Project 3- Mucosal Determinants of Virus Transmission

项目3-病毒传播的粘膜决定因素

• 批准号: 9141194
• 负责人: Guido Silvestri
• 金额: $ 60.22万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9141194
• 关键词: AIDS Vaccines; Affect; Animals; Antibodies; Antibody-mediated protection; Antiviral Agents; Apoptosis; CASP1 gene; CASP3 gene; CD4 Positive T Lymphocytes; Cell Death; Cells; Data; Development; Disease Progression; Environment; Equilibrium; Exposure to; Failure; Flow Cytometry; Founder Generation; Future; Gene Expression; Generations; Genes; Goals; HIV; HIV Envelope Protein gp120; HIV Vaccine Trials Network; HIV vaccine; Histology; Human; Humoral Immunities; Immune; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferon Type I; Interferons; Interleukin-1 beta; Interleukin-18; Intervention; Location; Macaca; Macaca mulatta; Mediating; Modeling; Molecular; Molecular Analysis; Mucous Membrane; Outcome; Pathway interactions; Phenotype; Population; Process; Program Research Project Grants; Property; Role; SIV; SIV Vaccines; Sampling; Signal Transduction; Source; T cell response; T-Lymphocyte; Techniques; Testing; Time; Vaccinated; Vaccines; Virus; Work; adaptive immunity; design; immunological intervention; in vivo; prevent; protective efficacy; response; simian human immunodeficiency virus; transcriptome sequencing; transmission process; vector-based vaccine; viral transmission

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.

艾滋病疫苗的设计很复杂，因为任何针对 HIV/SIV 的特异性免疫反应都旨在 预防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，艾滋病毒感染率增加 Step/Phambili 试验无效以及 HVTN-505 缺乏疗效表明疫苗诱导的 CD4+ T 细胞 应对措施可以减轻保护，在某些情况下还可以增加获取。本次活动的总体目标是 计划 项目拨款旨在检验以下假设：持久且平衡的 HIV 特异性体液免疫 需要做出反应来提供有效的保护，免受粘膜挑战，并避免自相矛盾的影响 可能会增强病毒获取。该项目的重点是疫苗是否会引起变化 粘膜微环境是影响并常常破坏体液保护作用的因素。 恒河猴（RM）以及人类的免疫力。粘膜的三个主要方面 将检查环境：（1）激活的 CD4+ T 细胞作为病毒潜在靶标的作用； (二)作用 先天免疫反应，特别是 I 型干扰素 (IFN-I) 和干扰素刺激基因 (ISG) - 介导途径，作为抗病毒因子和促炎因子； (3) 流产感染的潜在作用 以及诱导静止粘膜 CD4+ T 细胞焦亡细胞死亡作为炎症/激活的来源 促进传播的创始人病毒群体传播的信号。本项目中提出的研究 利用项目 1 中的动物和样本（这将阐明持久抗- gp120 反应）和项目 2（其中通过被动施用抗 gp120 所赋予的保护 抗体将在同时暴露于基于载体的疫苗的情况下进行测试，该疫苗已知可诱导强 对 HIV/SIV 的粘膜细胞免疫反应）。具体目标有三个。目标 1：检查如何 项目 1 和 2 中的体内干预影响数量、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 2 中的体内干预如何 影响粘膜组织的先天免疫环境，特别关注 IFN-I 和 ISG。目标 3： 确定接种疫苗的粘膜CD4+T细胞是否发生流产感染和炎性焦亡 猕猴并促进 SHIV 感染的扩大和传播。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，在以下环境中 存在保护性抗 gp120 抗体。该信息将验证有关因果关系的假设 平衡的粘膜免疫特征与体液免疫的保护功效之间的关系。这样的 信息将对未来艾滋病毒疫苗战略的制定产生重大转化影响。