整合的HBV DNA在慢性乙型肝炎患者病毒复制及慢性感染维持中的潜在作用

摘要/Abstract

摘要： 慢性乙型肝炎病毒(HBV)感染是我国病毒性肝炎、肝硬化和肝细胞癌(HCC)的主要病因。慢性感染的各个阶段都存在频繁的HBV DNA整合至宿主肝细胞基因组中的事件发生。但现阶段对HBV整合的认识多集中在其促HCC的发生上。监管整合的HBV DNA无法转录出超基因组全长的、支持病毒逆转录复制的前基因组RNA(pgRNA),但其是否能够通过产生和提供病毒包膜蛋白HBsAg及羧基端缺失的HBx蛋白等参与支持病毒复制,特别是在HBV慢性感染维持中是否具有潜在作用,仍然未知。本文回顾现有的与HBV DNA整合相关的知识体系,尤其关注其在病毒复制及慢性感染维持中的意义。

关键词: 乙型肝炎病毒, HBV DNA整合, 病毒复制, 慢性感染

李玉坤, 顾智强, 姜倩倩, 陈香梅, 鲁凤民. 整合的HBV DNA在慢性乙型肝炎患者病毒复制及慢性感染维持中的潜在作用[J]. 肝脏, 2022, 27(9): 953-955.

