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

• 批准号: 10221470
• 负责人: Michael Jeffrey Vinikoor
• 金额: $ 63.86万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 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/10221470
• 关键词: AIDS clinical trial group; Adult; Affect; Antibodies; Antigens; Antiviral Agents; 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/antagonist; intrahepatic; liver biopsy; novel; novel marker; novel therapeutics; predicting response; programmed cell death protein 1; reconstitution; response; single-cell RNA sequencing; viral DNA; virology

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.

项目概要/摘要 慢性乙型肝炎病毒 (HBV) 感染，影响全球 2.4 亿人，其中 5-20% 为 HIV 感染者 个体，由于对急性感染的免疫反应不足和共价键的持续存在而导致 宿主肝细胞中的闭合环状 DNA (cccDNA)。在核苷（酸）类似物治疗慢性乙型肝炎期间， “功能性治愈”，核心治疗目标是乙型肝炎表面抗原（HBsAg）丧失或 没有表面抗体发育，发生缓慢（~1%/年）。现在小说越来越多 如果没有实现病毒学治愈（即消除 cccDNA 库），包括恢复 HBV 特异性免疫力的药物。然而，免疫因素对 实现功能性治愈仍然知之甚少，因为 HBsAg 消失通常很少见，而且很少有研究表明 评估肝内免疫反应。为了指导 HIV-HBV 合并感染的新疗法的使用，更好的方法 需要了解 HIV 和 HBV 活性抗逆转录病毒治疗 (ART) 对免疫控制的影响 乙肝病毒。在赞比亚，我们建立了 HIV-HBV 合并感染者 (n=303) 和 HBV 的前瞻性队列 接受基于替诺福韦 (TDF) 的治疗的单一感染 (n=63) 成年人。在这个群体中，具有很强的本地化能力 实验室能力和肝脏采样的获取，我们记录了 HBsAg 丢失率惊人的高 (13.1%) HIV-HBV 患者在接受基于 TDF 的 ART 的头 2 年期间。我们现在建议利用这一独特的 研究 HBV 功能性治愈 HIV 感染的科学机会。我们的中心假设——在 ART 中—— 治疗 HIV-HBV 合并感染后，强大的免疫重建可增强 HBV 功能性治愈 响应——将在 3 个目标中进行测试。在目标 1 中，使用肝脏细针穿刺，我们将定义免疫 HIV-HBV 患者在基于 TDF 的治疗期间经历 HBsAg 丢失/减少的环境。表型 将比较 T 细胞和其他免疫细胞类型的反应和单细胞 RNA 测序特征 治疗期间的 HIV 状态和 CD4 变化。在目标 2 中，我们将确定 ART 引起的影响 HIV-HBV合并感染中免疫重建对cccDNA转录外周标志物变化的影响 包括定量 HBsAg 和两种新型标记物：乙型肝炎核心相关抗原和 HBV RNA。瞄准 3，我们将定义 HIV-HBV 共感染个体中 HBV 功能性治愈的临床预测因子。这 该项目结合了转化、临床和流行病学方法，并利用了现有的 NIH- 资助的队列，将导致更好地了解 (a) HIV 对 HBV 自然史的影响，(b) 如何影响 免疫疗法可能对 HIV-HBV 合并感染有效，以及 (c) 新型外周 cccDNA 标记是否有效 可以在这个人群中使用。拟议的研究还将推进更广泛的乙肝治疗议程， 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乙型肝炎的策略 功能性治愈。