TH17 cells in AIDS pathogenesis and HIV vaccines

描述（由申请人提供）：与人类HIV感染形成鲜明对比的是，非洲非人灵长类动物的自然SIV感染通常是非致病性的，尽管病毒复制相似。虽然这种截然不同的结果背后的机制在很大程度上仍然是未知的，但自然SIV感染的一个一致特征是缺乏慢性免疫激活。在HIV感染者中，粘膜免疫的丧失和微生物从肠腔易位到体循环有助于慢性免疫激活和疾病进展。在最近的一系列研究中，我们已经表明，人类和恒河猴（RM）的致病性HIV和SIV感染与粘膜CD 4 + Th 17细胞的优先消耗有关，这是一种T辅助细胞群，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。值得注意的是，在自然的非致病性SIV感染天然宿主物种白眉猴（SMs）期间没有观察到粘膜Th 17细胞的这种耗竭。该项目的首要目的是确定致病性和非致病性慢病毒感染中粘膜Th 17细胞不同调节的机制。我们将测试以下非互斥假设，以解释为什么Th 17细胞在SIV感染的SM中保留，而在HIV感染的人或SIV感染的RM中不保留：（i）Th 17细胞对直接病毒感染更具抵抗力[目标1];（ii）Th 17细胞更新和/或分化在维持Th 17稳态方面更有效[目标2];（iii）Th 17细胞更新和/或分化在维持Th 17稳态方面更有效[目标3]。（iii）Th 17细胞归巢至粘膜组织得到更好的保护[目标3]。阐明SIV感染的SM中Th 17细胞的保护机制可能为这些动物如何进化以在感染后保护粘膜免疫从而成为AIDS抗性提供基本见解。我们相信，这些信息将是相关的艾滋病疫苗的设计，将提供保护，从艾滋病毒相关的粘膜免疫功能障碍。我们最近发现，人类和恒河猴的致病性HIV/SIV感染与粘膜CD 4 + Th 17的优先消耗有关，这是一种被认为对粘膜免疫至关重要的细胞群，其严重程度与慢性免疫激活和疾病进展的水平相关。值得注意的是，Th 17细胞在非致病性SIV感染白眉猴期间以健康的频率保存。该项目的首要目的是确定致病性和非致病性慢病毒感染中粘膜Th 17细胞不同调节的机制。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了基础性的见解。我们认为，这些信息将最终为艾滋病疫苗的设计提供信息，从而保护人们免受艾滋病毒传播和疾病进展的影响。

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.