Identification of Novel Mucosal Immune Mechanisms Involved in Protection from HIV-1

项目概要/摘要 在全球HIV-1流行30多年之后，人们仍在寻求新的HIV-1预防战略。一 设计有效的HIV-1疫苗面临的挑战是缺乏已知的保护HIV-1的天然相关物。 感染一个相关的模型，以确定这种相关性是由个人谁保持血清阴性， 重复HIV-1暴露（HIV-1暴露血清阴性者，HESN）。对HESN的研究发现了证据 以HIV特异性免疫反应的形式保护免受HIV-1感染的潜在免疫相关性 以及免疫激活或免疫静止减少。然而，这些研究中的绝大多数是 重点是外周血中的免疫力，而不是最初病毒进入和复制的粘膜部位。 因此，我们计划使用一个新队列的粘膜取样，包括来自HIV-1的男性和女性HESN。 血清不一致夫妇和HIV未暴露（HUSN）男性和女性，结合最新技术水平 免疫学技术，以确定新的粘膜免疫保护机制，从HIV-1。 鉴于我们最近发现宫颈阴道HIV中和伊加增加与HIV-1水平升高有关， 1暴露，我们假设生殖器粘膜内的免疫反应将改变在HESN 相比之下，胡因此，在目标1中，我们将检查HESN生殖器粘膜中的局部T细胞反应。 与HUSN相比，我们希望观察到这些免疫细胞的反应和保留增加， HIV-1感染率较高的人群。正如我们和其他人已经证明的那样，免疫静止似乎 提供保护免受HIV-1感染，我们建议检查HIV特异性免疫以及免疫 在HESN和HUSN纵向激活。同时，我们将检查这些局部T细胞的稳定性， HESN男性和女性在PrEP启动后生殖道的反应，因为我们有证据表明， 增强PrEP使用者的粘膜免疫反应。最后，使用以前从 巢式伴侣PrEP病例对照研究，我们将在测试是否免疫特征的新变化，我们 鉴定与保护免受HIV-1感染相关。在目标2中，继续我们的微分发现， 宫颈阴道HIV中和伊加在HIV-1暴露较高和使用PrEP的女性中，我们将研究 HIV-1感染后男性和女性生殖道内局部抗体分泌细胞的机制 暴露和PrEP启动。总括而言，当我们完成建议的研究后， 男性和女性生殖道和血液中适应性免疫应答和激活的表征 在HESN的HIV-1暴露后，与措施的变化，发生纵向后PrEP治疗。 这些研究将可能为疫苗和其他艾滋病毒预防策略提供信息， 免疫相关的保护，也将解决一个关键的需要，以更好地了解机制， 人类粘膜免疫反应，因为这样的工作将提高我们的免疫病理学的知识， 免疫介导的对一系列慢性和传染性疾病的保护。

PROJECT SUMMARY/ABSTRACT More than 30 years into the global HIV-1 epidemic, novel HIV-1 prevention strategies are still being sought. A challenge to the design of an effective HIV-1 vaccine is the lack of known natural correlates of protection from infection. A relevant model to identify such correlates is offered by individuals who remain seronegative despite repeated HIV-1 exposures (HIV-1-exposed seronegatives, HESN). Studies of HESN have uncovered evidence of potential immune correlates of protection from HIV-1 infection in the form of HIV-specific immune responses and reduced immune activation, or immune quiescence. However, the vast majority of these studies were focused on immunity within the peripheral blood rather than mucosal sites of initial virus entry and replication. Thus, we plan to use mucosal sampling of a novel cohort including male and female HESN from HIV- serodiscordant couples and HIV-unexposed (HUSN) men and women, combined with state-of-the-art immunological techniques, to identify novel mucosal immune mechanisms of protection from HIV-1. Given our recent findings of an association of increased cervicovaginal HIV-neutralizing IgA and higher HIV- 1 exposure, we hypothesize that immune responses within the genital mucosa will be altered in HESN compared to HUSN. Thus, in Aim 1 we will examine local T cell responses in the genital mucosa of HESN compared to HUSN, and we expect to observe increased responses and retention of these immune cells in individuals with higher HIV-1 exposure. As we and others have shown that immune quiescence appears to offer protection from HIV-1 infection, we propose to examine both HIV-specific immunity as well as immune activation in HESN and HUSN longitudinally. In parallel, we will examine the stability of these local T cell responses in the genital tract upon PrEP initiation by HESN men and women, as we have evidence of higher magnitude mucosal immune responses in PrEP users. Finally, using previously archived samples from the nested Partners PrEP case-control study, we will in test whether the novel changes in immune signatures we identify are correlated with protection from HIV-1 infection. In Aim 2, following up on our finding of differential cervicovaginal HIV-neutralizing IgA in women with higher HIV-1 exposure and with PrEP use, we will examine mechanisms of local antibody-secreting cells within the genital tract of men and women following HIV-1 exposure and PrEP initiation. In sum, upon completion of our proposed studies, we will have a complete characterization of adaptive immune responses and activation in the male and female genital tracts and blood in HESN upon HIV-1 exposure, with measures of the changes that occur longitudinally upon PrEP treatment. These studies will potentially inform vaccine and other HIV prevention strategies though identification of immune correlates of protection, and will also address a critical need to better understand mechanisms of the human mucosal immune responses, as such work will enhance our knowledge of the immunopathology of and immune-mediated protection to a range of chronic and infectious diseases.