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Hepatitis B virus preCore/Core region variability in pregnant women in the Republic of Guinea. JOURNAL OF MICROBIOLOGY, EPIDEMIOLOGY AND IMMUNOBIOLOGY 2024; 101:61-71. [DOI: 10.36233/0372-9311-447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
Introduction. The vertical route of hepatitis B virus (HBV) transmission is a significant problem in African countries, which is characterized by late diagnosis of the disease and high mortality. The high prevalence of hepatocellular carcinoma (HCC) in Africa may be due to variability in the HBV preCore/Core region, mutations in which contribute to disease progression. Molecular genetic characterization of strains circulating among pregnant women may reflect the overall mutational profile of the pathogen in the population.
The objective of this study was to analyze the variability of the HBV preCore/Core region circulating among pregnant women in the Republic of Guinea.
Materials and methods. The study material included 480 plasma samples obtained from HBV-positive pregnant women from the Republic of Guinea. For all samples, the nucleotide sequences of the preCore/Core region of the HBV genome were sequenced and analyzed.
Results. Amino acid variability in the preCore region was determined in 211 (43.96%), and in the Core region in 473 (98.54%) patients. 12 polymorphic sites of the preCore region were identified in which amino acid substitutions occurred, including 8, 2 and 5 positions identified for genotypes E, A and D, respectively. In the Core region, 67 substitution positions were identified, including 46 in samples of genotype E, 23 in HBV genotype A and 26 in genotype D. It was shown that the distribution of substitutions in the preCore and Core regions in HBV genotypes E, A and D differs significantly with a predominance in mutations among HBV genotype E — p 0.0001. Individual characteristic mutations have been identified for each genotype. The most common clinically significant mutations in the preCore/Core region in the study group were identified, including pc-H5D (27,08%), pc-W28* (35,21%), c-E64D (33,54%), c-L116I/V/G (91,46 %), c-T146N (73,13%). The double mutation A1762T/G1764A in the basal core promoter was shown in 74 samples of HBV genotype E, which accounted for 15.42% of the total group and 16.59% of patients with HBV genotype E.
Conclusion. The frequency of clinically significant preCore/Core mutations among pregnant women in the Republic of Guinea was determined. The data obtained reflect their prevalence in the general population and can be used to predict the progression of chronic HBV among the region's population.
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Elizalde MM, Giadans CG, Campos RH, Flichman DM. Impact of core protein naturally selected mutants associated with HBeAg-negative status in HBV biosynthesis. J Med Virol 2023; 95:e29195. [PMID: 37881005 DOI: 10.1002/jmv.29195] [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: 07/12/2023] [Revised: 10/04/2023] [Accepted: 10/11/2023] [Indexed: 10/27/2023]
Abstract
Hepatitis B e antigen (HBeAg) loss represents a late stage of chronic hepatitis B virus (HBV) infection associated with a drastic decrease in HBV-DNA, a lower risk of disease progression, and the occurrence of several mutations in the preCore/core region. However, the underlying mechanisms supporting the downregulation of viral replication have yet to be elucidated. In the present study, the analysis of the frequency of subgenotype D1 core protein (HBc) mutations associated with HBeAg status revealed a higher mutation rate in HBeAg-negative sequences compared to HBeAg-positive ones. Particularly, 22 amino acids exhibited a higher frequency of mutation in HBeAg-negative sequences, while the remaining residues showed a high degree of conservation. Subsequently, the assessment of HBc mutants derived from HBeAg-negative patients in viral structure and replicative capacity revealed that HBc mutations have the ability to modulate the subcellular localization of the protein (either when the protein was expressed alone or in the context of viral replication), capsid assembly, and, depending on specific mutation patterns, alter covalently closed circular DNA (cccDNA) recycling and up- or downregulate viral replication. In conclusion, HBc mutations associated with HBeAg-negative status impact on various stages of the HBV life cycle modulating viral replication during the HBeAg-negative stage of infection.
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Affiliation(s)
- María Mercedes Elizalde
- Facultad de Medicina, Departamento de Microbiología, Parasitología e Inmunología, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Cecilia Graciela Giadans
- Facultad de Medicina, Departamento de Microbiología, Parasitología e Inmunología, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Rodolfo Héctor Campos
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Virología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Diego Martín Flichman
- Facultad de Medicina, Departamento de Microbiología, Parasitología e Inmunología, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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Zhao B, Qiao H, Zhao Y, Gao Z, Wang W, Cui Y, Li J, Guo Z, Chuai X, Chiu S. HBV precore G1896A mutation promotes growth of hepatocellular carcinoma cells by activating ERK/MAPK pathway. Virol Sin 2023; 38:680-689. [PMID: 37331658 PMCID: PMC10590694 DOI: 10.1016/j.virs.2023.06.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 06/14/2023] [Indexed: 06/20/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is one of the leading causes of hepatocellular carcinoma (HCC). The HBV genome is prone to mutate and several variants are closely related to the malignant transformation of liver disease. G1896A mutation (G to A mutation at nucleotide 1896) is one of the most frequently observed mutations in the precore region of HBV, which prevents HBeAg expression and is strongly associated with HCC. However, the mechanisms by which this mutation causes HCC are unclear. Here, we explored the function and molecular mechanisms of the G1896A mutation during HBV-associated HCC. G1896A mutation remarkably enhanced the HBV replication in vitro. Moreover, it increased tumor formation and inhibited apoptosis of hepatoma cells, and decreased the sensitivity of HCC to sorafenib. Mechanistically, the G1896A mutation could activate ERK/MAPK pathway to enhanced sorafenib resistance in HCC cells and augmented cell survival and growth. Collectively, our study demonstrates for the first time that the G1896A mutation has a dual regulatory role in exacerbating HCC severity and sheds some light on the treatment of G1896A mutation-associated HCC patients.
