Project 3- Mucosal Determinants of Virus Transmission

艾滋病疫苗的设计因以下事实而变得复杂：任何针对HIV/SIV的特异性免疫反应都旨在 防止传播或疾病进展不可避免地会导致激活的CD4+T细胞的产生， 可能矛盾地促进传播和/或疾病进展。事实上，中国艾滋病毒获得率的增加 无效的STEP/Phambili试验和在HVTN-505中的疗效缺乏表明疫苗诱导的CD4+T细胞 应对措施可以减轻保护，在某些情况下，还会增加收购。这件事的首要目标是 计划项目赠款是为了测试持久和平衡的艾滋病毒特异性体液免疫的假设 需要做出反应，以提供有效的粘膜保护，并避免出现自相矛盾的影响 可能会增强病毒的获取。这个项目的重点是疫苗是否会引起人类免疫功能的改变 粘膜微环境是影响并常常破坏体液保护效果的因素。 恒河猴(RMS)的免疫力，进而延伸到人类。粘膜的三个主要方面 将检查环境：(1)激活的CD4+T细胞作为病毒的潜在靶标的作用；(2)作用 先天性免疫反应，特别是I型干扰素(干扰素-I)和干扰素刺激基因(ISG) 介导的途径，如抗病毒和促炎因子；以及(3)流产感染的潜在作用 作为炎症/激活的来源，在静止的粘膜中诱导CD4+T细胞的嗜酸性细胞死亡 促进传播的创始人病毒种群传播的信号。本项目中提出的研究 利用项目1中的动物和样本(该项目将阐明持续反对的体液决定因素 Gp120反应)和项目2(其中通过被动注射抗gp120获得的保护 抗体将在同时接触已知可诱导强毒的载体疫苗的情况下进行测试。 对艾滋病毒/SIV的粘膜细胞免疫反应)。有三个具体目标。目标1：研究如何在 项目1和2中的活体干预影响数量、表型、激活状态、组织学位置和 粘膜中CD4+T细胞的基因表达。目标2：检查项目1和2中的体内干预如何 影响黏膜组织的天然免疫环境，尤其是干扰素-I和胰岛素样生长因子。目标3：实现 检测接种疫苗后小鼠粘膜CD4+T细胞是否发生流产感染和炎症性下垂 并促进新城疫病毒感染的扩大和传播。这项工作将提供一个全面的 猕猴疫苗模型中黏膜微环境的图片，在以下环境中 存在保护性的抗gp120抗体。这一信息将验证关于因果关系的假设 平衡的粘膜免疫模式与体液免疫保护效果之间的关系。是这样的 信息将对未来艾滋病毒疫苗战略的发展产生重大的翻译影响。

The design of an AIDS vaccine is complicated by the fact that any HIV/SIV-specific immune responses aimed at preventing transmission or disease progression inevitably result in the generation of activated CD4+ T cells that may paradoxically facilitate transmission and/or disease progression. Indeed, increased HIV acquisition in the ineffective Step/Phambili trials and the lack of efficacy in HVTN-505 indicate that vaccine-elicited CD4+ T-cell responses can mitigate protection and, in some cases, increase acquisition. The overarching goal of this Program Project grant is to test the hypothesis that durable and balanced HIV-specific humoral immune responses are needed to provide effective protection from mucosal challenge, and avoid paradoxical effects that may enhance virus acquisition. This project focuses on the question of whether vaccine-induced changes in the mucosal micro-environment are factors influencing, and often undermining, the protective efficacy of humoral immunity in rhesus macaques (RMs) and by extension, humans. Three main aspects of the mucosal environment will be examined: (1) the role of activated CD4+ T cells as potential targets for the virus; (2) the role of the innate immune response, and in particular type I interferon (IFN-I) and interferon-stimulated gene (ISG)- mediated pathways, as antiviral but also pro-inflammatory factors; and (3) the potential role of abortive infection and induction of pyroptotic cell death in quiescent mucosal CD4+ T cells as a source of inflammatory/activating signals facilitating spread of the transmitted founder virus populations. The studies proposed in in this project leverage animals and samples from Project 1 (which will elucidate the humoral determinants for persistent anti- gp120 responses) and Project 2 (in which the protection conferred by passive administration of an anti-gp120 antibody will be tested in the setting of concomitant exposure to a vector-based vaccine known to induce strong mucosal cellular immune responses to HIV/SIV). There are three specific aims. Aim 1: To examine how the in vivo interventions in Projects 1 and 2 affect the number, phenotype, activation state, histological location, and gene expression of mucosal CD4+ T cells. Aim 2: To examine how the in vivo interventions in Projects 1 and 2 affect the innate immune environment of mucosal tissues, with specific focus on IFN-I and ISGs. Aim 3: To determine whether abortive infection and inflammatory pyroptosis occur in mucosal CD4+ T cells of vaccinated macaques and promote expansion and dissemination of SHIV infection. This work will provide a comprehensive picture of the mucosal micro-environment in the macaque vaccine model, within the context of settings where protective anti-gp120 antibodies are present. This information will validate hypotheses regarding the causal relationships between balanced mucosal immune profiles and protective efficacy via humoral immunity. Such information will have significant translational impact on the development of future HIV vaccine strategies.