HBV-specific T cell immunity in HBV/HIV coinfection

项目摘要/摘要 在艾滋病毒携带者(PLWH)中，乙肝病毒(HBV)是一种常见的混合感染，导致高 与肝脏相关的死亡率。即使在早期开始包括乙肝病毒活性的抗逆转录病毒治疗 在核苷类似物(NA)中，乙肝病毒/艾滋病毒混合感染者的死亡率仍然高得令人无法接受。有一个 为感染乙肝病毒/艾滋病病毒的人提供额外的乙肝治疗的充分理由。乙肝病毒治疗研究议程 是(1)了解乙肝的生物学，特别是导致乙肝功能治愈(FC)的机制，这是 定义为血液中乙肝表面抗原的血清清除，以及(2)评估新的抗病毒和/或 免疫疗法可以提高HBVFc，使其从目前每年约1%的速度提高。但是，目前， PLWH在乙肝治疗研究中的代表性很低，而艾滋病毒感染几乎在所有研究中都是排除标准 乙肝新疗法的临床试验。加快对乙肝病毒感染者和艾滋病毒感染者的新疗法的使用 在HIV感染的背景下，需要更好地了解宿主对乙肝病毒的控制。这个项目的重点是 关于乙肝病毒控制的细胞免疫机制，特别是乙肝病毒特异性T细胞。我们的中心假设是 在乙肝病毒/艾滋病病毒混合感染中，CD4T细胞是介导乙肝病毒的免疫反应的重要组成部分 控制，包括FC。这一假设将通过三个具体目标进行检验。在目标1中，我们将调查 HIV合并感染相关免疫失调，尤其是CD_4耗竭对T细胞数量和数量的影响 乙肝病毒特异性T细胞反应的质量。在目标2中，我们将研究介导HBVFc的T细胞反应。 在非活动性乙肝病毒感染期间(即，低HBVDNA，正常ALT， 无--轻微的肝病)。在这组患者中，我们先前报告了相对较高的HBVFc比率。在《目标3》中，我们将 描述成人乙肝病毒特异性T细胞应答和肝内免疫格局的演变 急性乙肝病毒感染，通常导致HBVFC，合并和不合并艾滋病毒感染。以上是科学的 调查将在赞比亚(南部非洲)一个独特的乙肝临床队列内进行，其中包括成人 慢性和急性乙肝患者，合并和不合并HIV感染，特征纵向较大 在NA治疗前和治疗期间取大量血液和肝脏样本。到目前为止，已经确定了乙肝Fc&gt；40 队列中的次数，主要是在患有乙肝病毒/艾滋病毒混合感染的参与者中。这个项目的成功完成将 通过确定与乙肝病毒/艾滋病毒混合感染中的乙肝病毒Fc相关的免疫介质并通过定义 PLWH患者对HBVFc的特异性免疫屏障它还将有助于识别合并感染的患者群体 他们可能或多或少愿意根据他们目前或最低的CD4和当前水平使用新兴药物进行治疗 乙肝病毒控制水平。对特定的CD4T细胞和肝内免疫环境的深入分析也将是 这对我们理解无HIV的慢性乙肝病毒感染具有重要意义。

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.