乙型病毒肝炎分子研究进展
Advances in Molecular Research of Hepatitis B Virus
DOI: 10.12677/acm.2025.1572105, PDF,    国家自然科学基金支持
作者: 冀柯宇：空军军医大学军事预防医学系军队防疫与流行病学教研室，特殊作业环境危害评估与防治教育部重点实验室，陕西省环境健康危害评估与防护重点实验室，陕西 西安；空军军医大学基础医学院学员五大队，陕西 西安；徐琳莉, 袁筱婕*：空军军医大学军事预防医学系军队防疫与流行病学教研室，特殊作业环境危害评估与防治教育部重点实验室，陕西省环境健康危害评估与防护重点实验室，陕西 西安
关键词: 乙型肝炎病毒；基因组；进化；Hepatitis B Virus； Genome； Evolution
摘要: 乙型肝炎病毒(Hepatitis B virus, HBV)感染是全球重大公共卫生问题，其分子特征与进化溯源研究对临床防治具有关键意义。本文系统综述HBV的结构、基因多样性及进化起源。HBV具有复杂的病毒颗粒结构，包括感染性Dane颗粒和非感染性亚病毒颗粒，其基因组通过4个开放阅读框编码关键功能蛋白，依赖逆转录过程复制，其中共价闭合环状DNA (Covalently closed circular DNA, cccDNA)的稳定性是慢性感染难治的重要原因。HBV基因型(A~J)及亚型分布具显著地域特征，亚洲以B、C基因型为主，欧洲和地中海地区以D型为主，基因重组(如BC、CD重组体)和逆转录过程中的突变(如RT区耐药突变、Pre-S/S区抗原性突变)进一步加剧了病毒多样性。肝病毒科包含5个属，溯源研究表明，古代HBV基因组可追溯至新石器时代，灵长类及人类迁徙推动了病毒进化，但人HBV的起源仍存争议。中国作为HBV高负担国家，其防治进展对全球消除乙肝目标至关重要，未来需结合分子流行病学与病毒进化研究优化防控策略。
Abstract: Hepatitis B virus (HBV) infection is a major global public health issue, and research on its molecular characteristics and evolutionary tracing is of key significance for clinical prevention and treatment. This paper systematically reviews the structure, genetic diversity and evolutionary origin of HBV. HBV has a complex viral particle structure, including infectious Dane particles and non-infectious subviral particles. Its genome encodes key functional proteins through four open reading frames and relies on the reverse transcription process for replication. Among them, the stability of covalently closed circular DNA (cccDNA) is an important reason for the intractability of chronic infection. HBV genotypes (A~J) and subtypes show significant regional distribution characteristics. Genotypes B and C are dominant in Asia, while genotype D is predominant in Europe and the Mediterranean region. Genetic recombination (such as BC and CD recombinants) and mutations in the reverse transcription process (such as drug-resistant mutations in the RT region and antigenic mutations in the Pre-S/S region) further aggravate viral diversity. The family Hepadnaviridae contains five genera. Tracing studies have shown that ancient HBV genomes can be traced back to the Neolithic Age. The migration of primates and humans has promoted viral evolution, but the origin of human HBV remains controversial. As a country with a high HBV burden, China’s progress in prevention and treatment is crucial to the global goal of eliminating hepatitis B. In the future, it is necessary to optimize prevention and control strategies by combining molecular epidemiology and viral evolution research.
文章引用：冀柯宇, 徐琳莉, 袁筱婕. 乙型病毒肝炎分子研究进展[J]. 临床医学进展, 2025, 15(7): 1150-1158. https://doi.org/10.12677/acm.2025.1572105

参考文献

[1] 王明凤, 曹佳莉, 袁权, 等. 乙型肝炎病毒体外感染和复制的细胞模型[J]. 微生物学报, 2019, 59(12): 2263-2275.
[2] 赫晓林, 黄建炜, 许瑞安, 等. HBV病毒复制机制及慢性乙型肝炎药物靶点[J]. 中国药理学通报, 2015, 31(2): 152-156.
