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：
8238282
负责人：
Edmundo Nelson Kraiselburd
金额：
$ 72.83万
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/8238282
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

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

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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. 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.

描述（由申请人提供）：我们对宫颈阴道室中早期抗病毒机制的理解可能会降低HIV-1或SIV感染性，而在缺席IgG介导或CD8 T细胞反应的情况下，这是该建议的基础。非人类灵长类动物（NHP）模型也支持在存在抗HIV反应的情况下保持血清染色（暴露于血清阴性，ESN）的耐受性感染的证据，这些模型还支持重复的低剂量低剂量宫颈宫颈颈部挑战在恒河麦卡氏麦克氏麦芽疫虫中可能会导致MICTOSE越来越多地弥补，而这种挑战就会弥补，而遭受了屈光度的影响。环境（例如静脉病毒挑战）。现在，我们的初步数据首次显示了NHP中反复对SIV的宫颈染色性暴露会导致先天效应细胞浸润的增加，包括（1）等纤维细胞类动物树突状细胞表达IFN-A作为与组织APECEC 3G表达中的局部性相关的潜在诱导因子和（2）CD68 MIRPRICTRIPTOMES CD68 MORCR中的局部性增加。我们将检验以下假设：女性宫颈腔室中不传染性的病毒暴露可以诱导介导粘膜感染性降低状态的先天/IgA机制。具体而言，我们将：1。确定局部细胞宫颈组织浸润，IFN介导的基因表达和粘膜抗HIV IgA抗体反应在3个定义明确的基于性活动/伴侣的具有差异风险的女性中。 2。确定对非感染SIV E660暴露的重复宫颈体阴道暴露是否会诱导持续存在的先天细胞浸润（浆细胞类动物DCS，NK，NK，巨噬细胞），与粘膜SIV SIV特异性IGA抗体结合使用粘膜IGA抗体降低粘膜IGA抗体会降低粘膜感染感SIV MAC251。该提案代表了波多黎各大学，内布拉斯加州大学，明尼苏达大学，杜克大学，马萨诸塞大学，杜兰大学，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。公共卫生相关性（由申请人提供）：有必要制定新的策略来防止女性HIV-1传播。我们的应用程序旨在了解预期因其行为高度暴露于HIV-1的女性缺乏感染的相关性，并确定在她们中是否表现出特定的免疫反应（特定的先天免疫和IGA反应）。我们还将直接测试靶向非人类灵长类动物中候选先天和抗体反应的选择性激活的影响，以获取有关这些反应是否可以降低病毒传播的直接数据。