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1
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Xie C, Lu D. Evolution and diversity of the hepatitis B virus genome: Clinical implications. Virology 2024; 598:110197. [PMID: 39098184 DOI: 10.1016/j.virol.2024.110197] [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: 05/23/2024] [Revised: 07/14/2024] [Accepted: 07/30/2024] [Indexed: 08/06/2024]
Abstract
Hepatitis B virus (HBV) infection remains a significant global health burden. The genetic variation of HBV is complex. HBV can be divided into nine genotypes, which show significant differences in geographical distribution, clinical manifestations, transmission routes and treatment response. In recent years, substantial progress has been made through various research methods in understanding the development, pathogenesis, and antiviral treatment response of clinical disease associated with HBV genetic variants. This progress provides important theoretical support for a deeper understanding of the natural history of HBV infection, virus detection, drug treatment, vaccine development, mother-to-child transmission, and surveillance management. This review summarizes the mechanisms of HBV diversity, discusses methods used to detect viral diversity in current studies, and the impact of viral genome variation during infection on the development of clinical disease.
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Affiliation(s)
- Chengzuo Xie
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Daiqiang Lu
- Institute of Molecular and Medical Virology, Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control, School of Medicine, Jinan University, Guangzhou, Guangdong Province, 510632, China.
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2
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Jiang X, Chang L, Yan Y, Ji H, Sun H, Xiao Y, Song S, Feng K, Nuermaimaiti A, Wang L. Role of S Protein Transmembrane Domain Mutations in the Development of Occult Hepatitis B Virus Infection. Emerg Microbes Infect 2022; 11:2184-2196. [PMID: 35976035 PMCID: PMC9518280 DOI: 10.1080/22221751.2022.2114849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Occult HBV infection (OBI) is a special infection status during Hepatitis B virus (HBV) infection. The underlying mechanism of its occurrence remains unclear. This study conducted sequencing analysis on 104 OBI plasma samples and 524 HBsAg positive samples from 29 blood centres, and searched for high-frequency mutations in transmembrane domain (TMD) of S protein in the OBI population. Plasmids with TMD high-frequency mutations were constructed, in vivo and in vitro functional experiments were performed to investigate possible molecular mechanisms of OBI occurrence. We found 22 high-frequency TMD mutations in genotype B OBI strains. Among them, five mutations can lead to impairment of HBsAg secretion; seven mutations had accumulated intracellular HBsAg while extracellular HBsAg didn’t decrease compared to wildtype. This study chose C85R from TMD2, F220C, and F220Y from TMD4 for further exploration. Protein structure predication showed these three mutant HBsAg displayed changed hydrophilic properties and tended to accumulate in the phospholipid bilayer of cell membrane. Mutant HBsAg’s secretion disorder may induce OBI. On the other hand, V168A + V177A from TMD3 expressed increased HBsAg both in intracellular and extracellular levels. This mutation had most unstable natural conformation and may be inclined to transition into V177A or V168A + S174N + V177A. These three mutations were more prone to mixed infection, presenting a state of coexistence, thus approaching the impaired secretion pattern of OBI. This study demonstrated TMD mutations could contribute to the occurrence of OBI and provided a theoretical basis for OBI study and the functional cure of chronic hepatitis B virus infection.
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Affiliation(s)
- Xinyi Jiang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, P.R. China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China."
| | - Le Chang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, P.R. China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China."
| | - Ying Yan
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, P.R. China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China."
| | - Huimin Ji
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, P.R. China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China."
| | - Huizhen Sun
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, P.R. China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China."
| | - Yingzi Xiao
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, P.R. China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China."
| | - Shi Song
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, P.R. China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China."
| | - Kaihao Feng
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, P.R. China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China."
| | - Abudulimutailipu Nuermaimaiti
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, P.R. China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China."
| | - Lunan Wang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.,Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, P.R. China.,Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China."