[3] Erken, R., Loukachov, V., van Dort, K., van den Hurk, A., Takkenberg, R.B., de Niet, A., et al. (2022) Quantified Integrated Hepatitis B Virus Is Related to Viral Activity in Patients with Chronic Hepatitis B. Hepatology, 76, 196-206. [Google Scholar] [CrossRef] [PubMed]
[4] Péneau, C., Imbeaud, S., La Bella, T., Hirsch, T.Z., Caruso, S., Calderaro, J., et al. (2021) Hepatitis B Virus Integrations Promote Local and Distant Oncogenic Driver Alterations in Hepatocellular Carcinoma. Gut, 71, 616-626. [Google Scholar] [CrossRef] [PubMed]
[5] Kramvis, A. (2014) Genotypes and Genetic Variability of Hepatitis B Virus. Intervirology, 57, 141-150. [Google Scholar] [CrossRef] [PubMed]
[6] Liu, Z., Zhang, Y., Xu, M., Li, X. and Zhang, Z. (2021) Distribution of Hepatitis B Virus Genotypes and Subgenotypes. Medicine, 100, e27941. [Google Scholar] [CrossRef] [PubMed]
[7] Toyé, R.M., Cohen, D., Pujol, F.H., Sow-Sall, A., Lô, G., Hoshino, K., et al. (2021) Hepatitis B Virus Genotype Study in West Africa Reveals an Expanding Clade of Subgenotype A4. Microorganisms, 9, Article 623. [Google Scholar] [CrossRef] [PubMed]
[8] Liu, Y., Feng, Y., Li, Y., Ma, J., Jia, Y., Yue, W., et al. (2020) Characterization of a Novel Hepatitis B Virus Subgenotype B10 among Chronic Hepatitis B Patients in Yunnan, China. Infection, Genetics and Evolution, 83, Article 104322. [Google Scholar] [CrossRef] [PubMed]
[9] Lin, S.Y.C. and Woo, P.C.Y. (2025) Phylodynamics of Hepatitis B Virus Genotype B in East Asia: A Population Genomics Analysis. Journal of Biological Methods, 12, e99010048. [Google Scholar] [CrossRef] [PubMed]
[10] Bello, K.E., Mat Jusoh, T.N.A., Irekeola, A.A., Abu, N., Mohd Amin, N.A.Z., Mustaffa, N., et al. (2023) A Recent Prevalence of Hepatitis B Virus (HBV) Genotypes and Subtypes in Asia: A Systematic Review and Meta-Analysis. Healthcare, 11, Article 1011. [Google Scholar] [CrossRef] [PubMed]
[11] Feng, Y., Ran, J., Feng, Y., Miao, J., Zhao, Y., Jia, Y., et al. (2020) Genetic Diversity of Hepatitis B Virus in Yunnan, China: Identification of Novel Subgenotype C17, an Intergenotypic B/I Recombinant, and B/C Recombinants. Journal of General Virology, 101, 972-981. [Google Scholar] [CrossRef] [PubMed]
[12] Li, T., Chen, H., Sun, L. and Liu, J. (2022) Dating the Origin and Dispersal of Global Hepatitis B Virus Genotype C in Humans. Drug Discoveries & Therapeutics, 16, 85-92. [Google Scholar] [CrossRef] [PubMed]
[13] Spitz, N., Mello, F.C.A., Moreira, A.S., Gusatti, C.S., Martins, R.M.B., Gomes, S.A., et al. (2019) Reconstruction of the Spatial and Temporal Dynamics of Hepatitis B Virus Genotype D in the Americas. PLOS ONE, 14, e0220342. [Google Scholar] [CrossRef] [PubMed]
[14] Sant’Anna, T.B. and Araujo, N.M. (2023) Hepatitis B Virus Genotype D: An Overview of Molecular Epidemiology, Evolutionary History, and Clinical Characteristics. Microorganisms, 11, Article 1101. [Google Scholar] [CrossRef] [PubMed]
[15] Wolf, J.M., Pereira, V.R.Z.B., De Carli, S., Godoi, T.P.M., Wortmann, A.C., Stumm, G.Z., et al. (2020) Tracing Back Hepatitis B Virus Genotype D Introduction and Dissemination in South Brazil. Infection, Genetics and Evolution, 82, Article 104294. [Google Scholar] [CrossRef] [PubMed]
