整合的乙型肝炎病毒 DNA 在抗病毒治疗期间维持表面抗原的产

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整合的乙型肝炎病毒 DNA 在抗病毒治疗期间维持表面抗原的产生
Tanner Grudda 1，Hyon S Hwang 2，Maraake Taddese 2，Jeffrey Quinn 2，Mark S Sulkowski 2，Richard K Sterling 3，Ashwin Balagopal 2，Chloe L Thio 1
隶属关系
隶属关系

    1
    美国巴尔的摩约翰霍普金斯大学彭博公共卫生学院分子微生物学和免疫学系。
    2
    美国巴尔的摩约翰霍普金斯大学医学院医学系。
    3
    美国里士满弗吉尼亚联邦大学胃肠病学、肝病学和营养学系。

    PMID：35797115 DOI：10.1172/JCI161818

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乙型肝炎功能性治愈（定义为乙型肝炎表面抗原 (HBsAg) 和血液中的 HBV DNA 持续丢失）的重点是消除或沉默 HBV 复制的核内模板，即共价闭合环状 DNA (cccDNA)。然而，HBsAg 也来源于整合到宿主基因组 (iDNA) 中的 HBV DNA。目前的治疗方法对 iDNA 对循环 HBsAg 的贡献知之甚少。我们应用了多重 ddPCR 测定来证明 iDNA 负责维持某些个体的 HBsAg 数量。我们使用来自 16 名接受核苷（酸）类似物 (NUC) 治疗的 HIV/HBV 合并感染者的成对大块肝组织，证明在活检之间 HBsAg 下降幅度较大的人从 cccDNA 获得 HBsAg，而 HBsAg 水平稳定的人主要从 iDNA 获得。我们将我们的分析应用于来自三个人的配对组织中的单个肝细胞，并证明具有显着 HBsAg 下降的个体具有相应的具有转录活性 cccDNA 的感染细胞损失，而没有 HBsAg 下降的个体具有稳定或增加数量的从 iDNA 产生 HBsAg 的细胞.我们证明，虽然 NUC 疗法可能有效控制 cccDNA 复制和转录，但需要创新疗法来解决维持 HBsAg 产生的 iDNA 转录。

关键词：抗原；肝炎;传染病;分子生物学;病毒学。

StephenW

  Integrated hepatitis B virus DNA maintains surface antigen production during antivirals
Tanner Grudda  1 , Hyon S Hwang  2 , Maraake Taddese  2 , Jeffrey Quinn  2 , Mark S Sulkowski  2 , Richard K Sterling  3 , Ashwin Balagopal  2 , Chloe L Thio  1
Affiliations
Affiliations

    1
    Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America.
    2
    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America.
    3
    Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, United States of America.

    PMID: 35797115 DOI: 10.1172/JCI161818

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Abstract

The focus of hepatitis B functional cure, defined as sustained loss of hepatitis B surface antigen (HBsAg) and HBV DNA from blood, is on eliminating or silencing the intranuclear template for HBV replication, covalently closed circular DNA (cccDNA). However, HBsAg also derives from HBV DNA integrated into the host genome (iDNA). Little is known about the contribution of iDNA to circulating HBsAg with current therapeutics. We applied a multiplex ddPCR assay to demonstrate that iDNA is responsible for maintaining HBsAg quantities in some individuals. Using paired bulk liver tissue from 16 HIV/HBV coinfected persons on nucleos(t)ide analogue (NUC) therapy, we demonstrate that people with larger HBsAg declines between biopsies derive HBsAg from cccDNA whereas people with stable HBsAg levels derive predominantly from iDNA. We applied our assay to individual hepatocytes in paired tissues from three people and demonstrated that the individual with significant HBsAg decline had a commensurate loss of infected cells with transcriptionally active cccDNA, while individuals without HBsAg decline had stable or increasing numbers of cells producing HBsAg from iDNA. We demonstrate that while NUC therapy may be effective at controlling cccDNA replication and transcription, innovative treatments are required to address iDNA transcription that sustains HBsAg production.

Keywords: Antigen; Hepatitis; Infectious disease; Molecular biology; Virology.

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http://www.jci.org/articles/view/161818/files/pdf