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3
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Wang H, Wang M, Huang J, Xu R, Liao Q, Shan Z, Zheng Y, Rong X, Tang X, Li T, Wang W, Li C, Fu Y. Novel hepatitis B virus surface antigen mutations associated with occult genotype B hepatitis B virus infection affect HBsAg detection. J Viral Hepat 2020; 27:915-921. [PMID: 32336003 DOI: 10.1111/jvh.13309] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 02/12/2020] [Accepted: 03/30/2020] [Indexed: 02/06/2023]
Abstract
The causative factors of occult hepatitis B infection are complicated and not yet been fully elucidated. Mutations in hepatitis B virus (HBV) S gene are one of the factors may contributing to occult infection. In this study, 89 blood donors with genotype B occult HBV infection were investigated. Fifty-seven hepatitis B surface antigen (HBsAg)-positive/HBV DNA-positive blood donors served as control group for comparison. Occult HBV-related mutations with a high incidence (P < .05) in the S gene were identified. To further verify these occult infection-related mutations, a conservative full-gene expression vector of HBV B genotype (pHBV1.3B) was constructed. Then, the mutant plasmids on the basis of pHBV1.3B were constructed and transfected into HepG2 cells. Extracellular as well as intracellular HBsAg was analysed by electrochemical luminescence and cellular immunohistochemistry. Ten occult infection-related mutations (E2G, Q101R, K122R, M133T, D144E, G145R, V168A, S174N, L175S and I226S) were significantly more frequent in the occult infection group (P < .05). Five of the ten mutations (E2G, D144E, G145R, V168A and S174N) strongly decreased extracellular HBsAg level (P < .05) in the transfection system. Notably, the E2G mutation had the most significant impact on the ratio of extracellular HBsAg (3.8% vs pHBV1.3B) and intracellular HBsAg (239.3% vs pHBV1.3B) (P < .05), and the fluorescence density of E2G mutant HBsAg was significantly higher than that of pHBV1.3B (P < .0001). Hence, ten mutations were associated with genotype B occult HBV infection; E2G and V168A were novel mutations which we confirmed significantly affect HBsAg detection. E2G might cause HBsAg secretion impairment that results in intracellular accumulation and a decrease in HBsAg secretion.
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Affiliation(s)
- Hao Wang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.,Guangzhou Blood Center, Guangzhou, China
| | - Min Wang
- Guangzhou Blood Center, Guangzhou, China
| | | | - Ru Xu
- Guangzhou Blood Center, Guangzhou, China
| | - Qiao Liao
- Guangzhou Blood Center, Guangzhou, China
| | | | | | - Xia Rong
- Guangzhou Blood Center, Guangzhou, China
| | - Xi Tang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Tingting Li
- 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
| | - Chengyao Li
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yongshui Fu
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.,Guangzhou Blood Center, Guangzhou, China
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4
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Ostankova YO, Semenov AV, Zueva EB, Totolian AA. THE PREVALENCE OF OCCULT HEPATITIS B AMONG HBSAG-NEGATIVE PERSONS WITH HIV IN VELIKY NOVGOROD. ACTA ACUST UNITED AC 2019. [DOI: 10.22328/2077-9828-2019-11-1-64-70] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Aim: to estimate the prevalence of the occult hepatitis B virus among HIV-infected patients with the virological ineffectiveness of antiretroviral therapy in Veliky Novgorod. Materials and methods. Blood plasma samples from 76 HBsAg-negative HIVinfected patients with virological inefficiency of antiretroviral therapy from Veliky Novgorod were used in the work. For the detection of the hepatitis B virus, nucleic acids were isolated using the commercial kit AmplePrime Ribo-prep. For amplification and sequencing, overlapping pairs of specific primers were used, jointly flanking a 1475 base pair fragment including the 1169 base pair Pre-S1/Pre-S2/S region recommended for genotyping the hepatitis B virus. Results. Among 76 samples of hepatitis B virus DNA, 44 samples were found, which was 57,89%. None of the patients had HBsAg, and 6 patients (13,63%) had HBcor IgG and HBe IgG antibodies. On the basis of phylogenetic analysis, it was shown that only genotype D, which is the most common genotype of the hepatitis B virus in the Russian Federation, was detected in the examined group. The subgenotype D2 (47,72%) prevailed in comparison with the subgenotype D1 (34,09%) and the subgenotype D3 (18,18%). The distribution possible ways of the subgenotype D1 hepatitis B virus, which is uncharacteristic for the region, are discussed. Only one isolate of hepatitis B virus with mutations of drug resistance to nucleotide / nucleoside analogue therapy has been identified — amino acid substitution in the polymerase gene of the virus (L180M, M204V) associated with the development of resistance to lamivudine, entecavir, telbivudine and tenofovir. Conclusion. The high prevalence of occult hepatitis B among HIVinfected patients indicates a lack current tests for the diagnosis of chronic HBV infections. The identification of occult hepatitis B in HIV-infected individuals seems appropriate for timely treatment of patients and requires the use more sensitive methods.