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Affiliation(s)
- Baoxin Zhao
- Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Hongxiu Qiao
- Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Yan Zhao
- Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Zhiyun Gao
- Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Weijie Wang
- Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Yan Cui
- Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Jian Li
- Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Zhanjun Guo
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
| | - Xia Chuai
- Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega Science, Chinese Academy of Sciences, Wuhan, 430207, China.
| | - Sandra Chiu
- Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
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Colón-Thillet R, Stone D, Loprieno MA, Klouser L, Roychoudhury P, Santo TK, Xie H, Stensland L, Upham SL, Pepper G, Huang ML, Aubert M, Jerome KR. Liver-Humanized NSG-PiZ Mice Support the Study of Chronic Hepatitis B Virus Infection and Antiviral Therapies. Microbiol Spectr 2023; 11:e0517622. [PMID: 37199630 PMCID: PMC10269919 DOI: 10.1128/spectrum.05176-22] [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: 02/14/2023] [Accepted: 04/27/2023] [Indexed: 05/19/2023] Open
Abstract
Hepatitis B virus (HBV) is a pathogen of major public health importance that is largely incurable once a chronic infection is established. Only humans and great apes are fully permissive to HBV infection, and this species restriction has impacted HBV research by limiting the utility of small animal models. To combat HBV species restrictions and enable more in vivo studies, liver-humanized mouse models have been developed that are permissive to HBV infection and replication. Unfortunately, these models can be difficult to establish and are expensive commercially, which has limited their academic use. As an alternative mouse model to study HBV, we evaluated liver-humanized NSG-PiZ mice and showed that they are fully permissive to HBV. HBV selectively replicates in human hepatocytes within chimeric livers, and HBV-positive (HBV+) mice secrete infectious virions and hepatitis B surface antigen (HBsAg) into blood while also harboring covalently closed circular DNA (cccDNA). HBV+ mice develop chronic infections lasting at least 169 days, which should enable the study of new curative therapies targeting chronic HBV, and respond to entecavir therapy. Furthermore, HBV+ human hepatocytes in NSG-PiZ mice can be transduced by AAV3b and AAV.LK03 vectors, which should enable the study of gene therapies that target HBV. In summary, our data demonstrate that liver-humanized NSG-PiZ mice can be used as a robust and cost-effective alternative to existing chronic hepatitis B (CHB) models and may enable more academic research labs to study HBV disease pathogenesis and antiviral therapy. IMPORTANCE Liver-humanized mouse models have become the gold standard for the in vivo study of hepatitis B virus (HBV), yet their complexity and cost have prohibited widespread use of existing models in research. Here, we show that the NSG-PiZ liver-humanized mouse model, which is relatively inexpensive and simple to establish, can support chronic HBV infection. Infected mice are fully permissive to hepatitis B, supporting both active replication and spread, and can be used to study novel antiviral therapies. This model is a viable and cost-effective alternative to other liver-humanized mouse models that are used to study HBV.
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Affiliation(s)
- Rossana Colón-Thillet
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Daniel Stone
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Michelle A. Loprieno
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Lindsay Klouser
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Pavitra Roychoudhury
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Tracy K. Santo
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Hong Xie
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Laurence Stensland
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Sarah L. Upham
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Gregory Pepper
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Meei-Li Huang
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Martine Aubert
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Keith R. Jerome
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
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Ostankova YV, Serikova EN, Semenov AV, Zueva EB, Valutite DE, Schemelev AN, Zurochka VA, Totolian AA. Molecular and genetic characterization of the hepatitis B virus full-length genome sequences identified in HBsAg-negative blood donors in Ural Federal District. JOURNAL OF MICROBIOLOGY, EPIDEMIOLOGY AND IMMUNOBIOLOGY 2023. [DOI: 10.36233/0372-9311-325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Introduction. The World Health Organization estimates that as of 2019, more than 296 million people were living with chronic hepatitis B virus (HBV) infection. The prevalence of HBsAg-negative, occult form of the disease in blood donors varies depending on the region of the world and the sensitivity of the methods of analysis used. Considering that the genetic diversity of viruses demonstrates space and time variations and taking into account that the genetic profile of isolates in key groups, which may turn into a source of the pathogen spread, is important for forecasting of the epidemiological situation, the attention should be given to identification of HBV genotypes currently circulating among regular blood donors in regions of the Russian Federation.
The aim of this work was molecular and genetic characterization of HBV genomes identified in HBsAg-negative blood donors in the Ural Federal District.
Materials and methods. The study material was 1400 plasma samples obtained from HBsAg-negative blood donors in Ural Federal District. The study included the testing for HBsAg, anti-HBs IgG and anti-HBcore IgG antibodies, HBV DNA. For all identified HBV DNA containing samples, sequencing and analysis of the nucleotide sequences of the complete HBV genomes were performed.
Results. The prevalence of HBV DNA was 4.93%, including 4 (0.28%) cases of false occult hepatitis B. Among anti-HBcore IgG-positive samples, HBV DNA was found in 18.08% of cases, while in persons with detected HBV DNA the anti-HBcore IgG positivity rate was 46.38%. In 8.69% of the isolates, anti-HBs IgG antibodies and viral DNA were detected simultaneously in the absence of anti-HBcore IgG. Based on phylogenetic analysis, HBV subgenotypes distribution in HBsAg-negative blood donors was as follows: D3 53.62%, D2 21.74%, D1 18.84%, C2 5.8%. The high variability in the S, C, P regions of the virus genome in the examined group was shown. In all cases of HBsAg-negative chronic HBV infection identified in blood donors, viral sequences contained at least one amino acid substitution in positions, mutations in which are associated with immune escape. In 3 (4.35%) cases mutations in reverse transcriptase region of P gene that are associated with resistance to the following drugs were identified: lamivudine, telbivudine, entecavir. Mutations in the preCore/Core regions that contribute to the progression of liver disease were also identified.
Conclusion. Occult HBsAg-negative chronic HBV infection poses a threat of HBV transmission through transfusion of blood and its components due to the extremely low viral load, which does not allow the virus to be detected using routinely used diagnostic kits. The situation can be exacerbated by the abundance and diversity of virus amino acid substitutions that we have identified, including immune escape mutations, drug resistance mutations, and mutations that contribute to the progression of the disease.
