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.

项目总结/摘要 慢性B型肝炎病毒（HBV）感染，影响全球2.4亿人，包括5-20%的HIV感染者 个体，结果是对急性感染的免疫应答不足和共价结合的持续存在。 闭合环状DNA（cccDNA）。在慢性HBV的核苷（酸）类似物治疗期间， “功能性治愈”，中心治疗目标定义为B型肝炎表面抗原（HBsAg）丧失， 无表面抗体形成，发生缓慢（~1%/年）。现在有越来越多的小说 如果不能达到病毒学治愈则增加HBV功能治愈的开发中的疗法（即，消除 cccDNA储库），包括恢复HBV特异性免疫的试剂。然而，免疫因素的关键， 实现功能性治愈仍然知之甚少，因为HBsAg丢失通常是罕见的，很少有研究 评估肝内免疫应答。为了指导新疗法在HIV-HBV合并感染中的应用， 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 的HBV。在赞比亚，我们建立了一个HIV-HBV合并感染（n=303）和HBV 单感染（n=63）的成年人服用基于替诺福韦（TDF）的疗法。在这个群体中， 实验室能力和获得肝脏采样，我们记录了HBsAg丢失率惊人的高（13.1%） 我们现在建议利用这种独特的方法， 研究HIV感染中HBV功能性治愈的科学机会。我们的中心假设-在ART中- 治疗HIV-HBV合并感染，强大的免疫重建释放增强的HBV功能治愈 响应-将在3个目标中进行测试。在目标1中，使用肝脏细针抽吸，我们将定义免疫 在基于TDF的治疗期间，HIV-HBV患者经历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应答和单细胞RNA测序特征 治疗期间的HIV状态和CD 4变化。在目标2中，我们将确定ART诱导的 外周血cccDNA转录标志物变化对HIV-HBV混合感染免疫重建的影响 包括定量HBsAg和两种新的标志物，B型肝炎核心相关抗原和HBV RNA。在Aim中 3、确定HIV-HBV合并感染者中HBV功能性治愈的临床预测因素。这 该项目结合了翻译，临床和流行病学方法，并利用现有的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 免疫疗法可能对HIV-HBV合并感染有效，以及（c）是否有新型外周cccDNA标志物 可用于这一人群。拟议的研究还将推进更广泛的HBV治疗议程， 包括将联合收割机免疫调节与靶向病毒学干预相结合， 功能性治疗