)
| | - V L Andronova
- Gamaleya Institute of Epidemiology and Microbiology, Ministry of Health, Moscow, Russia
| | - S S Grigorian
- Gamaleya Institute of Epidemiology and Microbiology, Ministry of Health, Moscow, Russia
| | - E I Isaeva
- Gamaleya Institute of Epidemiology and Microbiology, Ministry of Health, Moscow, Russia
| | - P G Deryabin
- Gamaleya Institute of Epidemiology and Microbiology, Ministry of Health, Moscow, Russia
| | - D V Mishin
- Gamaleya Institute of Epidemiology and Microbiology, Ministry of Health, Moscow, Russia
| | - A A Balakina
- Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Moscow oblast, Russia
| | | | - A A Terentyev
- Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Moscow oblast, Russia
| | - G A Galegov
- Gamaleya Institute of Epidemiology and Microbiology, Ministry of Health, Moscow, Russia
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17
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Eight Weeks of Ledipasvir/Sofosbuvir in Kidney Transplant Recipients With Hepatitis C Genotype 1 Infection. Transplant Direct 2017. [PMID: 29536030 PMCID: PMC5828686 DOI: 10.1097/txd.0000000000000744] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Short treatment duration of ledipasvir/sofosbuvir (LDV/SOF) has been successfully used to treat hepatitis C virus (HCV) genotype 1 infection in treatment-naive noncirrhotic patients with viral loads (VLs) under 6 million IU/mL. However, this short duration has not been studied in renal transplant recipients (RTRs), a patient population on lifelong immunosuppression. Here, we describe 3 RTRs who received 8 weeks of LDV/SOF, meeting the standard criteria for shortened treatment duration. All 3 patients tolerated treatment well and achieved sustained virologic response at 12 weeks (SVR 12).
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18
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Barriocanal M, Fortes P. Long Non-coding RNAs in Hepatitis C Virus-Infected Cells. Front Microbiol 2017; 8:1833. [PMID: 29033906 PMCID: PMC5625025 DOI: 10.3389/fmicb.2017.01833] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 09/06/2017] [Indexed: 12/13/2022] Open
Abstract
Hepatitis C virus (HCV) often leads to a chronic infection in the liver that may progress to steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Several viral and cellular factors are required for a productive infection and for the development of liver disease. Some of these are long non-coding RNAs (lncRNAs) deregulated in infected cells. After HCV infection, the sequence and the structure of the viral RNA genome are sensed to activate interferon (IFN) synthesis and signaling pathways. These antiviral pathways regulate transcription of several cellular lncRNAs. Some of these are also deregulated in response to viral replication. Certain viral proteins and/or viral replication can activate transcription factors such as MYC, SP1, NRF2, or HIF1α that modulate the expression of additional cellular lncRNAs. Interestingly, several lncRNAs deregulated in HCV-infected cells described so far play proviral or antiviral functions by acting as positive or negative regulators of the IFN system, while others help in the development of liver cirrhosis and HCC. The study of the structure and mechanism of action of these lncRNAs may aid in the development of novel strategies to treat infectious and immune pathologies and liver diseases such as cirrhosis and HCC.
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Affiliation(s)
| | - Puri Fortes
- Department of Gene Therapy and Hepatology, Navarra Institute for Health Research (IdiSNA), Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain
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19
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Zhang Q, Wang Y, Zhai N, Song H, Li H, Yang Y, Li T, Guo X, Chi B, Niu J, Crispe IN, Su L, Tu Z. HCV core protein inhibits polarization and activity of both M1 and M2 macrophages through the TLR2 signaling pathway. Sci Rep 2016; 6:36160. [PMID: 27786268 PMCID: PMC5082373 DOI: 10.1038/srep36160] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 10/11/2016] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) establishes persistent infection in most infected patients, and eventually causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma in some patients. Monocytes and macrophages provide the first line of defense against pathogens, but their roles in HCV infection remains unclear. We have reported that HCV core protein (HCVc) manipulates human blood-derived dendritic cell development. In the present study, we tested whether HCVc affects human blood-derived monocyte differentiating into macrophages. Results showed that HCVc inhibits monocyte differentiation to either M1 or M2 macrophages through TLR2, associated with impaired STATs signaling pathway. Moreover, HCVc inhibits phagocytosis activity of M1 and M2 macrophages, M1 macrophage-induced autologous and allogeneic CD4+ T cell activation, but promotes M2 macrophage-induced autologous and allogeneic CD4+ T cell activation. In conclusion, HCVc inhibits monocyte-derived macrophage polarization via TLR2 signaling, leading to dysfunctions of both M1 and M2 macrophages in chronic HCV infected patients. This may contribute to the mechanism of HCV persistent infection, and suggest that blockade of HCVc might be a novel therapeutic approach to treating HCV infection.
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Affiliation(s)
- Qianqian Zhang
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
- Department of Hepatobiliary and Pancreatic Diseases, the First Hospital of Jilin University, Changchun, China
- College of Clinical Medicine, Jining Medical University, Jining, China
| | - Yang Wang
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
| | - Naicui Zhai
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
| | - Hongxiao Song
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
| | - Haijun Li
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
| | - Yang Yang
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
| | - Tianyang Li
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
| | - Xiaolin Guo
- Department of Hepatobiliary and Pancreatic Diseases, the First Hospital of Jilin University, Changchun, China
| | - Baorong Chi
- Department of Hepatobiliary and Pancreatic Diseases, the First Hospital of Jilin University, Changchun, China
| | - Junqi Niu
- Department of Hepatobiliary and Pancreatic Diseases, the First Hospital of Jilin University, Changchun, China
| | - Ian Nicholas Crispe
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
- Department of Pathology, University of Washington, Seattle, WA, USA
| | - Lishan Su
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Zhengkun Tu
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
- Department of Hepatobiliary and Pancreatic Diseases, the First Hospital of Jilin University, Changchun, China
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