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Belaiba Z, Ayouni K, Gdoura M, Kammoun Rebai W, Touzi H, Sadraoui A, Hammemi W, Yacoubi L, Abdelati S, Hamzaoui L, Msaddak Azzouz M, Chouikha A, Triki H. Whole genome analysis of hepatitis B virus before and during long-term therapy in chronic infected patients: Molecular characterization, impact on treatment and liver disease progression. Front Microbiol 2022; 13:1020147. [PMID: 36325017 PMCID: PMC9618822 DOI: 10.3389/fmicb.2022.1020147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 09/15/2022] [Indexed: 07/23/2023] Open
Abstract
Hepatitis B virus (HBV) infection remains a serious public health concern worldwide despite the availability of an efficient vaccine and the major improvements in antiviral treatments. The aim of the present study is to analyze the mutational profile of the HBV whole genome in ETV non-responder chronic HBV patients, in order to investigate antiviral drug resistance, immune escape, and liver disease progression to Liver Cirrhosis (LC) or Hepatocellular Carcinoma (HCC). Blood samples were collected from five chronic hepatitis B patients. For each patient, two plasma samples were collected, before and during the treatment. Whole genome sequencing was performed using Sanger technology. Phylogenetic analysis comparing the studied sequences with reference ones was used for genotyping. The mutational profile was analyzed by comparison with the reference sequence M32138. Genotyping showed that the studied strains belong to subgenotypes D1, D7, and D8. The mutational analysis showed high genetic variability. In the RT region of the polymerase gene, 28 amino acid (aa) mutations were detected. The most significant mutations were the pattern rtL180M + rtS202G + rtM204V, which confer treatment resistance. In the S gene, 35 mutations were detected namely sP120T, sT126S, sG130R, sY134F, sS193L, sI195M, and sL216stop were previously described to lead to vaccine, immunotherapy, and/or diagnosis escape. In the C gene, 34 mutations were found. In particular, cG1764A, cC1766G/T, cT1768A, and cC1773T in the BCP; cG1896A and cG1899A in the precore region and cT12S, cE64D, cA80T, and cP130Q in the core region were associated with disease progression to LC and/or HCC. Other mutations were associated with viral replication increase including cT1753V, cG1764A/T, cC1766G/T, cT1768A, and cC1788G in the BCP as well as cG1896A and cG1899A in the precore region. In the X gene, 30 aa substitutions were detected, of which substitutions xT36D, xP46S, xA47T, xI88F, xA102V, xI127T, xK130M, xV131I, and xF132Y were previously described to lead to LC and/or HCC disease progression. In conclusion, our results show high genetic variability in the long-term treatment of chronic HBV patients causing several effects. This could contribute to guiding national efforts to optimize relevant HBV treatment management in order to achieve the global hepatitis elimination goal by 2030.
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Affiliation(s)
- Zeineb Belaiba
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Kaouther Ayouni
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Mariem Gdoura
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Wafa Kammoun Rebai
- Laboratory of Biomedical Genomics and Oncogenetics (LR16IPT05), Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Henda Touzi
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Amel Sadraoui
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Walid Hammemi
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Lamia Yacoubi
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Salwa Abdelati
- Department of Gastroenterology, Polyclinic of CNSS, Sousse, Tunisia
| | - Lamine Hamzaoui
- Department of Gastroenterology, Hospital of Tahar Maamouri, Nabeul, Tunisia
| | | | - Anissa Chouikha
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Henda Triki
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
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Roca TP, Villar LM, Nogueira Lima FS, Vasconcelos MPA, Borzacov LMP, Silva EDCE, do Lago BV, da Silva MTL, Botelho Souza LF, Salcedo JMV, dos Santos ADO, Vieira DS. Genomic Variability of Hepatitis B Virus Circulating in Brazilian Western Amazon. Viruses 2022; 14:v14102100. [PMID: 36298655 PMCID: PMC9611064 DOI: 10.3390/v14102100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 12/02/2022] Open
Abstract
The emergence of clinically relevant mutations in the hepatitis B virus (HBV) genome has been a matter of great debate because of the possibility of escape from the host’s immune system, the potential to cause more severe progression of liver diseases and the emergence of treatment-resistant variants. Here we characterized the circulating variants of HBV in Rondônia State, in the north of Brazil. Serum samples of 62 chronic HBV carriers were subjected to PCR assays and clinical data were collected. Mutations and genotypes were characterized through direct sequencing. The findings show the presence of subgenotypes A1 (54.83%, 34/62), D3 (16.13%, 10/62), F2 (16.13%, 10/62), A2 (4.84%, 3/62), D2 (3.23%, 2/62), D1 (1.61%, 1/62), D4 (1.61%, 1/62) and F4 (1.61%, 1/62). Deletions in the pre-S2 region were found in 13.79% (8/58) of the samples, mutations in the S gene in 59.68% (37/62) and RT mutations in 48.39% (30/62). We found a variable genotypic distribution in different locations and important mutations related to immune escape and drug resistance in Western Amazonia, which contributed to genetic surveillance and provided important information to help control the disease.
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Affiliation(s)
- Tárcio Peixoto Roca
- Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-900, Brazil
- Laboratory of Molecular Virology, Oswaldo Cruz Foundation of Rondônia—FIOCRUZ/RO, Porto Velho 76812-245, Brazil
- Correspondence: (T.P.R.); (L.M.V.)
| | - Livia Melo Villar
- Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-900, Brazil
- Correspondence: (T.P.R.); (L.M.V.)
| | - Felipe Souza Nogueira Lima
- Laboratory of Molecular Virology, Oswaldo Cruz Foundation of Rondônia—FIOCRUZ/RO, Porto Velho 76812-245, Brazil
| | | | | | | | - Bárbara Vieira do Lago
- Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-900, Brazil
| | - Mayara Torquato Lima da Silva
- Laboratory of Biotechnology and Structural Bioengineering, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | | | - Juan Miguel Villalobos Salcedo
- Laboratory of Molecular Virology, Oswaldo Cruz Foundation of Rondônia—FIOCRUZ/RO, Porto Velho 76812-245, Brazil
- Tropical Medicine Research Center of Rondônia—CEPEM/RO, Porto Velho 76812-329, Brazil
| | | | - Deusilene Souza Vieira
- Laboratory of Molecular Virology, Oswaldo Cruz Foundation of Rondônia—FIOCRUZ/RO, Porto Velho 76812-245, Brazil
- Tropical Medicine Research Center of Rondônia—CEPEM/RO, Porto Velho 76812-329, Brazil
- Postgraduate Program in Experimental Biology, Federal University of Rondônia—PGBIOEXP/UNIR, Porto Velho 76801-059, Brazil
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Precore/core mutations of hepatitis B virus genotype D arising in different states of infection. Clin Exp Hepatol 2022; 8:21-28. [PMID: 35415256 PMCID: PMC8984791 DOI: 10.5114/ceh.2022.114253] [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: 12/23/2021] [Accepted: 01/19/2022] [Indexed: 11/17/2022] Open
Abstract
Aim of the study Precore/core variations and liver disease progression have been suggested. In this study, we aimed to determine the frequency of precore/core mutations in hepatitis B virus (HBV)-infected patients at various clinical stages. Material and methods In total, 73 HBV-infected patients including 26 inactive carriers (IC), 20 chronic active (CA), and 27 patients with liver cirrhosis/hepatocellular carcinoma (C/HCC) were randomly selected. The HBV DNA was extracted from the sera and subjected to nested PCR for amplification of precore/core region. The PCR product was then sequenced by the Sanger method. Results The stop codon of W28*(G1896A) was determined as the most prevalent mutation (55%) of the precore region. The comparison of groups also demonstrated that core substitutions at residues of S21, E40 and I105 (< 0.05) correlated with the development of the inactive carrier state. Furthermore, the total substitutions in Th epitopes (117-131) were significantly higher in the C/HCC group than the IC and CA groups (p = 0.001). Conclusions Our results indicated a high frequency of W28* mutation in HBV studied patients. Moreover, variations including S21, E40 and I105 and R151 that were mapped onto cellular epitopes might be related to inactive state development.
