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

项目摘要/摘要 在全球艾滋病毒-1流行30多年后，人们仍在寻求新的艾滋病毒-1预防战略。一个 设计有效的HIV-1疫苗面临的挑战是缺乏已知的天然相关保护因素，以防止 感染。一种识别这种相关性的相关模型是由血清阴性的个体提供的，尽管 反复接触HIV-1(HIV-1暴露的血清阴性，HESN)。对HESN的研究发现了证据 以HIV特异性免疫反应的形式预防HIV-1感染的潜在免疫相关因素 并降低免疫活性，或免疫停滞。然而，这些研究中的绝大多数是 重点放在外周血液中的免疫，而不是最初病毒进入和复制的粘膜部位。 因此，我们计划使用来自HIV的包括男性和女性HESN在内的一个新的队列的粘膜样本。 血清不一致夫妇和未接触艾滋病毒(HUSN)的男性和女性，结合最先进的 免疫学技术，以确定针对HIV-1的新的粘膜免疫保护机制。 鉴于我们最近的发现，宫颈阴道中和HIV的IgA增加与更高的HIV- 1暴露，我们假设HESN患者生殖器粘膜内的免疫反应将发生改变。 与胡森相比。因此，在目标1中，我们将检测HESN生殖器粘膜中的局部T细胞反应 与HUSN相比，我们预计将观察到这些免疫细胞在 有较高HIV-1暴露的个人。正如我们和其他人已经表明的那样，免疫静止似乎可以 为了提供对HIV-1感染的保护，我们建议既检查HIV特异性免疫，也检查免疫 HESN和HUSN的纵向激活。同时，我们将检查这些局部T细胞的稳定性 生殖道对HESN男性和女性启动PrEP的反应，因为我们有证据表明 PrEP使用者的黏膜免疫反应强度。最后，使用以前存档的 嵌套式伙伴PrEP病例对照研究，我们将在测试中检验新的免疫标志是否发生变化 识别与预防艾滋病毒-1感染相关。在目标2中，跟进我们发现的差异 在HIV-1高暴露和使用PrEP的妇女中，我们将检查宫颈阴道中和HIV-IgA HIV-1感染后男性和女性生殖道局部抗体分泌细胞的机制 曝光和PrEP启动。总括而言，当我们完成建议的研究后，我们将会有一个完整的 男性和女性生殖道和血液中适应性免疫反应和激活的特征 HESN对HIV-1暴露的影响，以及PrEP治疗后纵向发生的变化的衡量标准。 这些研究将潜在地为疫苗和其他艾滋病毒预防战略提供参考，通过确定 免疫保护的相关性，还将解决更好地了解免疫保护机制的迫切需要 人类黏膜免疫反应，因为这样的工作将加强我们对和 对一系列慢性和传染性疾病的免疫介导性保护。

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.