参考文献

[1] Iannacone M, Guidotti L G. Immunobiology and pathogenesis of hepatitis B virus infection. Nat Rev Immunol, 2021, 22: 19-32.
[2] Tsai KN, Kuo CF, Ou JJ. Mechanisms of Hepatitis B Virus Persistence. Trends Microbiol, 2018, 26: 33-42.
[3] Wang J, Huang H, Liu Y, et al. HBV Genome and Life Cycle. Adv Exp Med Biol, 2020, 1179: 17-37.
[4] Bousali M, Papatheodoridis G, Paraskevis D, et al. Hepatitis B Virus DNA Integration, Chronic Infections and Hepatocellular Carcinoma. Microorganisms, 2021,9:1787.
[5] Li X, Zhang J, Yang Z, et al. The function of targeted host genes determines the oncogenicity of HBV integration in hepatocellular carcinoma. J Hepatol, 2014, 60: 975-84.
[6] Li W, Wei W, Hou F, et al. The integration model of hepatitis B virus genome in hepatocellular carcinoma cells based on high-throughput long-read sequencing. Genomics, 2022, 114: 23-30.
[7] Van Buuren N, Ramirez R, Soulette C, et al. Targeted long-read sequencing reveals clonally expanded HBV-associated chromosomal translocations in patients with chronic hepatitis B. JHEP Rep, 2022, 4: 100449.
[8] Zhang D, Zhang K, Protzer U, et al. HBV Integration Induces Complex Interactions between Host and Viral Genomic Functions at the Insertion Site. J Clin Transl Hepatol, 2021, 9: 399-408.
[9] Budzinska MA, Shackel NA, Urban S, et al. Cellular Genomic Sites of Hepatitis B Virus DNA Integration. Genes (Basel), 2018, 9:365.
[10] Saitta C, Tripodi G, Barbera A, et al. Hepatitis B virus (HBV) DNA integration in patients with occult HBV infection and hepatocellular carcinoma. Liver Int, 2015, 35: 2311-2317.
[11] Larsson S B, Tripodi G, Raimondo G, et al. Integration of hepatitis B virus DNA in chronically infected patients assessed by Alu-PCR. J Med Virol, 2018, 90: 1568-1575.
[12] D'souza S, Lau KC, Coffin CS, et al. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol, 2020, 26: 5759-5783.
[13] Bonilla Guerrero R, Roberts LR. The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma. J Hepatol, 2005, 42: 760-777.
[14] Jiang S, Yang Z, Li W, et al. Re-evaluation of the carcinogenic significance of hepatitis B virus integration in hepatocarcinogenesis. PLoS One, 2012, 7: e40363.
[15] Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol, 2016, 64: S84-S101.
[16] Erken R, Loukachov V, Van Dort K, et al. Quantified integrated hepatitis B virus is related to viral activity in patients with chronic hepatitis B. Hepatology, 2022, 76: 196-206.
[17] Abulaiti A, Gu Z, Jiang Q, et al. Letter to the Editor: Low sensitivity of RT-Alu-PCR in detection of HBV integrated chimeric transcripts. Hepatology, 2022.
[18] Tu T, Zhang H. Viral integrations in chronic hepatitis B infection: Purposeless passenger or problematic promoter of persistence? Hepatology, 2022, 76: 15-17.
[19] Meier M A, Calabrese D, Suslov A, et al. Ubiquitous expression of HBsAg from integrated HBV DNA in patients with low viral load. J Hepatol, 2021, 75: 840-847.
[20] Freitas N, Cunha C, Menne S, et al. Envelope proteins derived from naturally integrated hepatitis B virus DNA support assembly and release of infectious hepatitis delta virus particles. J Virol, 2014, 88: 5742-5754.
[21] Pollicino T, Cacciola I, Saffioti F, et al. Hepatitis B virus PreS/S gene variants: pathobiology and clinical implications. J Hepatol, 2014, 61: 408-417.
[22] Kim BK, Choi SH, Ahn SH, et al. Pre-S mutations of hepatitis B virus affect genome replication and expression of surface antigens. J Gastroenterol Hepatol, 2014, 29: 843-50.
[23] Wang T, Dai Y, Zhang M, et al. Sequence analysis of the Pre-S gene in chronic asymptomatic HBV carriers with low-level HBsAg. Int J Mol Med, 2018, 42: 2689-2699.
[24] Wang HC, Huang W, Lai MD, et al. Hepatitis B virus pre-S mutants, endoplasmic reticulum stress and hepatocarcinogenesis. Cancer Sci, 2006, 97: 683-688.
[25] Wang X, Wei Z, Cheng B, et al. Endoplasmic reticulum stress promotes HBV production by enhancing use of the autophagosome/multivesicular body axis. Hepatology, 2022, 75: 438-454.
[26] Decorsière A, Mueller H, Van Breugel PC, et al. Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor. Nature, 2016, 531: 386-389.
[27] Lucifora J, Arzberger S, Durantel D, et al. Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection. J Hepatol, 2011, 55: 996-1003.
[28] Gong DY, Chen EQ, Huang FJ, et al. Role and functional domain of hepatitis B virus X protein in regulating HBV transcription and replication in vitro and in vivo. Viruses, 2013, 5: 1261-1271.
[29] Tu T, Zhang H, Urban S. Hepatitis B Virus DNA Integration: In Vitro Models for Investigating Viral Pathogenesis and Persistence. Viruses, 2021, 13:180.
[30] Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection. Gut, 2012, 61: 1754-1764.
[31] Montali I, Vecchi A, Rossi M, et al. Antigen Load and T Cell Function: A Challenging Interaction in HBV Infection. Biomedicines, 2022, 10.
[32] Allweiss L, Volz T, Giersch K, et al. Proliferation of primary human hepatocytes and prevention of hepatitis B virus reinfection efficiently deplete nuclear cccDNA in vivo. Gut, 2018, 67: 542-552.
[33] Yan Y, Allweiss L, Yang D, et al. Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection. Emerg Microbes Infect, 2019, 8: 879-894.
[34] Murakami Y, Minami M, Daimon Y, et al. Hepatitis B virus DNA in liver, serum, and peripheral blood mononuclear cells after the clearance of serum hepatitis B virus surface antigen. J Med Virol, 2004, 72: 203-14.
[35] Kimbi GC, Kramvis A, Kew MC. Integration of hepatitis B virus DNA into chromosomal DNA during acute hepatitis B. World J Gastroenterol, 2005, 11: 6416-6421.
[36] Tseng TC, Kao JH. Clinical utility of quantitative HBsAg in natural history and nucleos(t)ide analogue treatment of chronic hepatitis B: new trick of old dog. J Gastroenterol, 2013, 48: 13-21.
[37] Wooddell CI, Yuen MF, Chan HL, et al. RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci Transl Med, 2017, 9:eaan0241.
[38] Gan W, Gao N, Gu L, et al. Reduction in Intrahepatic cccDNA and Integration of HBV in Chronic Hepatitis B Patients with a Functional Cure. J Clin Transl Hepatol, 2022.