TH17 cells in AIDS pathogenesis and HIV vaccines

描述（由申请人提供）：与人类的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，尽管病毒复制率同样很高。虽然这种截然不同的结果背后的机制在很大程度上仍然未知，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向体循环的易位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（RMs）的致病性HIV和SIV感染与粘膜CD4+ Th17细胞的优先耗竭有关，Th17细胞是一种T辅助细胞群，被认为对维持粘膜屏障的完整性和抗微生物分子的产生至关重要。值得注意的是，这种粘膜Th17细胞的损耗在天然宿主黑白眉（SMs）的自然、非致病性SIV感染过程中没有观察到。该项目的总体目标是确定在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。我们将检验以下非互斥假设，以解释为什么在siv感染的SMs中保存了Th17细胞，而在hiv感染的人类或siv感染的rm中没有保存Th17细胞：(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稳态方面更有效[Aim 2]；（iii） Th17细胞归巢粘膜组织得到更好的保存[Aim 3]。阐明在siv感染的SMs中保存Th17细胞的机制可能为这些动物如何进化到在感染时保持粘膜免疫从而变得抗艾滋病提供基本的见解。我们相信，这一信息将与艾滋病疫苗的设计有关，该疫苗将赋予保护免受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CD4+ Th17的优先耗竭有关，Th17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水平和疾病进展有关。值得注意的是，在非致病性SIV感染期间，Th17细胞被保存在一个健康的频率。该项目的总体目标是确定在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。这些机制的阐明可能为HIV/ siv相关粘膜免疫功能障碍的发病机制提供基础性的见解。我们认为，这一信息最终将为艾滋病疫苗的设计提供信息，从而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.