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Chen CY, Hajinicolaou C, Walabh P, Ingasia LAO, Song E, Kramvis A. Molecular characterization of hepatitis B virus (HBV) isolated from a pediatric case of acute lymphoid leukemia, with a delayed response to antiviral treatment: a case report. BMC Pediatr 2022; 22:168. [PMID: 35361141 PMCID: PMC8969373 DOI: 10.1186/s12887-022-03204-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 03/09/2022] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Tenofovir disoproxil fumarate (TDF) is effectively used as the first-line antiviral for chronic hepatitis B virus (HBV) infection in adults and children older than 12 years. To date, no confirmed case of virologic breakthrough (VBT) in a pediatric case has been reported. CASE PRESENTATION Here we describe a case of a 5-year old, asymptomatically infected with HBV infection two months after chemotherapy for precursor B acute lymphoblastic leukemia (ALL). Although the 5-year old male is South African, his family originated from Guinea. At the end of the one-year follow-up, the infection progressed to chronic HBV infection, with a high viral load. At 36 weeks (8 months) post-treatment with lamivudine (LAM), there was a partial virologic response (PVR) and after 61 weeks (14 months), he was switched to TDF rescue monotherapy. Even with TDF treatment, he still experienced VBT and subsequent PVR. The full-length genome of HBV isolated 78 weeks after the switch to rescue TDF monotherapy was sequenced and belonged to genotype E. In addition to the LAM mutations (rtS256G and rtM267L), missense mutations in B-cell, T-cell, HLA class I and II-restricted epitopes emerged, which were to evade and escape host surveillance, leading to delayed viral clearance, persistence and disease progression. Two further events of VBT occurred between weeks 113 and 141 of TDF rescue-therapy. Viral loads and liver enzymes are normalizing progressively with long-term therapy. CONCLUSION Although the host immune reconstitution may be delayed, prolonged TDF treatment was effective in treating this pediatric case of HBV infection with VBT and PVR.
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Affiliation(s)
- Chien-Yu Chen
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
| | - Christina Hajinicolaou
- Department of Paediatrics, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.,Paediatric Gastroenterology, Hepatology and Nutrition Unit, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.,Paediatric Gastroentrology, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Priya Walabh
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa
| | - Luicer Anne Olubayo Ingasia
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
| | - Ernest Song
- Department of Internal Medicine, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.
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10
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Li H, Qian F, Zou W, Jin F, Li D, Zhang Y. OUP accepted manuscript. Trans R Soc Trop Med Hyg 2022; 116:874-880. [PMID: 35543271 DOI: 10.1093/trstmh/trac040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 02/17/2022] [Accepted: 04/16/2022] [Indexed: 11/14/2022] Open
Affiliation(s)
- Haiyan Li
- Department of Laboratory Medicine, Huzhou Maternity and Child Health Care Hospital, 2 East Street, Huzhou, Zhejiang Province, China
| | - Fuchu Qian
- Department of Precision Medicine, Affiliated Central Hospital Huzhou University, Huzhou Central Hospital, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China
- Huzhou Key Laboratory of Molecular Medicine, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China
| | - Weihua Zou
- Department of Laboratory Medicine, Affiliated Central Hospital Huzhou University, Huzhou Central Hospital, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China
| | - Fang Jin
- Department of Precision Medicine, Affiliated Central Hospital Huzhou University, Huzhou Central Hospital, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China
- Huzhou Key Laboratory of Molecular Medicine, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China
| | - Dongli Li
- Department of Precision Medicine, Affiliated Central Hospital Huzhou University, Huzhou Central Hospital, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China
- Huzhou Key Laboratory of Molecular Medicine, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China
| | - Yaqin Zhang
- Department of Laboratory Medicine, Huzhou Maternity and Child Health Care Hospital, 2 East Street, Huzhou, Zhejiang Province, China
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11
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Sun H, Shi C, Ye Z, Yao B, Li C, Wang X, Qian Q. The role of mesenchymal stem cells in liver injury. Cell Biol Int 2021; 46:501-511. [PMID: 34882906 PMCID: PMC9303694 DOI: 10.1002/cbin.11725] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/07/2021] [Accepted: 07/03/2021] [Indexed: 11/10/2022]
Abstract
Recently, mesenchymal stem cell (MSC) therapy has been suggested as an effective alternate approach for the treatment of hepatic diseases. MSCs have potential therapeutic value, because these have high self-renewal ability, are capable of multipotent differentiation, and have low immunogenicity. Furthermore, MSCs have the potential to differentiate into hepatocytes, and the therapeutic value exists in their immune-modulatory properties and secretion of trophic factors, such as growth factors and cytokines. Moreover, MSCs can suppress inflammatory responses, reduce hepatocyte apoptosis, increase hepatocyte regeneration, regress liver fibrosis, and enhance liver functionality. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Haoyu Sun
- Shanghai Cell Therapy Group, Shanghai, China
| | | | - Zhenlong Ye
- Shanghai Cell Therapy Group, Shanghai, China
| | - Bi Yao
- Shanghai Cell Therapy Group, Shanghai, China
| | - Chen Li
- Shanghai Cell Therapy Group, Shanghai, China
| | | | - Qijun Qian
- Shanghai Cell Therapy Group, Shanghai, China
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12
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Chen J, Liu B, Tang X, Zheng X, Lu J, Zhang L, Wang W, Candotti D, Fu Y, Allain JP, Li C, Li L, Li T. Role of core protein mutations in the development of occult HBV infection. J Hepatol 2021; 74:1303-1314. [PMID: 33453326 DOI: 10.1016/j.jhep.2020.12.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 11/04/2020] [Accepted: 12/14/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND & AIMS Occult HBV infection (OBI) is associated with transfusion-transmitted HBV infection and hepatocellular carcinoma. Studies on OBI genesis have concentrated on mutations in the S region and the regulatory elements. Herein, we aimed to determine the role of mutations in the core region on OBIs. METHODS An OBI strain (SZA) carrying 9 amino acid (aa) substitutions in the core protein/capsid (Cp) was selected by sequence alignment and Western blot analysis from 26 genotype B OBI samples to extensively explore the impact of Cp mutations on viral antigen production in vitro and in vivo. RESULTS A large panel of 30 Cp replicons were generated by a replication-competent pHBV1.3 carrying SZA or wild-type (WT) Cp in a 1.3-fold over-length of HBV genome, in which the various Cp mutants were individually introduced by repairing site mutations of SZA-Cp or creating site mutations of WT-Cp by site-directed mutagenesis. The expression of HBcAg, HBeAg, and HBsAg and viral RNA was quantified from individual SZA and WT Cp mutant replicons in transfected Huh7 cells or infected mice, respectively. An analysis of the effect of Cp mutants on intracellular or extracellular viral protein production indicated that the W62R mutation in Cp had a critical impact on the reduction of HBcAg and HBeAg production during HBV replication, whereas P50H and/or S74G mutations played a limited role in influencing viral protein production invivo. CONCLUSIONS W62R and its combination mutations in HBV Cp might massively affect HBcAg and HBeAg production during viral replication, which, in turn, might contribute to the occurrence of OBI. LAY SUMMARY Occult hepatitis B virus infections (OBIs) have been found to be associated with amino acid mutations in the S region of the HBV, but the role of mutations in the core protein (Cp) remains unclear. In this study, an OBI strain (SZA) carrying 9 amino acid substitutions in Cp has been examined comprehensively in vitro and in vivo. The W62R mutation in Cp majorly reduces HBcAg and HBeAg production during HBV replication, potentially contributing to the occurrence of OBI.
