TH17 CELLS IN AIDS PATHOGENESIS AND HIV VACCINES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 与人类感染艾滋病毒相比，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。最近，我们发现人类和恒河猴(RMS)的致病性HIV和SIV感染与粘膜中CD4+Th17细胞的优先耗竭有关，而CD4+Th17细胞是维持粘膜屏障完整性和产生抗微生物分子的关键T辅助细胞。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。 本项目的目的是确定在致病性和非致病性感染中负责调节粘膜Th17细胞的机制(S)。我们将测试以下假设来解释为什么Th17细胞被保存在SIV感染的SMS中，而不是在HIV感染者或SIV感染的RMS中：(I)Th17细胞对病毒感染的抵抗力更强[目标1]；(Ii)Th17细胞的更新和/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]。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。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In contrast to HIV infection in humans, natural SIV infections of African nonhuman primates are typically non-pathogenic 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. Recently, 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 critical for the maintenance of mucosal barrier integrity and 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 Aim of this project is to identify mechanism(s) responsible for the regulation of mucosal Th17 cells in pathogenic and nonpathogenic infections. We will test the following 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 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]. 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.