TH17 cells in AIDS pathogenesis and HIV vaccines

描述(申请人提供)：与人类感染艾滋病毒形成鲜明对比的是，非洲非人类灵长类动物的自然SIV感染通常是非致病性的，尽管病毒复制类似。虽然这种截然不同的结果背后的机制在很大程度上仍不清楚，但自然SIV感染的一个一致特征是缺乏慢性免疫激活。在感染艾滋病毒的人中，粘膜免疫功能的丧失和微生物从肠腔到全身循环的移位导致了慢性免疫激活和疾病进展。在最近的一系列研究中，我们发现人类和恒河猴(RMS)的致病性HIV和SIV感染与粘膜CD4+Th17细胞的优先耗竭有关，这是一种被认为对维持粘膜屏障完整性和产生抗微生物分子至关重要的T辅助细胞群。值得注意的是，在自然的、非致病性的SIV感染自然寄主物种--黑眉猴(SMS)的过程中，没有观察到这种粘膜Th17细胞的耗竭。该项目的主要目标是确定致病性和非致病性慢病毒感染中粘膜Th17细胞的不同调节机制(S)。我们将测试以下非互斥假设来解释为什么Th17细胞在SIV感染的SMS中被保存，而在HIV感染者或SIV感染的RMS中却没有：(I)Th17细胞对直接病毒感染更具抵抗力[目标1]；(Ii)Th17细胞更新和/或分化在维持Th17动态平衡方面更有效[目标2]；(Iii)Th17细胞归巢到粘膜组织中保存得更好[目标3]。阐明SIV感染的SMS中Th17细胞的潜在保存机制可能为这些动物如何进化以在感染时保持粘膜免疫从而产生抗爱滋病能力提供基本的见解。我们相信，这些信息将与艾滋病疫苗的设计相关，该疫苗将提供保护，使其免受艾滋病毒相关的粘膜免疫功能障碍的影响。我们最近发现，人类和恒河猴的致病性HIV/SIV感染与粘膜CD4+Th17优先耗尽有关，而粘膜CD4+Th17被认为是粘膜免疫的关键细胞群，其严重程度与慢性免疫激活水平和疾病进展相关。值得注意的是，在非致病性SIV感染煤烟芒果期间，Th17细胞以健康的频率保存下来。该项目的主要目标是确定致病性和非致病性慢病毒感染中粘膜Th17细胞的不同调节机制(S)。这些机制的阐明可能为HIV/SIV相关的粘膜免疫功能障碍的发病机制提供基础性的认识。我们相信，这些信息最终将为艾滋病疫苗的设计提供信息，该疫苗将提供保护，防止艾滋病毒传播和疾病进展。

DESCRIPTION (provided by applicant): In stark contrast to HIV infection in humans, natural SIV infections of African non-human primates are typically nonpathogenic despite similarly high virus replication. While the mechanisms underlying this strikingly different outcome are still largely unknown, a consistent feature of natural SIV infections is the lack of chronic immune activation. In HIV-infected humans, loss of mucosal immunity and microbial translocation from the intestinal lumen to the systemic circulation contribute to chronic immune activation and disease progression. In a series of recent studies, we have shown that pathogenic HIV and SIV infections of humans and rhesus macaques (RMs) are associated with preferential depletion of mucosal CD4+ Th17 cells, a T helper cell population deemed critical for the maintenance of mucosal barrier integrity and the production of anti-microbial molecules. Remarkably, this depletion of mucosal Th17 cells is not observed during natural, nonpathogenic SIV infection of sooty mangabeys (SMs), a natural host species. The overarching Aim of this project is to identify the mechanism(s) responsible for the different regulation of mucosal Th17 cells in pathogenic and nonpathogenic lentiviral infections. We will test the following non-mutually exclusive hypotheses to explain why Th17 cells are preserved in SIV-infected SMs but not in HIV-infected humans or SIV-infected RMs: (i) Th17 cells are more resistant to direct virus infection [Aim 1]; (ii) Th17 cell renewal and/or differentiation are more effective in maintaining Th17 homeostasis [Aim 2]; (iii) Th17 cell homing to mucosal tissues is better preserved [Aim 3]. Elucidation of the mechanisms underlying the preservation of Th17 cells in SIV-infected SMs may provide fundamental insights on how these animals have evolved to preserve mucosal immunity upon infection and thus become AIDS resistant. We believe that this information will be relevant to the design of an AIDS vaccine that will confer protection from the HIV-associated mucosal immune dysfunction. We recently showed that pathogenic HIV/SIV infections of humans and rhesus macaques are associated with preferential depletion of mucosal CD4+ Th17, a cell population deemed critical for mucosal immunity, whose severity correlates with the levels of chronic immune activation and disease progression. Remarkably, Th17 cells are preserved at a healthy frequency during nonpathogenic SIV infection of sooty mangabeys. The overarching Aim of this project is to identify the mechanism(s) responsible for the different regulation of mucosal Th17 cells in pathogenic and nonpathogenic lentiviral infections. The elucidation of these mechanisms may provide fundamental insights on the pathogenesis of the HIV/SIV-associated mucosal immune dysfunction. We believe that this information will ultimately inform the design of an AIDS vaccine that will confer protection from HIV transmission and disease progression.