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

• 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
• 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' 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

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）：我们对宫颈阴道隔室中早期抗病毒机制的理解仍然不完整，这是本提案的基础，该机制可能在不存在IgG介导或CD 8 T细胞应答的情况下降低HIV-1或SIV感染性。血清反应阴性的艾滋病毒高度暴露妇女对感染的抵抗力证据非人灵长类动物（NHP）模型也支持在存在抗HIV应答的情况下对小鼠（暴露的血清阴性，ESN）的免疫应答，其中在恒河猴中重复的低剂量宫颈-阴道攻击可导致难治性状态，其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。我们的初步数据首次显示，NHP中反复的宫颈-阴道暴露于SIV可导致先天性效应细胞浸润的增加，包括（1）表达IFN-α的浆细胞样树突状细胞作为与组织APOBEC 3G表达局部增加相关的潜在诱导因子，和（2）携带Fc受体的细胞中的CD 68巨噬细胞浸润。我们将检验以下假设：女性宫颈-阴道隔室中的非感染性病毒暴露可诱导先天性/伊加机制介导粘膜感染性降低的状态。具体来说，我们将：1。在3组明确定义的女性中，确定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伊加抗体反应，这些女性具有基于性活动/伴侣的不同暴露风险。2.确定重复的宫颈阴道暴露于非感染性SIV E660暴露是否诱导持续的先天性细胞浸润（浆细胞样DC、NK、巨噬细胞），其与粘膜SIV特异性伊加抗体水平结合降低粘膜感染性SIV mac 251。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、马萨诸塞州大学、杜兰大学、国家癌症研究所和Wistar研究所之间的合作努力。 公共卫生相关性（由申请人提供）：有必要制定新的战略，以防止艾滋病毒-1在妇女中传播。我们的申请旨在了解预期通过其行为高度暴露于HIV-1的女性中缺乏感染的相关性，并确定特定的免疫应答（特异性先天免疫和伊加应答）是否在她们中过度表达。我们还将直接测试在非人灵长类动物中靶向候选先天和抗体应答的选择性激活的影响，以获得关于这些应答是否可以减少病毒传播的直接数据。