[16] Lago, B.V., do Espirito-Santo, M.P., Costa, V.D., Marques, V.A., Villar, L.M., Lewis-Ximenez, L.L., et al. (2019) Genetic Diversity of the Hepatitis B Virus Subgenotypes in Brazil. Viruses, 11, Article 860. [Google Scholar] [CrossRef] [PubMed]
[17] Lusida, M.I., Nugrahaputra, V.E., Soetjipto Handajani, R., Nagano-Fujii, M., Sasayama, M., et al. (2008) Novel Subgenotypes of Hepatitis B Virus Genotypes C and D in Papua, Indonesia. Journal of Clinical Microbiology, 46, 2160-2166. [Google Scholar] [CrossRef] [PubMed]
[18] Pourkarim, M.R., Amini-Bavil-Olyaee, S., Kurbanov, F., et al. (2014) Molecular Identification of Hepatitis B Virus Genotypes/Subgenotypes: Revised Classification Hurdles and Updated Resolutions. World Journal of Gastroenterology, 20, 7152-7168. [Google Scholar] [CrossRef] [PubMed]
[19] Wolf, J.M., Pereira, V.R.Z.B., Simon, D. and Lunge, V.R. (2020) Evolutionary History of Hepatitis B Virus Genotype H. Journal of Medical Virology, 93, 4004-4009. [Google Scholar] [CrossRef] [PubMed]
[20] Wolf, J.M., De Carli, S., Pereira, V.R.Z.B., Simon, D. and Lunge, V.R. (2020) Temporal Evolution and Global Spread of Hepatitis B Virus Genotype G. Journal of Viral Hepatitis, 28, 393-399. [Google Scholar] [CrossRef] [PubMed]
[21] Araujo, N.M. and Osiowy, C. (2022) Hepatitis B Virus Genotype G: The Odd Cousin of the Family. Frontiers in Microbiology, 13, Article 872766. [Google Scholar] [CrossRef] [PubMed]
[22] Shen, T., Yan, X.M., Liu, H.X., Zhang, B.X., Li, L., Zhang, J.P., et al. (2014) Genotype I of Hepatitis B Virus Was Found in East Xishuangbanna, China and Molecular Dynamics of HBV/I. Journal of Viral Hepatitis, 22, 37-45. [Google Scholar] [CrossRef] [PubMed]
[23] Li, G.J., Hue, S., Harrison, T.J., et al. (2013) Hepatitis B Virus Candidate Subgenotype I1 Varies in Distribution Throughout Guangxi, China and May Have Originated in Longan County, Guangxi. Journal of Medical Virology, 85, 799-807. [Google Scholar] [CrossRef] [PubMed]
[24] Arankalle, V.A., Gandhe, S.S., Borkakoty, B.J., Walimbe, A.M., Biswas, D. and Mahanta, J. (2010) A Novel HBV Recombinant (Genotype I) Similar to Vietnam/Laos in a Primitive Tribe in Eastern India. Journal of Viral Hepatitis, 17, 501-510. [Google Scholar] [CrossRef] [PubMed]
[25] Tatematsu, K., Tanaka, Y., Kurbanov, F., Sugauchi, F., Mano, S., Maeshiro, T., et al. (2009) A Genetic Variant of Hepatitis B Virus Divergent from Known Human and Ape Genotypes Isolated from a Japanese Patient and Provisionally Assigned to New Genotype J. Journal of Virology, 83, 10538-10547. [Google Scholar] [CrossRef] [PubMed]
[26] Chen, J., Li, L., Yin, Q. and Shen, T. (2023) A Review of Epidemiology and Clinical Relevance of Hepatitis B Virus Genotypes and Subgenotypes. Clinics and Research in Hepatology and Gastroenterology, 47, Article 102180. [Google Scholar] [CrossRef] [PubMed]
[27] Ye, L., Zhang, Y., Mei, Y., Nan, P. and Zhong, Y. (2010) Detecting Putative Recombination Events of Hepatitis B Virus: An Updated Comparative Genome Analysis. Chinese Science Bulletin, 55, 2373-2379. [Google Scholar] [CrossRef] 