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Affiliation(s)
| | - A. V. Semenov
- Saint-Petersburg Pasteur Institute; First St. Petersburg state medical University named after academician I. P. Pavlov; North-West State Medical University named after I.I.Mechnikov, Saint-Petersburg
| | | | - A. A. Totolian
- Saint-Petersburg Pasteur Institute; First St. Petersburg state medical University named after academician I. P. Pavlov
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Gencay M, Hübner K, Gohl P, Seffner A, Weizenegger M, Neofytos D, Batrla R, Woeste A, Kim HS, Westergaard G, Reinsch C, Brill E, Thu Thuy PT, Hoang BH, Sonderup M, Spearman CW, Pabinger S, Gautier J, Brancaccio G, Fasano M, Santantonio T, Gaeta GB, Nauck M, Kaminski WE. Ultra-deep sequencing reveals high prevalence and broad structural diversity of hepatitis B surface antigen mutations in a global population. PLoS One 2017; 12:e0172101. [PMID: 28472040 PMCID: PMC5417417 DOI: 10.1371/journal.pone.0172101] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 01/31/2017] [Indexed: 02/07/2023] Open
Abstract
The diversity of the hepatitis B surface antigen (HBsAg) has a significant impact on the performance of diagnostic screening tests and the clinical outcome of hepatitis B infection. Neutralizing or diagnostic antibodies against the HBsAg are directed towards its highly conserved major hydrophilic region (MHR), in particular towards its “a” determinant subdomain. Here, we explored, on a global scale, the genetic diversity of the HBsAg MHR in a large, multi-ethnic cohort of randomly selected subjects with HBV infection from four continents. A total of 1553 HBsAg positive blood samples of subjects originating from 20 different countries across Africa, America, Asia and central Europe were characterized for amino acid variation in the MHR. Using highly sensitive ultra-deep sequencing, we found 72.8% of the successfully sequenced subjects (n = 1391) demonstrated amino acid sequence variation in the HBsAg MHR. This indicates that the global variation frequency in the HBsAg MHR is threefold higher than previously reported. The majority of the amino acid mutations were found in the HBV genotypes B (28.9%) and C (25.4%). Collectively, we identified 345 distinct amino acid mutations in the MHR. Among these, we report 62 previously unknown mutations, which extends the worldwide pool of currently known HBsAg MHR mutations by 22%. Importantly, topological analysis identified the “a” determinant upstream flanking region as the structurally most diverse subdomain of the HBsAg MHR. The highest prevalence of “a” determinant region mutations was observed in subjects from Asia, followed by the African, American and European cohorts, respectively. Finally, we found that more than half (59.3%) of all HBV subjects investigated carried multiple MHR mutations. Together, this worldwide ultra-deep sequencing based genotyping study reveals that the global prevalence and structural complexity of variation in the hepatitis B surface antigen have, to date, been significantly underappreciated.