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Affiliation(s)
- Jingna Chen
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China; Department of Laboratory Medicine, General Hospital of Southern Theatre Command of PLA, Guangzhou, China; Department of Clinical Laboratory, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Bochao Liu
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Xi Tang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China; Department of Infectious Diseases, The First Foshan People's Hospital, Foshan, China
| | - Xin Zheng
- Shenzhen Blood Center, Shenzhen, China
| | - Jinhui Lu
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Ling Zhang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Wenjing Wang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Daniel Candotti
- Department of Blood Transmitted Agents, National Institute of Blood Transfusion, Paris, France
| | - Yongshui Fu
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China; Guangzhou Blood Center, Guangzhou, China
| | - Jean-Pierre Allain
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China; Department of Haematology, University of Cambridge, Cambridge, UK
| | - Chengyao Li
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
| | - Linhai Li
- Department of Laboratory Medicine, General Hospital of Southern Theatre Command of PLA, Guangzhou, China.
| | - Tingting Li
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
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Shivlata L, Pacholi S, Chouksey VK, Barde PV. Molecular characterization of hepatitis B virus reveals circulation of multiple subgenotypes of genotype D with clinically important mutations in central India. Indian J Med Microbiol 2021; 39:67-72. [PMID: 33515632 DOI: 10.1016/j.ijmmb.2021.01.002] [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: 06/28/2020] [Accepted: 12/14/2020] [Indexed: 11/19/2022]
Abstract
PURPOSE Hepatitis B virus (HBV) is one of the leading causes of morbidity and mortality across the globe. The pathogenesis, clinical outcomes, disease progression and response to antiviral treatment of HBV depend on infecting genotypes and mutations across HBV genome. There is a lack of such information from central India. The present study was planned to identify genotype/subgenotype and epidemiologically important mutation in HBV circulating in the area. METHODS Samples positive for HBsAg by ELISA from 2012 to 2016 were included and analysed in this retrospective study. The amplification of partial S gene (n = 25) and full genome (n = 10) was carried out to determine the genotype/subgenotype and genome wide mutations of HBV. The sequencing data was analysed using bioinformatics tools. RESULTS All 25 sequences belonged to genotype D; subgenotypes D1, D2, D3 and D5 with dominance of D1 were detected in the study subjects. Mutational profiling revealed the presence of nucleotide substitutions in promoter/regulatory/precore region associated with liver disease progressions. The amino acid (aa) changes associated with vaccine escape, immune escape, antiviral resistance and progression to liver cirrhosis (LC) or hepatocellular carcinoma (HCC) were detected. CONCLUSIONS This maiden molecular study on HBV from central India indicates that the genotype D with subgenotypes D1, D2, D3 and D5 harbouring mutations of clinical and epidemiological importance are in circulation. This study will serve as a baseline for future. Studies with larger sample size may aid in identifying the circulation of more genotypes.
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Affiliation(s)
- L Shivlata
- Division of Virology and Zoonoses, ICMR-National Institute of Research in Tribal Health, Nagpur Road, Jabalpur, MP, India.
| | - Sanchita Pacholi
- Division of Virology and Zoonoses, ICMR-National Institute of Research in Tribal Health, Nagpur Road, Jabalpur, MP, India.
| | - Vivek Kumar Chouksey
- Division of Virology and Zoonoses, ICMR-National Institute of Research in Tribal Health, Nagpur Road, Jabalpur, MP, India.
| | - Pradip V Barde
- Division of Virology and Zoonoses, ICMR-National Institute of Research in Tribal Health, Nagpur Road, Jabalpur, MP, India.
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14
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Mbamalu C, Ekejindu I, Enweani I, Kalu S, Igwe D, Akaeze G. Hepatitis B virus precore/core region mutations and genotypes among hepatitis B virus chronic carriers in South-Eastern, Nigeria. Int J Health Sci (Qassim) 2021; 15:26-38. [PMID: 33708042 PMCID: PMC7934135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
Abstract
OBJECTIVES The study aimed at detecting the prevailing hepatitis B virus (HBV) genotypes and the presence of clinically relevant mutations in the precore/core gene of the HBV DNA, among patients with chronic infection in South-eastern, Nigeria. METHODS A total of 72 participants with chronic HBV infection were enrolled into the study. Plasma samples from those with detectable HBV DNA were subjected to nested Polymerase Chain Reaction amplification using the precore/core specific primers. This resulted to the successful amplification and sequencing of the HBV precore/core region DNA from 16 participants. Mutation analysis on the precore/core region detected the presence of certain HBV precore/core gene mutations. Genotyping was carried out by phylogenetic analysis. RESULTS The precore region mutation at nucleotide position 1896, which is a G to A change resulting to a nonsense mutation, was detected in 6.25% of the participants. Other HBV precore region mutations that were detected include: G1899A, T1846A, G1862C, G1888A, T1821C, C1826T, A1827C, A1850T, C1858T, precore start codon Kozak sequence mutations and some novel core region mutations such as G/A1951T and G1957A. Genotyping revealed the existence of HBV genotype/subgenotype A1 (87.5%) and D (12.5%) among the participants. There was no significant difference in the occurrence of specific precore/core mutations among the HBV/hepatitis C virus dually infected and HBV mono-infected participants. CONCLUSION The data suggest the likelihood of a more severe outcome of hepatitis caused by HBV in South-eastern Nigeria due to the occurrence of a variety of precore/core mutation, which resulted to HBeAg-negative chronic HBV infection among the participants.