[28] Huy, T.T.T. and Abe, K. (2004) Molecular Epidemiology of Hepatitis B and C Virus Infections in Asia. Pediatrics International, 46, 223-230. [Google Scholar] [CrossRef] [PubMed]
[29] Sugauchi, F., Orito, E., Ichida, T., Kato, H., Sakugawa, H., Kakumu, S., et al. (2002) Hepatitis B Virus of Genotype B with or without Recombination with Genotype C over the Precore Region plus the Core Gene. Journal of Virology, 76, 5985-5992. [Google Scholar] [CrossRef] [PubMed]
[30] Sugauchi, F., Orito, E., Ichida, T., Kato, H., Sakugawa, H., Kakumu, S., et al. (2003) Epidemiologic and Virologic Characteristics of Hepatitis B Virus Genotype B Having the Recombination with Genotype C. Gastroenterology, 124, 925-932. [Google Scholar] [CrossRef] [PubMed]
[31] Cui, C., Shi, J., Hui, L., Xi, H., Zhuoma,, Quni,, et al. (2002) The Dominant Hepatitis B Virus Genotype Identified in Tibet Is a C/D Hybrid. Journal of General Virology, 83, 2773-2777. [Google Scholar] [CrossRef] [PubMed]
[32] Liu, T., Wang, F., Zhang, S., Wang, F., Meng, Q., Zhang, G., et al. (2017) Whole-Gene Analysis of Two Groups of Hepatitis B Virus C/D Inter-Genotype Recombinant Strains Isolated in Tibet, China. PLOS ONE, 12, e0179846. [Google Scholar] [CrossRef] [PubMed]
[33] Martel, N., Gomes, S.A., Chemin, I., Trépo, C. and Kay, A. (2013) Improved Rolling Circle Amplification (RCA) of Hepatitis B Virus (HBV) Relaxed-Circular Serum DNA (RC-DNA). Journal of Virological Methods, 193, 653-659. [Google Scholar] [CrossRef] [PubMed]
[34] Liu, C.J. and Kao, J.H. (2013) Global Perspective on the Natural History of Chronic Hepatitis B: Role of Hepatitis B Virus Genotypes A to J. Seminars in Liver Disease, 33, 97-102. [Google Scholar] [CrossRef] [PubMed]
[35] Araujo, N.M. (2015) Hepatitis B Virus Intergenotypic Recombinants Worldwide: An Overview. Infection, Genetics and Evolution, 36, 500-510. [Google Scholar] [CrossRef] [PubMed]
[36] Milosevic, I., Delic, D., Lazarevic, I., Pavlovic, I.P., Korac, M., Bojovic, K., et al. (2013) The Significance of Hepatitis B Virus (HBV) Genotypes for the Disease and Treatment Outcome among Patients with Chronic Hepatitis B in Serbia. Journal of Clinical Virology, 58, 54-58. [Google Scholar] [CrossRef] [PubMed]
[37] Gohar, M., Rehman, I.U., Ullah, A., Khan, M.A., Yasmin, H., Ahmad, J., et al. (2023) Phylogenetic Analysis and Emerging Drug Resistance against Different Nucleoside Analogues in Hepatitis B Virus Positive Patients. Microorganisms, 11, Article 2622. [Google Scholar] [CrossRef] [PubMed]
[38] He, X., Wang, F., Huang, B., et al. (2015) Detection and Analysis of Resistance Mutations of Hepatitis B Virus. International Journal of Clinical and Experimental Medicine, 8, 9630-9639.
[39] Zoulim, F. and Locarnini, S. (2009) Hepatitis B Virus Resistance to Nucleos(t)ide Analogues. Gastroenterology, 137, 1593-1608. [Google Scholar] [CrossRef] [PubMed]
[40] Chen, X.X., Xiang, K.H., Zhang, H.P., et al. (2020) Occult HBV Infection in Patients with Autoimmune Hepatitis: A Virological and Clinical Study. Journal of Microbiology, Immunology, and Infection, 53, 946-954.