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Affiliation(s)
- Mikael Gencay
- Roche Diagnostics International Ltd, Rotkreuz, Switzerland
| | - Kirsten Hübner
- Bioscientia Institute for Medical Diagnostics, Ingelheim, Germany
| | - Peter Gohl
- Bioscientia Institute for Medical Diagnostics, Ingelheim, Germany
| | - Anja Seffner
- Department of Molecular Genetics and Microbiology, MVZ Labor Dr. Limbach & Kollegen GbR, Heidelberg, Germany
| | - Michael Weizenegger
- Department of Molecular Genetics and Microbiology, MVZ Labor Dr. Limbach & Kollegen GbR, Heidelberg, Germany
| | | | - Richard Batrla
- Roche Diagnostics International Ltd, Rotkreuz, Switzerland
| | | | - Hyon-suk Kim
- Department of Laboratory Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, South Korea
| | | | | | - Eva Brill
- Bioscientia Institute for Medical Diagnostics, Ingelheim, Germany
| | - Pham Thi Thu Thuy
- Hepatology Department, Medic Medical Center, Ho Chi Minh City, Vietnam
| | - Bui Huu Hoang
- Gastroenterology Department, Ho Chi Minh City University Medical Center, Ho Chi Minh City, Vietnam
| | - Mark Sonderup
- Division of Hepatology and Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
| | - C. Wendy Spearman
- Division of Hepatology and Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
| | - Stephan Pabinger
- AIT Austrian Institute of Technology, Health and Environment Department, Molecular Diagnostics, Vienna, Austria
| | | | - Giuseppina Brancaccio
- Infectious Diseases and Viral Hepatitis Unit, Second University of Naples, Naples, Italy
| | - Massimo Fasano
- Infectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Teresa Santantonio
- Infectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Giovanni B. Gaeta
- Infectious Diseases and Viral Hepatitis Unit, Second University of Naples, Naples, Italy
| | - Markus Nauck
- Bioscientia Institute for Medical Diagnostics, Ingelheim, Germany
- * E-mail: (WEK); (MN)
| | - Wolfgang E. Kaminski
- Bioscientia Institute for Medical Diagnostics, Ingelheim, Germany
- * E-mail: (WEK); (MN)
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6
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Hossain MG, Ueda K. Investigation of a Novel Hepatitis B Virus Surface Antigen (HBsAg) Escape Mutant Affecting Immunogenicity. PLoS One 2017; 12:e0167871. [PMID: 28045894 PMCID: PMC5207502 DOI: 10.1371/journal.pone.0167871] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 11/21/2016] [Indexed: 02/07/2023] Open
Abstract
Mutation in the hepatitis B virus surface antigen (HBsAg) may affect the efficiency of diagnostic immunoassays or success of vaccinations using HBsAg. Thus, antigenicity and immunogenicity analyses of the mutated HBsAg are necessary to develop novel diagnostic tools and efficient vaccinations. Here, the in vitro antigenicity of three wild-type HBsAg open reading frames (ORFs) (adr4, W1S [subtype adr] and W3S [subtype adr]) isolated from clinically infected patients and nineteen synthesized single/double/multiple amino acid-substituted mutants were tested with commercial ELISA kits. Immunofluorescence staining of transfected cells and Western blot analysis confirmed that these ORFs were expressed at comparable levels in HEK-293 cells. W1S and adr4 were clearly detected, whereas W3S could not be detected. Using the same commercial immunoassay kit, we found that the single mutants, K120P and D123T, were marginally reactive, whereas W3S-aW1S and the double mutant, K120P/D123T, exhibited antigenicity roughly equivalent to the wild-type wako1S. On the other hand, the single mutants of W1S, P120K and T123D, significantly impaired the reactivity, while W1S-aW3S and the double mutant of W1S, P120K/T123D, resulted in a complete loss of antigenicity. In addition, ELISA revealed reduced HBs antigenicity of two mutants, W1S N146G and W1S Q129R/G145R. These commercial ELISA-based antigenic reactivities of HBsAg were also strongly correlated with the predicted Ai alterations of affected amino acids due to the specific mutation. In conclusion, this study showed for the first time that lysine (K120) and aspartate (D123) simultaneously affected HBsAg antigenicity, leading to diagnostic failure. These findings will improve diagnostic assays and vaccine development.
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Affiliation(s)
- Md. Golzar Hossain
- Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Keiji Ueda
- Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- * E-mail:
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7
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Ostankova YV, Semenov AV, Faizullaev KN, Kazakova EI, Kozlov AV, Musabaev EI, Totolyan AA. MOLECULAR-BIOLOGICAL MARKERS OF HEPATITIS В IN PATIENTS WITH LIVER FIBROSIS/CIRRHOSIS IN UZBEKISTAN. JOURNAL OF MICROBIOLOGY, EPIDEMIOLOGY AND IMMUNOBIOLOGY 2016. [DOI: 10.36233/0372-9311-2016-5-34-43] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Aim. Evaluate prevalence of genetic variants of hepatitis В viruses in population of various regions of Uzbekistan with hepatitis of various genesis and different severity levels of liver fibrosis and cirrhosis. Materials and methods. Blood plasma and liver biopsy from 39 patients with different severity levels of liver fibrosis and cirrhosis served as study material. Genotyping based on direct sequencing of Pre-Sl/Pre-S2/S HBV DNA region was applied. Results. Hepatitis В virus was detected in 32 samples ofthe 39 provided, frequency of occurrence - 82%, respectively. Phylogenetic analysis has shown, that only genotype D was detected among the examined patients, hepatitis В virus subtype D1 predominated (84.38%) compared with D2 (3.12%) and D3 (12.5%) subtypes. Conclusion. Large-scale sequencing of HBV in Central Asia will allow to evaluate routes of transmission and time of evolutionary separation of virus isolates. Understanding the epidemiology of the infectious process is important for development of programs for prophylaxis and therapy of the infection.