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Affiliation(s)
- Chinenye Mbamalu
- Medical Laboratory Services, Alex Ekwueme Federal University Teaching Hospital, Abakaliki, Ebonyi State, Nigeria,Address for correspondence: Chinenye Mbamalu, Medical Laboratory Services, Alex Ekwueme Federal University Teaching Hospital, Abakaliki, Ebonyi State, Nigeria. Telephone: +2348068993161. E-mail:
| | - Ifeoma Ekejindu
- Department of Medical Laboratory Science, Faculty of Health Sciences and Technology, Nnamdi Azikiwe University, Nnewi Campus, Anambra State, Nigeria
| | - Ifeoma Enweani
- Department of Medical Laboratory Science, Faculty of Health Sciences and Technology, Nnamdi Azikiwe University, Nnewi Campus, Anambra State, Nigeria
| | - Stephen Kalu
- Department of HIV Care, PCR Laboratory Unit, Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria
| | - David Igwe
- Department of Biotechnology, Ebonyi State University, Abakaliki, Ebonyi State, Nigeria,Department of Plant Pathology and Plant-Microbe Biology/Boyce Thompson Institute for Plant Research, Cornell University, Ithaca, New York, USA
| | - Gloria Akaeze
- Department of HIV Care, PCR Laboratory Unit, Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria
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Guvenir M, Arikan A. Hepatitis B Virus: From Diagnosis to Treatment. Pol J Microbiol 2020; 69:391-399. [PMID: 33574867 PMCID: PMC7812357 DOI: 10.33073/pjm-2020-044] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/22/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B infection is still a global concern progressing as acute-chronic hepatitis, severe liver failure, and death. The infection is most widely transmitted from the infected mother to a child, with infected blood and body fluids. Pregnant women, adolescents, and all adults at high risk of chronic infection are recommended to be screened for hepatitis B infection. The initial analysis includes serological tests that allow differentiation of acute and chronic hepatitis. Molecular assays performed provide detection and quantification of viral DNA, genotyping, drug resistance, and precore/core mutation analysis to confirm infection and monitor disease progression in chronic hepatitis B patients. All patients with chronic hepatitis B should be treated with antiviral medications and regularly monitored for efficient treatment. The current treatment is based on nucleos(t)ide analogs and pegylated interferons that save lives by decreasing liver cancer death, liver transplant, slow or reverse the progression of liver disease as well as the virus infectivity.
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Affiliation(s)
- Meryem Guvenir
- Near East University, Vocational School of Health Services, Nicosia, Northern Cyprus
| | - Ayse Arikan
- Near East University, Faculty of Medicine, Department of Medical Microbiology, Nicosia, Northern Cyprus
- Near East University, DESAM Institute, Nicosia, Northern Cyprus
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16
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Gu S, Lv L, Lin X, Li X, Dai J, Zhang J, Kong R, Xie W, Li J. Using structural analysis to explore the role of hepatitis B virus mutations in immune escape from liver cancer in Chinese, European and American populations. J Biomol Struct Dyn 2020; 40:1586-1596. [PMID: 33030111 DOI: 10.1080/07391102.2020.1830852] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Hepatitis B virus (HBV) infection is an important problem threatening human health. After HBV virus invades human body, it may assemble a complete virus particle in the cytoplasm to trigger the immune reaction, especially the interaction between the HBV virus and the host that mediated by CD8+ T cell. We collected the sequences of HBV from the HBVdb database, then screened candidate mutation sites in Chinese, European and American populations based on conservation and physicochemical properties. After that we constructed the three-dimensional structure of Major histocompatibility complex class I (MHC I) -peptide complexes, performed molecular docking, run molecular dynamics to compare the binding free energy, stability, and affinity of MHC I-peptide complexes with the aim to estimate the effect of peptide mutation. The specific HBV virus subtypes of the Chinese, European and American population were studied and the candidate mutation sites were used to predict the mutant peptide antigen. Finally, based on physical and chemical properties and peptide antigen prediction scores, 21 HBV mutation sites were selected. Then combined with specific Human lymphocyte antigen (HLA) subtypes, 11 mutations were found to have a significant negative impact on affinity, stability and binding free energy. Overall, our work found important potential mutations, which provide an evaluation of HBV mutations and a clue of it in immunotherapy.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Shuanglin Gu
- Key Laboratory of DGHD, MOE, Institute of Life Sciences, Southeast University, Nanjing, China
| | - Li Lv
- Key Laboratory of DGHD, MOE, Institute of Life Sciences, Southeast University, Nanjing, China
| | - Xue Lin
- Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China
| | - Xingyu Li
- Key Laboratory of DGHD, MOE, Institute of Life Sciences, Southeast University, Nanjing, China
| | - Juncheng Dai
- Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China
| | - Jianqiong Zhang
- Key Laboratory of DGHD, MOE, Institute of Life Sciences, Southeast University, Nanjing, China
| | - Ren Kong
- Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China
| | - Wei Xie
- Key Laboratory of DGHD, MOE, Institute of Life Sciences, Southeast University, Nanjing, China
| | - Jian Li
- Key Laboratory of DGHD, MOE, Institute of Life Sciences, Southeast University, Nanjing, China
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17
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Yll M, Cortese MF, Guerrero-Murillo M, Orriols G, Gregori J, Casillas R, González C, Sopena S, Godoy C, Vila M, Tabernero D, Quer J, Rando A, Lopez-Martinez R, Esteban R, Riveiro-Barciela M, Buti M, Rodríguez-Frías F. Conservation and variability of hepatitis B core at different chronic hepatitis stages. World J Gastroenterol 2020; 26:2584-2598. [PMID: 32523313 PMCID: PMC7265140 DOI: 10.3748/wjg.v26.i20.2584] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/08/2020] [Accepted: 05/18/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Since it is currently not possible to eradicate hepatitis B virus (HBV) infection with existing treatments, research continues to uncover new therapeutic strategies. HBV core protein, encoded by the HBV core gene (HBC), intervenes in both structural and functional processes, and is a key protein in the HBV life cycle. For this reason, both the protein and the gene could be valuable targets for new therapeutic and diagnostic strategies. Moreover, alterations in the protein sequence could serve as potential markers of disease progression.
AIM To detect, by next-generation sequencing, HBC hyper-conserved regions that could potentially be prognostic factors and targets for new therapies.