[41] Pollicino, T., Cacciola, I., Saffioti, F. and Raimondo, G. (2014) Hepatitis B Virus PreS/S Gene Variants: Pathobiology and Clinical Implications. Journal of Hepatology, 61, 408-417. [Google Scholar] [CrossRef] [PubMed]
[42] Magnius, L., Mason, W.S., Taylor, J., Kann, M., Glebe, D., Dény, P., et al. (2020) ICTV Virus Taxonomy Profile: Hepadnaviridae. Journal of General Virology, 101, 571-572. [Google Scholar] [CrossRef] [PubMed]
[43] Nie, F.Y., Tian, J.H., Lin, X.D., et al. (2019) Discovery of a Highly Divergent Hepadnavirus in Shrews from China. Virology, 531, 162-170. [Google Scholar] [CrossRef] [PubMed]
[44] He, B., Zhang, F., Xia, L., Hu, T., Chen, G., Qiu, W., et al. (2014) Identification of a Novel Orthohepadnavirus in Pomona Roundleaf Bats in China. Archives of Virology, 160, 335-337. [Google Scholar] [CrossRef] [PubMed]
[45] Krause-Kyora, B., Susat, J., Key, F.M., Kühnert, D., Bosse, E., Immel, A., et al. (2018) Neolithic and Medieval Virus Genomes Reveal Complex Evolution of Hepatitis B. eLife, 7, e36666. [Google Scholar] [CrossRef] [PubMed]
[46] Mühlemann, B., Jones, T.C., et al. (2018) Ancient Hepatitis B Viruses from the Bronze Age to the Medieval Period. Nature, 557, 418-423. [Google Scholar] [CrossRef] [PubMed]
[47] Bar-Gal, G.K., Kim, M.J., Klein, A., et al. (2012) Tracing Hepatitis B Virus to the 16th Century in a Korean Mummy. Hepatology, 56, 1671-1680. [Google Scholar] [CrossRef] [PubMed]
[48] Beard, K.C., Qi, T., Dawson, M.R., Wang, B. and Li, C. (1994) A Diverse New Primate Fauna from Middle Eocene Fissure-Fillings in Southeastern China. Nature, 368, 604-609. [Google Scholar] [CrossRef] [PubMed]
[49] Datta, S. (2020) Excavating New Facts from Ancient Hepatitis B Virus Sequences. Virology, 549, 89-99. [Google Scholar] [CrossRef] [PubMed]
[50] Locarnini, S.A., Littlejohn, M. and Yuen, L.K.W. (2021) Origins and Evolution of the Primate Hepatitis B Virus. Frontiers in Microbiology, 12, Article 653684. [Google Scholar] [CrossRef] [PubMed]
[51] Chaimanee, Y., Chavasseau, O., Beard, K.C., Kyaw, A.A., Soe, A.N., Sein, C., et al. (2012) Late Middle Eocene Primate from Myanmar and the Initial Anthropoid Colonization of Africa. Proceedings of the National Academy of Sciences, 109, 10293-10297. [Google Scholar] [CrossRef] [PubMed]
[52] de Carvalho Dominguez Souza, B.F., König, A., Rasche, A., de Oliveira Carneiro, I., Stephan, N., Corman, V.M., et al. (2018) A Novel Hepatitis B Virus Species Discovered in Capuchin Monkeys Sheds New Light on the Evolution of Primate Hepadnaviruses. Journal of Hepatology, 68, 1114-1122. [Google Scholar] [CrossRef] [PubMed]
[53] Bergström, A., Stringer, C., Hajdinjak, M., Scerri, E.M.L. and Skoglund, P. (2021) Origins of Modern Human Ancestry. Nature, 590, 229-237. [Google Scholar] [CrossRef] [PubMed]
[54] Hammer, M.F., Woerner, A.E., Mendez, F.L., Watkins, J.C. and Wall, J.D. (2011) Genetic Evidence for Archaic Admixture in Africa. Proceedings of the National Academy of Sciences, 108, 15123-15128. [Google Scholar] [CrossRef] [PubMed]
[55] Bollyky, P., Rambaut, A., Grassley, N., Carman, W. and Holmes, E. (1998) Hepatitis B Virus Has a Recent New World Evolutionary Origin. Journal of Hepatology, 28, Article 96.
[56] Souza, B.F., Drexler, J.F., Lima, R.S., et al. (2014) Theories about Evolutionary Origins of Human Hepatitis B Virus in Primates and Humans. The Brazilian Journal of Infectious Diseases, 18, 535-543. [Google Scholar] [CrossRef] [PubMed]
[57] Oppenheimer, S. (2012) Out-of-Africa, the Peopling of Continents and Islands: Tracing Uniparental Gene Trees across the Map. Philosophical Transactions of the Royal Society B: Biological Sciences, 367, 770-784. [Google Scholar] [CrossRef] [PubMed]
[58] Takahashi, K., Brotman, B., Usuda, S., Mishiro, S. and Prince, A.M. (2000) Full-Genome Sequence Analyses of Hepatitis B Virus (HBV) Strains Recovered from Chimpanzees Infected in the Wild: Implications for an Origin of HBV. Virology, 267, 58-64. [Google Scholar] [CrossRef] [PubMed]
[59] Paraskevis, D., Magiorkinis, G., Magiorkinis, E., Ho, S.Y.W., Belshaw, R., Allain, J., et al. (2013) Dating the Origin and Dispersal of Hepatitis B Virus Infection in Humans and Primates. Hepatology, 57, 908-916. [Google Scholar] [CrossRef] [PubMed]

为你推荐