HBV-specific T cell immunity in HBV/HIV coinfection

HBV/HIV 共感染中的 HBV 特异性 T 细胞免疫

• 批准号: 10771782
• 负责人: GEORG Michael LAUER
• 金额: $ 73.84万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-07 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10771782
• 关键词: Acceleration; Acute Hepatitis; Address; Adult; Antiviral Therapy; Biological Response Modifiers; Biology; Blood; Blood Volume; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Chronic Hepatitis; Chronic Hepatitis B; Clinical; Clinical Trials; Combined Modality Therapy; Data; Development; Disease; Disease Progression; Enrollment; Evolution; Exclusion Criteria; Fine needle aspiration biopsy; Flow Cytometry; Frequencies; Functional disorder; Generations; HIV; HIV Infections; Heart; Hepatitis B; Hepatitis B Infection; Hepatitis B Surface Antigens; Hepatitis B Virus; Immune; Immune response; Immunity; Immunologics; Immunology; Immunotherapy; In Vitro; Infection; Investigation; Knowledge; Liver; Liver diseases; Mediating; National Institute of Allergy and Infectious Disease; Newly Diagnosed; Outcome; Participant; Patients; Peripheral; Persons; Pharmaceutical Preparations; Phenotype; Policies; Population; Primary carcinoma of the liver cells; Recovery; Reporting; Research; Role; Safety; Sampling; Site; Southern Africa; T cell response; T-Lymphocyte; Testing; Therapeutic; Translating; United States National Institutes of Health; Viral; Virus Diseases; Zambia; antiretroviral therapy; co-infection; cohort; e Antigens; experience; interest; intrahepatic; mortality; novel; novel therapeutics; nucleoside analog; peripheral blood; prevent; programs; response; seroconversion; transcriptome sequencing; viral DNA; virtual

Project Summary/Abstract Among people living with HIV (PLWH), hepatitis B virus (HBV) is a common coinfection that contributes to high rates of liver-related mortality. Even with early initiation of antiretroviral therapies that include HBV-active nucleoside analogs (NA), mortality in people with HBV/HIV coinfection remains unacceptably high. There is a strong rationale for additional HBV therapies for people with HBV/HIV infection. The HBV cure research agenda is to (1) understand HBV biology, particularly the mechanisms that lead to HBV functional cure (FC), which is defined as seroclearance of the hepatitis B surface antigen in blood, and (2) to evaluate novel antiviral and/or immunotherapies that can increase HBV FC from its current rate of ~1% per year. However, at the present, PLWH are poorly represented in HBV cure research, and HIV infection is an exclusion criterion in virtually all clinical trials of novel HBV therapeutics. To accelerate the use of novel therapies in patients with HBV/HIV coinfection, a better understanding is needed of host control of HBV in the setting of HIV. This project focuses on cellular immune mechanisms of HBV control, particularly HBV-specific T cells. Our central hypothesis is that in HBV/HIV coinfection, CD4 T cells represent a critical component of the immune response mediating HBV control, including FC. This hypothesis will be tested through 3 specific aims. In Aim 1, we will investigate the impact of HIV coinfection-associated immune dysregulation, especially CD4 depletion, on the quantity and quality of HBV-specific T cell responses. In Aim 2, we will investigate the T-cell responses mediating HBV FC in patients with HBV/HIV coinfection who are treated during inactive HBV infection (i.e., low HBV DNA, normal ALT, no-minimal liver disease). In this group, we previously reported relatively high rates of HBV FC. In Aim 3, we will characterize the evolution of HBV-specific T cell responses and the intrahepatic immune landscape during adult acute HBV infection that typically results in HBV FC, with and without HIV coinfection. The above scientific investigation will occur within a unique HBV clinical cohort in Zambia (Southern Africa), which includes adult patients with chronic and acute HBV infection, with and without HIV coinfection, and features longitudinal large volume blood and liver sampling before and during NA therapy. To date HBV FC has been ascertained >40 times in the cohort, mainly in participants with HBV/HIV coinfection. Successful completion of this project will change the field by identifying immune mediators associated with HBV FC in HBV/HIV coinfection and by defining specific immunological barriers to HBV FC in PLWH. It also will help to identify patient groups with coinfection who may be more or less amenable to cure with emerging drugs based on their current or nadir CD4 and current level of HBV control. In-depth analysis of specific CD4 T cells and the intrahepatic immune milieu will also be highly significant in our understanding of chronic HBV infection without HIV.

项目摘要/摘要 在艾滋病毒（PLWH）的患者中，乙型肝炎病毒（HBV）是一种常见的共同感染，有助于高 与肝有关的死亡率的发生率。即使早期开始抗逆转录病毒疗法，包括HBV活性 核苷类似物（NA），HBV/HIV共感染患者的死亡率仍然不可接受。有一个 针对HBV/HIV感染患者的其他HBV疗法的强大原理。 HBV治疗研究议程 是（1）了解HBV生物学，尤其是导致HBV功能治愈（FC）的机制，这是 定义为血液中丙型肝炎表面抗原的血清清除，（2）评估新型抗病毒和/或 可以将HBV FC从目前的每年约1％提高的免疫疗法。但是，目前， PLWH在HBV治疗研究中的代表性不佳，HIV感染是几乎所有的排除标准 新型HBV疗法的临床试验。加速HBV​​/HIV患者的新型疗法 共同感染，需要更好地理解HIV环境中HBV的宿主控制。这个项目集中在 关于HBV对照的细胞免疫机制，尤其是HBV特异性T细胞。我们的中心假设是 在HBV/HIV共感染中，CD4 T细胞代表了介导HBV的免疫反应的关键成分 控制，包括FC。该假设将通过3个特定目标进行检验。在AIM 1中，我们将调查 HIV共同感染相关的免疫失调，尤其是CD4耗竭，对数量的影响 HBV特异性T细胞反应的质量。在AIM 2中，我们将研究介导HBV FC的T细胞响应 在非活动性HBV感染期间接受治疗的HBV/HIV共感染患者（即低HBV DNA，正常ALT， 无肝病）。在这一组中，我们以前报道了HBV FC的相对较高的速率。在AIM 3中，我们将 表征成人期间HBV特异性T细胞反应的演变和肝内免疫景观 急性HBV感染通常会导致HBV FC，有或没有HIV共感染。上述科学 调查将在赞比亚（南部非洲）的独特HBV临床队列中进行，其中包括成人 患有慢性和急性HBV感染的患者，有和没有HIV共感染，并具有纵向大的患者 NA治疗之前和期间的体积血液和肝脏采样。迄今为止，HBV FC已确定> 40 在队列中，主要是在HBV/HIV共感染的参与者中。成功完成该项目将 通过识别与HBV/HIV共感染中与HBV FC相关的免疫介质通过确定与HBV FC相关的免疫介质的改变并定义 PLWH中HBV FC的特定免疫障碍。它也将有助于识别与共感染的患者群体 谁可能或多或少地根据当前或Nadir CD4和当前的新兴药物治愈新兴药物 HBV控制水平。对特定CD4 T细胞和肝内免疫环境的深入分析也将是 我们对没有HIV的慢性HBV感染的理解非常重要。