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

描述(由申请人提供)：我们对宫颈-阴道间隔的早期抗病毒机制的理解仍不完整，该机制可能在没有免疫球蛋白介导的T细胞反应或CD8 T细胞反应的情况下降低HIV-1或SIV的传染性，并是该提议的基础。非人灵长类动物(NHP)模型也支持高HIV暴露女性在抗HIV反应存在的情况下保持血清阴性(暴露血清阴性，ESN)对感染的抵抗力的证据，在这些模型中，恒河猴反复低剂量的宫颈-阴道挑战可以导致难治状态，这种状态只能通过增加感染剂量或绕过粘膜微环境(例如静脉病毒挑战)来克服。我们的初步数据首次显示，在NHP中反复暴露于SIV可以导致固有效应细胞浸润的增加，包括(1)浆细胞样树突状细胞表达干扰素-α作为潜在的诱导因子与组织APOBEC 3G表达的局部增加相关；(2)CD68巨噬细胞在Fc受体承载细胞之间渗透。我们将检验这一假设，即女性宫颈-阴道隔室中的非感染性病毒暴露可以诱导一种先天的/IgA机制，介导一种粘膜感染性降低的状态。具体地说，我们将：1.确定三组明确的妇女中局部细胞宫颈组织浸润物、干扰素介导的基因表达和粘膜抗HIV IgA抗体反应的存在，这些妇女的暴露风险根据性行为/伴侣的不同而不同。2.确定宫颈-阴道反复暴露于非感染性SIV E660是否会诱导持续的固有细胞浸润(浆细胞样树突状细胞、NK细胞、巨噬细胞)，与粘膜SIV特异性IgA抗体水平相结合，降低粘膜感染性SIV mac251。这项提案代表了波多黎各大学、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、国家癌症研究所和维斯塔尔研究所之间的合作努力。

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.