Project 3- Mucosal Determinants of Virus Transmission

艾滋病疫苗的设计是复杂的，因为任何针对艾滋病毒/SIV的特异性免疫反应都是复杂的。 防止传播或疾病进展不可避免地导致活化的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，艾滋病毒感染率的增加， 无效的Step/Phambili试验和HVTN-505缺乏疗效表明，疫苗诱导的CD4 + T细胞 反应可能会减少保护，在某些情况下，增加收购。这个项目的首要目标是 计划项目赠款是为了检验持久和平衡的艾滋病毒特异性体液免疫的假设， 需要对粘膜攻击提供有效的保护，并避免矛盾的作用， 可能会增强病毒感染。这个项目的重点是疫苗引起的变化是否在 粘膜微环境是影响和经常破坏体液免疫保护功效的因素， 恒河猴（RM）和人类的免疫力。粘膜的三个主要方面 将检查环境：（1）活化的CD4 + T细胞作为病毒潜在靶点的作用;（2）活化的CD4 + T细胞作为病毒潜在靶点的作用。 的先天免疫应答，特别是I型干扰素（IFN-I）和干扰素刺激基因（ISG）- 介导的途径，作为抗病毒，但也促炎因子;和（3）流产感染的潜在作用 和诱导静止粘膜CD4 + T细胞中的热凋亡细胞死亡作为炎性/活化的来源 促进传播的创始者病毒种群传播的信号。本项目中提出的研究 利用来自项目1的动物和样本（将阐明持续性抗- gp120应答）和项目2（其中被动给予抗gp120应答所赋予的保护作用 将在同时暴露于已知可诱导强免疫应答的基于载体的疫苗的情况下检测抗体。 对HIV/SIV的粘膜细胞免疫应答）。有三个具体目标。目标1：研究如何在 项目1和2中的体内干预影响了细胞数量、表型、激活状态、组织学位置和 粘膜CD4 + T细胞的基因表达。目标2：研究项目1和项目2中的体内干预措施 影响粘膜组织的先天免疫环境，特别关注IFN-I和ISG。目标3： 确定在接种疫苗的小鼠的粘膜CD4 + T细胞中是否发生流产感染和炎性焦亡。 猕猴和促进扩大和传播SHIV感染。这项工作将提供全面的 猕猴疫苗模型中粘膜微环境的图片，在环境中， 存在保护性抗GP 120抗体。这些信息将验证关于因果关系的假设。 平衡的粘膜免疫特征和通过体液免疫的保护功效之间的关系。等 这些信息将对未来艾滋病毒疫苗战略的发展产生重大的转化影响。

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.