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.

用减毒SIV毒株对猕猴进行疫苗接种一直提供最有效的保护 针对致病性SIV的挑战，并提供了最好的实验模型，以确定具体的 负责保护的机构。我们小组最近的研究表明， 针对阴道攻击的保护性免疫的成熟发生在接种后5至20周之间。 SIVAnef疫苗接种，这与细胞和体液免疫应答的演变有关。 此外，SIVAnef接种的动物没有表现出最近描述的pDC动员， CD 4 + T细胞的募集发生在幼稚动物阴道攻击后早期。基于这些 根据观察，我们假设SIVAnef能够阻断SIV复制和传播的关键阶段， 阴道激发后前7天。由于我们以前的研究主要集中在较晚的时间点（>7 攻击后30天）和外周血中免疫应答的检查，这些新出现的数据 要求对阴道激发后组织中的早期事件进行新的全面分析， 接种SIVAnef疫苗的动物。本提案的目标是将一组创新技术应用于连续 攻毒前后对SIVAnef免疫动物进行尸检，以阐明适应性和 介导SIVAnef诱导的保护作用的先天免疫应答，并确定遏制位点 女性生殖道内病毒复制的证据具体目标包括：1：考察 SIVAnef诱导的雌性生殖道适应性和先天性免疫应答; 2.以识别 病毒遏制部位，并表征SIVAnef疫苗接种后阴道攻击后的局部免疫应答 动物; 3。为了检测B细胞去除对抗阴道炎的保护性免疫的影响， 由SIVAnef诱导的攻击。这些研究将提供新的见解，保护机制， SIVAnef诱导免疫，提供了免疫学和病毒学分析的直接比较， 动物接种替代载体，并最终指导识别的机制， 保护粘膜免受慢病毒感染。