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8
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Zhu HL, Li X, Li J, Zhang ZH. Genetic variation of occult hepatitis B virus infection. World J Gastroenterol 2016; 22:3531-3546. [PMID: 27053845 PMCID: PMC4814639 DOI: 10.3748/wjg.v22.i13.3531] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 12/13/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
Occult hepatitis B virus infection (OBI), characterized as the persistence of hepatitis B virus (HBV) surface antigen (HBsAg) seronegativity and low viral load in blood or liver, is a special form of HBV infection. OBI may be related mainly to mutations in the HBV genome, although the underlying mechanism of it remains to be clarified. Mutations especially within the immunodominant "α" determinant of S protein are "hot spots" that could contribute to the occurrence of OBI via affecting antigenicity and immunogenicity of HBsAg or replication and secretion of virion. Clinical reports account for a large proportion of previous studies on OBI, while functional analyses, especially those based on full-length HBV genome, are rare.
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9
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Zhang Z, Zhang L, Dai Y, Zhang Y, Li J, Li X. Occult hepatitis B virus infection: influence of S protein variants. Virol J 2016; 13:10. [PMID: 26786229 PMCID: PMC4717550 DOI: 10.1186/s12985-016-0464-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 01/07/2016] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND In occult hepatitis B viral infection (OBI), the persistence of hepatitis B virus (HBV) DNA is associated with a lack of hepatitis B surface antigen (HBsAg). To assess the possible role of HBsAg immune escape variants in OBI patients, variability in the HBV S gene was evaluated for OBI patients as well as chronic HBV infection patients from the same families. METHODS We selected 17 HBV DNA-positive/HBsAg-negative patients (OBI group) and 15 HBV DNA- and HBsAg-positive patients from OBI families (control group). The S gene was amplified and cloned, and at least 15 clones per patient were sequenced and analyzed. RESULTS Although the incidence of stop codon mutations within the S region was higher in the OBI group (13.6 %) than in the control group (1.5 %, P < 0.001), this type of mutation, together with insertion and deletion mutations, was prevalent in only three OBI patients. In the major hydrophilic region (MHR), a median of 0.75 residues were altered in every 100 residues for the OBI patients, whereas 0.95 out of 100 residues were changed in the control group (P = 0.428). Furthermore, some variants that are generally considered immune escape variants, such as mutations at positions s145, s147, and s123, were only observed in less than 5 % of all the clones sequenced, in either OBI or control group. CONCLUSIONS Our data suggest that HBsAg variants may not play a major role in OBI pathogenesis.
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Affiliation(s)
- Zhenhua Zhang
- Department of Infectious Diseases, the First Affiliated Hospital, Anhui Medical University, Hefei, 230022, China.
- School of Pharmacy, Anhui Medical University, Hefei, China.
| | - Ling Zhang
- Department of Infectious Diseases, the First Affiliated Hospital, Anhui Medical University, Hefei, 230022, China.
| | - Yu Dai
- Department of Infectious Diseases, the First Affiliated Hospital, Anhui Medical University, Hefei, 230022, China.
| | - Yafei Zhang
- Department of Infectious Diseases, the First Affiliated Hospital, Anhui Medical University, Hefei, 230022, China.
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei, China.
| | - Xu Li
- Department of Infectious Diseases, the First Affiliated Hospital, Anhui Medical University, Hefei, 230022, China.
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10
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Kim JW. Occult hepatitis B virus infection: clearance or disguise? Clin Mol Hepatol 2014; 20:249-50. [PMID: 25320727 PMCID: PMC4197172 DOI: 10.3350/cmh.2014.20.3.249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Revised: 09/17/2014] [Indexed: 12/02/2022] Open
Affiliation(s)
- Jin-Wook Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea and Seoul National University Bundang Hospital, Seongnam, Korea
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