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

暴露的未感染者的早期先天/IgA 抗 HIV/SIV 反应

基本信息

批准号：
8447536
负责人：
Edmundo Nelson Kraiselburd
金额：
$ 73.15万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8447536
关键词：
Address Affect Antibodies Antibody Formation Antiviral Agents Antiviral Response Area Behavior Binding Biological Biopsy CD3 Antigens CD32 Antigens CD4 Positive T Lymphocytes CD8B1 gene Cells Cervical Data Dendritic Cells Dose Effector Cell Environment Event Exposure to FCGR3B gene Fc Receptor Female Functional disorder Funding Gene Expression Genital system Grant HIV HIV Vaccine Trials Network HIV-1 Hour Human IL3RA gene IgG Receptors Immune Immune response Immunoglobulin A Immunoglobulin G Infection Institutes Interferons Intravenous Leucocytic infiltrate Liquid substance Macaca mulatta Massachusetts Mediating Microarray Analysis Minnesota Modeling National Cancer Institute National Institute of Allergy and Infectious Disease Natural Immunity Natural Killer Cells Nebraska Outcome Phenotype Plasma Positioning Attribute Predisposition Puerto Rico RNA Refractory Research Infrastructure Resistance Resistance to infection Risk SIV Sampling Series Serum Sex Behavior Specimen Study models T cell response Testing The Wistar Institute Time Tissues Universities Vaccines Vagina Viral Virus Woman Women&apos s Group Work anti-IgA base design high risk in vitro activity macrophage nonhuman primate particle prevent protein expression public health relevance response sex transmission process

项目摘要

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.

描述（由申请人提供）：我们对宫颈阴道区室中早期抗病毒机制的理解可能会在缺乏 IgG 介导或 CD8 T 细胞反应的情况下降低 HIV-1 或 SIV 感染性，但这一理解仍然不完整，这是此研究的基础提议。非人灵长类动物 (NHP) 模型也支持在存在抗 HIV 反应的情况下仍保持血清阴性（暴露血清阴性，ESN）的高度 HIV 暴露女性的感染抵抗力的证据，其中重复低剂量宫颈阴道挑战恒河猴中的病毒可导致难治性状态，只能通过增加感染剂量或绕过粘膜微环境（例如静脉内病毒攻击）来克服。我们的初步数据现在首次表明，在 NHP 中反复宫颈阴道暴露于 SIV 可导致先天效应细胞浸润增加，包括（1）表达 IFN-a 作为与局部相关的潜在诱导因子的浆细胞样树突状细胞。组织 APOBEC 3G 表达增加，(2) CD68 巨噬细胞浸润到 Fc 受体承载细胞中。我们将检验以下假设：女性子宫颈阴道室中的非感染性病毒暴露可诱导先天/IgA 机制介导粘膜感染性降低的状态。具体来说，我们将： 1. 确定 3 个明确定义的女性组中是否存在局部细胞宫颈组织浸润、IFN 介导的基因表达和粘膜抗 HIV IgA 抗体反应，这些女性组的暴露风险因性活动/伴侣而异。 2. 确定宫颈阴道反复暴露于非传染性 SIV E660 暴露是否会诱导持续的先天性细胞浸润（浆细胞样 DC、NK、巨噬细胞），与粘膜 SIV 特异性 IgA 抗体水平相结合可降低粘膜感染性 SIV mac251。该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、国家癌症研究所和威斯塔研究所之间的合作努力。