Early Innate/IgA Anti-HIV/SIV Response in Exposed Uninfected

描述（由申请人提供）：我们对宫颈阴道腔室早期抗病毒机制的理解仍然不完整，该机制可能在缺乏igg介导或CD8 t细胞反应的情况下降低HIV-1或SIV的感染性。非人类灵长类动物（NHP）模型也支持在存在抗hiv反应的情况下，仍然血清阴性（暴露血清阴性，ESN）的高度hiv暴露妇女对感染具有抵抗力的证据，其中恒河猴的反复低剂量宫颈阴道攻击可导致难耐状态，只能通过增加感染剂量或绕过粘膜微环境（例如静脉病毒攻击）来克服。我们的初步数据现在首次表明，在NHP中，宫颈阴道反复暴露于SIV可导致先天效应细胞浸润增加，包括：(1)表达IFN-a的浆细胞样树突状细胞作为一种潜在的诱导因子，与组织APOBEC 3G表达的局部增加有关，以及(2)CD68巨噬细胞浸润在fc受体细胞中。我们将验证女性宫颈阴道隔室非感染性病毒暴露可以诱导先天/IgA机制介导粘膜感染性降低状态的假设。具体来说，我们将：1。根据性行为/性伴侣的不同暴露风险，确定3组明确定义的妇女局部宫颈细胞组织浸润、ifn介导的基因表达和粘膜抗hiv IgA抗体反应的存在。2. 确定宫颈阴道反复暴露于非感染性SIV E660暴露是否会诱导持续的先天细胞浸润（浆细胞样dc， NK，巨噬细胞），并结合粘膜SIV特异性IgA抗体水平降低粘膜传染性SIV mac251。该提案是波多黎各大学、内布拉斯加大学、明尼苏达大学、杜克大学、马萨诸塞大学、杜兰大学、国家癌症研究所和Wistar研究所的合作成果。

DESCRIPTION (provided by applicant): Our understanding of early anti-viral mechanisms in the cervico-vaginal compartment that may reduce HIV-1 or SIV infectivity in the absence IgG-mediated or CD8 T-cell responses remains incomplete and is the basis for this proposal. Evidence for resistance to infection in highly HIV-exposed women that remain seronegative (exposed sero-negative, ESN) in presence of anti-HIV responses is also supported by non-human primate (NHP) models where repeated low-dose cervico-vaginal challenges in Rhesus macaques can result in a refractory state that can only be overcome by increased infectious doses or by-pass of the mucosal micro- environment (e.g. intravenous viral challenge). Our preliminary data now shows for the first time that repeated cervico-vaginal exposures to SIV in the NHP can result in an increase in innate effector cell infiltrates including (1) plasmacytoid dendritic cells expressing IFN-a as a potential inductive factor associated with the local increase in tissue APOBEC 3G expression, and (2) CD68 macrophages infiltrates among Fc-receptor bearing cells. We will test the hypothesis that uninfectious viral exposures in the female cervico-vaginal compartment can induce an innate/IgA mechanism mediating a state of reduced mucosal infectivity. Specifically, we will: 1. Determine the presence of local cellular cervical tissue infiltrate, IFN-mediated gene expression, and mucosal anti-HIV IgA antibody responses in 3 well-defined groups of women with differential exposure risk based on sexual activity/partners. 2. Determine if repeated cervico-vaginal exposures to non-infectious SIV E660 exposures induce a persistent innate cellular infiltrate (plasmacytoid DCs, NK, macrophages) that in combination with mucosal SIV-specific IgA antibody levels decreases mucosal infectivity SIV mac251. This proposal represents a collaborative effort between The University of Puerto Rico, Nebraska University, University of Minnesota, Duke University, University of Massachusetts, Tulane University, National Cancer Institute, and The Wistar Institute. PUBLIC HEALTH RELEVANCE (provided by applicant): There is a need to develop new strategies to prevent HIV-1 transmission in women. Our application seeks to understand correlates of lack of infection in women expected to be highly exposed to HIV-1 by their behavior and to determine if a particular immune response (specific innate immunity and IgA responses) is over- represented in them. We also will test directly the impact of targeting the selective activation of candidate innate and antibody response in non-human primates to obtain direct data as to whether these responses can decrease viral transmission.