Mechanisms of HBV Functional Cure During Tenofovir-based ART in HIV/HBV Coinfection

HIV/HBV 合并感染中基于替诺福韦的 ART 期间 HBV 功能性治愈的机制

基本信息

批准号：
10462553
负责人：
Michael Jeffrey Vinikoor
金额：
$ 64.27万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462553
关键词：
AIDS clinical trial group Adult Affect Antibodies Antigens Biological Markers CD4 Lymphocyte Count Cells Chronic Chronic Hepatitis B Circular DNA Clinical Clinical Research Core Biopsy Country DNA DNA Markers Development Epidemiology Fibrosis Fine needle aspiration biopsy Funding Genetic Transcription Genotype Goals HIV HIV Infections HIV therapy Hepatitis B Hepatitis B Surface Antigens Hepatitis B Virus Hepatocyte Immune Immune response Immunity Immunologic Factors Immunologics Immunotherapy Individual Intervention Kidney Kinetics Laboratories Liver Measures Mediating Modeling Natural History Outcome Patients Peripheral Phenotype Population Predictive Factor Prospective cohort RNA Research Risk Sampling Serology Surface Surrogate Markers T-Lymphocyte Tenofovir Testing Therapeutic Toxic effect United States National Institutes of Health Viral Virus Work Zambia acute infection analog antiretroviral therapy base bone cell type clinical predictors co-infection cohort elastography exhaustion experience genetic signature immune reconstitution immunoregulation inhibitor intrahepatic liver biopsy novel novel marker novel therapeutics predicting response programmed cell death protein 1 reconstitution response single-cell RNA sequencing viral DNA

项目摘要

PROJECT SUMMARY/ABSTRACT Chronic hepatitis B virus (HBV) infection, affecting 240 million worldwide including 5-20% of HIV-infected individuals, results from an inadequate immune response to acute infection and persistence of covalently closed circular DNA (cccDNA) in the host hepatocyte. During nucleos(t)ide analog therapy for chronic HBV, `functional cure', the central therapeutic goal defined by loss of hepatitis B surface antigen (HBsAg) with or without surface antibody development, occurs slowly (~1%/year). There are now a growing number of novel therapies in development to increase HBV functional cure if not achieve virological cure (i.e., elimination of the cccDNA reservoir), including agents to restore HBV-specific immunity. Yet, the immune factors critical to achieving functional cure remain poorly understood because HBsAg loss is usually rare and few studies have assessed intrahepatic immune responses. To guide the use of novel therapies in HIV-HBV coinfection, a better understanding is needed of the impact of HIV and HBV-active antiretroviral therapy (ART) on immune control of HBV. In Zambia, we established a prospective cohort of HIV-HBV coinfected (n=303) and HBV monoinfected (n=63) adults taking tenofovir (TDF)-based therapies. Within this cohort, which has strong local laboratory capacity and access to liver sampling, we documented a strikingly high rate (13.1%) of HBsAg loss among HIV-HBV patients during the first 2 years on TDF-based ART. We now propose to exploit this unique scientific opportunity to investigate HBV functional cure in HIV infection. Our central hypothesis – that in ART- treated HIV-HBV coinfection, robust immune reconstitution unleashes an enhanced HBV functional cure response – will be tested in 3 aims. In Aim 1, using liver fine needle aspirations, we will define the immune milieu in which HIV-HBV patients experience HBsAg loss/reduction during TDF-based therapy. Phenotypic responses and single cell RNA-sequencing signatures of T cells and other immune cell types will be compared by HIV status and CD4 changes during therapy. In Aim 2, we will determine the impact of ART-induced immune reconstitution in HIV-HBV coinfection on the change in peripheral markers of cccDNA transcription including quantitative HBsAg and two novel markers, hepatitis B core-related antigens and HBV RNA. In Aim 3, we will define the clinical predictors of HBV functional cure among HIV-HBV coinfected individuals. This project, which combines translational, clinical, and epidemiological approaches, and leverages an existing NIH- funded cohort, will lead to a better understanding of (a) the impact of HIV on HBV natural history, (b) how immunological therapies might work in HIV-HBV coinfection, and (c) whether novel peripheral cccDNA markers can be used in this population. The proposed research will also advance the broader HBV cure agenda, including the strategy to combine immune modulation with targeted virological interventions to achieve HBV functional cure.

项目摘要/摘要慢性丙型肝炎病毒（HBV）感染，全球影响2.4亿个，包括5-20％的HIV感染个体，是由于对急性感染的免疫反应不足和共价持续性而导致的宿主肝细胞中的闭合圆形DNA（CCCDNA）。在用于慢性HBV的核（T）IDE模拟治疗期间 “功能治愈”，这是由乙型肝炎表面抗原（HBSAG）或用或没有表面抗体的发展，会缓慢发生（约1％/年）。现在有越来越多的小说如果无法实现病毒学治疗，则在发育中的疗法增加HBV功能治愈（即消除 CCCDNA储层），包括恢复HBV特异性免疫力的药物。然而，免疫因素至关重要实现功能治疗仍然很少理解，因为HBSAG损失通常很少，而且很少有研究评估了肝内免疫反应。为了指导在HIV-HBV共感染中使用新型疗法，更好需要了解HIV和HBV活性抗逆转录病毒疗法（ART）对免疫控制的影响 HBV。在赞比亚，我们建立了预期的HIV-HBV共同感染（n = 303）和HBV的队列单感染（n = 63）的成年人接受替诺福韦（TDF）的疗法。在这个队列中，有强大的本地我们记录了实验室能力和获取肝脏采样的方法，我们记录了HBSAG损失的惊人高率（13.1％）在最初两年中，HIV-HBV患者在基于TDF的ART上。我们现在建议利用这种独特的研究HIV感染中HBV功能治疗的科学机会。我们的中心假设 - 在艺术中治疗的HIV-HBV共感染，可靠的免疫重建释放的HBV功能治愈响应 - 将以3个目标进行测试。在AIM 1中，使用肝细针吸气，我们将定义免疫在基于TDF的治疗期间，HIV-HBV患者在HIV-HBV患者中经历了HBSAG损失/减少的环境。表型将比较T细胞和其他免疫细胞类型的响应和单细胞RNA-RNA再生特征在治疗过程中，艾滋病毒状况和CD4变化。在AIM 2中，我们将确定艺术引起的影响 HIV-HBV共同感染的免疫重建包括定量HBSAG和两个新型标记，乙型肝炎B核心相关抗原和HBV RNA。目标 3，我们将定义HIV-HBV共感染个体中HBV功能治疗的临床预测因子。这项目结合了转化，临床和流行病学方法，并利用现有的NIH- 资助的队列将使（a）艾滋病毒对HBV自然历史的影响更好地理解（b）免疫疗法可能在HIV-HBV共感染中起作用，（c）新型外围CCCDNA标记是否是否可以在这个人群中使用。拟议的研究还将推进更广泛的HBV治疗议程，包括将免疫调节与有针对性的病毒学干预措施相结合以实现HBV的策略功能治疗。