METHODS Thirty-eight of 45 patients with chronic HBV initially selected were included and grouped according to liver disease stage [chronic hepatitis B infection without liver damage (CHB, n = 16), liver cirrhosis (LC, n = 5), and hepatocellular carcinoma (HCC, n = 17)]. HBV DNA was extracted from patients’ plasma. A region between nucleotide (nt) 1863 and 2483, which includes HBC, was amplified and analyzed by next-generation sequencing (Illumina MiSeq platform). Sequences were genotyped by distance-based discriminant analysis. General and intergroup nt and amino acid (aa) conservation was determined by sliding window analysis. The presence of nt insertion and deletions and/or aa substitutions in the different groups was determined by aligning the sequences with genotype-specific consensus sequences.
RESULTS Three nt (nt 1900-1929, 2249-2284, 2364-2398) and 2 aa (aa 117-120, 159-167) hyper-conserved regions were shared by all the clinical groups. All groups showed a similar pattern of conservation, except for five nt regions (nt 1946-1992, 2060-2095, 2145-2175, 2230-2250, 2270-2293) and one aa region (aa 140-160), where CHB and LC, respectively, were less conserved (P < 0.05). Some group-specific conserved regions were also observed at both nt (2306-2334 in CHB and 1935-1976 and 2402-2435 in LC) and aa (between aa 98-103 in CHB and 28-30 and 51-54 in LC) levels. No differences in insertion and deletions frequencies were observed. An aa substitution (P79Q) was observed in the HCC group with a median (interquartile range) frequency of 15.82 (0-78.88) vs 0 (0-0) in the other groups (P < 0.05 vs CHB group).
CONCLUSION The differentially conserved HBC and HBV core protein regions and the P79Q substitution could be involved in disease progression. The hyper-conserved regions detected could be targets for future therapeutic and diagnostic strategies.
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MESH Headings
- Adult
- Aged
- Base Sequence/genetics
- Biomarkers
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Conserved Sequence/genetics
- DNA, Viral/blood
- DNA, Viral/genetics
- DNA, Viral/isolation & purification
- Disease Progression
- Female
- Genes, Viral/genetics
- Hepatitis B virus/genetics
- Hepatitis B virus/isolation & purification
- Hepatitis B, Chronic/blood
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/therapy
- Hepatitis B, Chronic/virology
- Humans
- Liver Cirrhosis/blood
- Liver Cirrhosis/pathology
- Liver Cirrhosis/virology
- Liver Neoplasms/blood
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Male
- Middle Aged
- Prognosis
- Sequence Analysis, DNA
- Viral Core Proteins/genetics
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Affiliation(s)
- Marçal Yll
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Maria Francesca Cortese
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Mercedes Guerrero-Murillo
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Department of Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Gerard Orriols
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Josep Gregori
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Rosario Casillas
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Carolina González
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Sara Sopena
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Cristina Godoy
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Marta Vila
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - David Tabernero
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Josep Quer
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Ariadna Rando
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Rosa Lopez-Martinez
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Rafael Esteban
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autónoma de Barcelona, Barcelona 08035, Spain
| | - Mar Riveiro-Barciela
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autónoma de Barcelona, Barcelona 08035, Spain
| | - Maria Buti
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autónoma de Barcelona, Barcelona 08035, Spain
| | - Francisco Rodríguez-Frías
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
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Wang W, Tian SL, Wang H, Shao CC, Wang YZ, Li YL. Association of Hepatitis B Virus DNA Level and Follow-up Interval With Hepatocellular Carcinoma Recurrence. JAMA Netw Open 2020; 3:e203707. [PMID: 32338753 PMCID: PMC7186860 DOI: 10.1001/jamanetworkopen.2020.3707] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
IMPORTANCE Antiviral treatment is important in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) comprehensive therapy. A high HBV DNA level is an independent risk factor for HBV-related HCC, but no quantifiable clinical index is available to date. OBJECTIVE To evaluate the feasibility and availability of the novel HBV DNA quantitation-time index (HDQTI), which includes HBV DNA quantitation and follow-up, to predict HBV-related HCC prognosis. DESIGN, SETTING, AND PARTICIPANTS This retrospective prognostic study of patients with HCC from multiple centers in China was performed from January 1, 2002, to December 31, 2016. The median follow-up time was 18 months, and the longest follow-up time was 147 months. Data analysis was performed from January 1, 2017, to December 31, 2018. MAIN OUTCOMES AND MEASURES Clinical characteristics, antitumor management, antiviral treatment, HDQTI scores, follow-up information, and overall survival were recorded and analyzed. A receiver operating characteristic curve and accompanying area under the curve were calculated for HDQTI. RESULTS A total of 842 patients (mean [SD] age, 61.80 [9.85] years; 513 [60.9%] male) were included in the study. Of all included patients, 734 received no antiviral therapy before diagnosis (no previous diagnosis of HBV infection), 43 underwent nonstandard antiviral therapy, and 65 received regular antiviral therapy. Compared with the group without antiviral treatment, the Barcelona Clinic Liver Cancer (BCLC) stage was earlier (A:B:C, 73.8%:26.2%:0% to 5.7%:65.5%:28.8%, P < .001), the mean (SD) tumor size was smaller (2.89 [1.26] to 7.56 [3.28] cm, P < .001), the ratio of baseline HBV DNA level of more than 105 copies/mL was lower (10.8% to 40.6%, P < .001), and the ratio of the α1-fetoprotein level more than 400 ng/mL was less (21.5% to 78.2%, P < .001) in the standard antiviral treatment group, whereas the nonstandard treatment group was between the 2 groups. Recurrence occurred in 39 of 109 BCLC stage A cases. Patients with HDQTI scores higher than 34 had high risk of recurrence; at this cutoff level, the sensitivity of the HDQTI was 76.9% and the specificity was 92.9%, with an area under curve of 0.928. Patients in various BCLC stages had similar trends in overall survival and HDQTI scores (BCLC stage A: HDQTI score <34, not applicable; HDQTI score ≥34, 44.0 months; 95% CI, 38.3-49.7 months; BCLC stage B: HDQTI score <34, 35.0 months; 95% CI, 33.3-36.7 months; HDQTI score ≥34, 17.0 months; 95% CI, 14.5-19.5 months; P = .002; BCLC stage C: HDQTI score <34, 18.0 months; 95% CI, 16.5-19.6 months; HDQTI scores ≥34, 10.0 months; 95% CI, 8.5-11.5 months; P = .005). CONCLUSIONS AND RELEVANCE The findings suggest that the HDQTI can be used as an independent prognostic indicator of recurrence in HBV-related HCC. Shorter follow-up intervals and accurate imaging evaluation are recommended in patients with HDQTI scores of 34 or higher.
