Live Attenuated SIV-Mediated Protection Against Mucosal SIV Infection

减毒活 SIV 介导的针对粘膜 SIV 感染的保护

• 批准号: 8198148
• 负责人: R. PAUL JOHNSON
• 金额: $ 60.16万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8198148
• 关键词: AIDS Vaccines; Animals; Antibodies; Antibody Formation; Attenuated; Autopsy; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8B1 gene; Containment; Coupled; Data; Development; Dose; Evaluation; Event; Evolution; Experimental Models; Female; Goals; HIV; Immune response; Immunity; Immunologics; Immunology; Immunophenotyping; Infection; Life; Macaca; Mediating; Monkeys; Pathology; Phase; Play; Role; SIV; SIV Vaccines; Site; Staging; Subfamily lentivirinae; Systems Biology; T cell response; Techniques; Time; Tissues; Vaccinated; Vaccination; Vaccine Research; Vaccines; Vagina; Viral; base; innovation; insight; nonhuman primate; novel; peripheral blood; reproductive; response; tositumomab; transmission process; vaginal transmission; vector; virology

Vaccination of macaques with attenuated SIV strains has consistently provided the most effective protection against pathogenic SIV challenge and offers the best available experimental model to define specific mechanisms responsible for protection. Recent studies from our group have demonstrated that a significant maturation of protective immunity against vaginal challenge occurs between 5 and 20 weeks after vaccination with SIVAnef, which is associated with evolution of both cellular and humoral immune responses. Furthermore, SIVAnef-vaccinated animals do not manifest the recently described mobilization of pDCs and recruitment of CD4+ T cells that occurs early after vaginal challenge of naive animals. Based on these observations, we hypothesize that SIVAnef is able to block critical stages of SIV replication and spread in the first 7 days after vaginal challenge. Since our previous studies have largely focused on later time points (>7 days after challenge) and examination of immune responses in the peripheral blood, these emerging data dictate a new and comprehensive analysis of the early events in tissues following vaginal challenge of SIVAnef-vaccinated animals. The goal of this proposal is to apply a panel of innovative techniques to serial necropsies of SIVAnef-vaccinated animals before and after challenge to elucidate the roles of adaptive and innate immune responses in mediating protection induced by SIVAnef and to identify the sites of containment of viral replication within the female reproductive tract. Specific aims include: 1: To examine the evolution of adaptive and innate immune responses in the female reproductive tract induced by SIVAnef; 2. To identify sites of viral containment and characterize local immune responses following vaginal challenge of SIVAnef-vaccinated animals; and 3. To examine the effect of B cell depletion on protective immunity against vaginal challenge induced by SIVAnef. These studies will provide novel insights into mechanisms of protective immunity induced by SIVAnef, offer a direct comparison of both immunologic and virologic analyses for animals vaccinated with alternative vectors, and ultimately guide the identification of mechanisms of protection against mucosal infection with lentiviruses.

给猕猴接种 SIV 减毒株疫苗始终提供最有效的保护 对抗致病性 SIV 挑战，并提供最佳可用实验模型来定义特定的 负责保护的机制。我们小组最近的研究表明，一个重要的 针对阴道攻击的保护性免疫力在术后 5 至 20 周内成熟 接种 SIVanef 疫苗，这与细胞和体液免疫反应的进化有关。 此外，接种 SIVAnef 的动物并未表现出最近描述的 pDC 动员和 CD4+ T 细胞的募集发生在幼稚动物的阴道攻击后早期。基于这些 根据观察，我们假设 SIVAnef 能够阻止 SIV 复制和传播的关键阶段 阴道挑战后的前 7 天。由于我们之前的研究主要集中在较晚的时间点（>7 攻击后几天）和外周血中免疫反应的检查，这些新出现的数据 规定对阴道挑战后组织中的早期事件进行新的全面分析 接种过 SIVanef 疫苗的动物。该提案的目标是将一组创新技术应用于串行 对接种 SIVanef 的动物在攻击前后进行尸检，以阐明适应性和免疫反应的作用 先天免疫反应介导 SIVanef 诱导的保护并识别遏制位点 女性生殖道内的病毒复制。具体目标包括： 1：检验演变 SIVanef 诱导的女性生殖道适应性和先天免疫反应； 2. 识别 病毒遏制位点并表征 SIVanef 疫苗接种后阴道攻击后的局部免疫反应 动物; 3. 检查 B 细胞耗竭对阴道保护性免疫的影响 SIVanef 引起的挑战。这些研究将为保护机制提供新的见解 SIVanef 诱导的免疫，提供了免疫学和病毒学分析的直接比较 用替代载体接种动物，并最终指导识别机制 防止慢病毒粘膜感染。