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Affiliation(s)
- Wei Wang
- Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan, China
- Interventional Research Institute of Shandong University, Jinan, China
| | - Shilin-L. Tian
- Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan, China
- Interventional Research Institute of Shandong University, Jinan, China
| | - Hui Wang
- Interventional Research Institute of Shandong University, Jinan, China
- Department of Interventional Medicine, Jilin Cancer hospital, Changchun, China
| | - Chun-Chun Shao
- Interventional Research Institute of Shandong University, Jinan, China
- Center of Evidence-based Medicine, Institute of Medical Sciences, The Second Hospital of Shandong University, Jian, China
| | - Yong-Zheng Wang
- Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan, China
- Interventional Research Institute of Shandong University, Jinan, China
| | - Yu-Liang Li
- Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan, China
- Interventional Research Institute of Shandong University, Jinan, China
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19
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Characterization of Hepatitis B Virus and Human Immunodeficiency Virus among HIV/HBV Co-Infected Patients from the Republic of Guinea. ACTA ACUST UNITED AC 2019. [DOI: 10.21055/0370-1069-2019-3-118-124] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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20
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Al-Sadeq DW, Taleb SA, Zaied RE, Fahad SM, Smatti MK, Rizeq BR, Al Thani AA, Yassine HM, Nasrallah GK. Hepatitis B Virus Molecular Epidemiology, Host-Virus Interaction, Coinfection, and Laboratory Diagnosis in the MENA Region: An Update. Pathogens 2019; 8:63. [PMID: 31083509 PMCID: PMC6630671 DOI: 10.3390/pathogens8020063] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 04/18/2019] [Accepted: 05/08/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) is an enveloped partial double-stranded DNA virus that can cause acute and chronic hepatitis. According to the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC), 257 million people are living with HBV. Moreover, 20,900 acute hepatitis B cases were reported in 2016. Hepatitis B is highly prevalent in the African, Western Pacific, Eastern Mediterranean, South-East Asia, and European regions, respectively. Due to the high mutational rate of HBV and lack of reverse transcriptase proofreading activity, ten different genotypes with different geographical distributions have been identified. HBV pathogenesis and severity of infection depend on several host and viral factors, particularly, the genetic variability of both the host and virus. Although HBV infection is a global health concern, there is a lack of adequate studies and reports in the Middle East and North Africa (MENA) region. Here, we provide a review on HBV epidemiology, pathogenesis, host-pathogen interactions, coinfection with selected viruses, and laboratory diagnosis, focusing on studies conducted in the MENA region to determine the current situation of the HBV infection and outline the future study areas.
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Affiliation(s)
- Duaa W Al-Sadeq
- Biomedical Research Center, Qatar University, Doha 2713, Qatar.
- Biomedical Science Department, College of Health Sciences, Qatar University, Doha 2713, Qatar.
| | - Sara A Taleb
- Biomedical Science Department, College of Health Sciences, Qatar University, Doha 2713, Qatar.
| | - Roan E Zaied
- Biomedical Science Department, College of Health Sciences, Qatar University, Doha 2713, Qatar.
| | - Sara M Fahad
- Biomedical Research Center, Qatar University, Doha 2713, Qatar.
| | - Maria K Smatti
- Biomedical Research Center, Qatar University, Doha 2713, Qatar.
| | - Balsam R Rizeq
- Biomedical Research Center, Qatar University, Doha 2713, Qatar.
- Department of Biological and Environmental Sciences, College of Arts & Sciences, Qatar University, Doha 2713, Qatar.
| | - Asmaa A Al Thani
- Biomedical Research Center, Qatar University, Doha 2713, Qatar.
- Biomedical Science Department, College of Health Sciences, Qatar University, Doha 2713, Qatar.
| | - Hadi M Yassine
- Biomedical Research Center, Qatar University, Doha 2713, Qatar.
| | - Gheyath K Nasrallah
- Biomedical Research Center, Qatar University, Doha 2713, Qatar.
- Biomedical Science Department, College of Health Sciences, Qatar University, Doha 2713, Qatar.
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21
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Yang F, Wu L, Xu W, Liu Y, Zhen L, Ning G, Song J, Jiao Q, Zheng Y, Chen T, Xie C, Peng L. Diverse Effects of the NTCP p.Ser267Phe Variant on Disease Progression During Chronic HBV Infection and on HBV preS1 Variability. Front Cell Infect Microbiol 2019; 9:18. [PMID: 30881922 PMCID: PMC6407604 DOI: 10.3389/fcimb.2019.00018] [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: 11/23/2018] [Accepted: 01/22/2019] [Indexed: 12/12/2022] Open
Abstract
The sodium taurocholate co-transporting polypeptide (NTCP) acts as a cellular receptor for the hepatitis B virus (HBV) infection on host hepatocytes. We aim to investigate how the NTCP p.Ser267Phe variant affects HBV-related disease progression and analyze viral genomic variability under a host genetic background carrying the p.Ser267Phe variant. A total of 3187 chronic hepatitis B (CHB) patients were enrolled and genotyped for the p.Ser267Phe variant. The variant's association with disease progression was evaluated by logistic regression analysis. We also enrolled 83 treatment-naive CHB patients to analyze the variability of the HBV preS1 region. The frequency of the NTCP p.Ser267Phe variant was significantly lower in patients diagnosed with acute-on-chronic liver failure [OR (95% CI) = 0.33 (0.18-0.58), P = 1.34 × 10-4], cirrhosis [OR (95% CI) = 0.47 (0.31-0.72), P = 4.04 × 10-4], and hepatocellular carcinoma [OR (95% CI) = 0.54 (0.34-0.86), P = 9.83 × 10-3] as compared with CHB controls under the additive model after adjustment. Furthermore, the percentage of amino acid mutations in HBV preS1 region was significantly higher in the NTCP p.Ser267Phe heterozygote group than in the NTCP wild type homozygote group (P < 0.05). We herein demonstrate that the NTCP p.Ser267Phe variant is a protective factor reducing CHB patient risk for liver failure, cirrhosis, and hepatocellular carcinoma. A host genetic background carrying NTCP p.Ser267Phe exerts selective pressure on the virus, leading to more variability.
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Affiliation(s)
- Fangji Yang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Lina Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wenxiong Xu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ying Liu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Limin Zhen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Gang Ning
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jie Song
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qian Jiao
- Department of Severe Liver Disease, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yongyuan Zheng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Tongtong Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chan Xie
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liang Peng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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