Pathogenesis of Rebound SIV/HIV Viremia after Antiretrovral Therapy

抗逆转录病毒治疗后反弹 SIV/HIV 病毒血症的发病机制

• 批准号: 9323662
• 负责人: Richard D'Aquila
• 金额: $ 160.28万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-05 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323662
• 关键词: APOCEC3G gene; Address; Aftercare; Anatomy; Anti-Infective Agents; Biopsy; Cell model; Cells; Colon; Disease remission; Early treatment; FRAP1 gene; Female; Future; Goals; HIV; HIV Infections; Human; Immune; Individual; Infection; Interruption; Intervention; Laboratories; Macaca; Mediating; Memory; Metabolic; Modeling; Mucous Membrane; Mus; Myeloid Cell Activation; Myeloid Cells; Observational Study; Outcome; Pathogenesis; Predisposition; Production; Proviruses; Receptor Activation; Research; Risk; SIV; Source; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Time; Tissue Model; Tissues; Tonsil; Toxic effect; Viral reservoir; Viremia; Virion; Virus; Virus Latency; activation product; antiretroviral therapy; base; cell type; cytokine; design; humanized mouse; in vivo; inhibitor/antagonist; innovation; insight; microbial; novel; programs; reactivation from latency; reproductive tract; response; tool; treatment strategy; viral rebound

Project Summary This program project will add to understanding the pathogenesis of SIV/HIV viremia rebound with the long-term goal of innovating therapeutic strategies enabling sustained remission of HIV infection in a “best-case” scenario. This scenario involves initiating antiretroviral therapy (ART) soon after infection (“early ART”) and stopping it after a defined duration - along with short-term use of a new, adjunctive treatment strategy that will markedly increase the proportion of subjects with sustained remission after stopping early ART. This proposal will define the cells in mucosal and other tissues that SIV/HIV persistently infects early after infection; characterize T cell activation-triggered mechanisms hypothesized to both initiate virus production after early ART stops as well as to cause a cascade of target cell susceptibility and virus infectivity that leads to viremia rebound; and begin testing mechanism-informed, cell-based interventions to interrupt these “vicious cycles.” Aims address the following 3 hypotheses about rebound after stopping early ART. 1. Persistent virus reservoirs are established in mucosal cells soon after infection, and initiate viremia rebound. We will identify the cell types/subtypes in which SIV initially establishes latency in colon and female reproductive tract mucosa in the first days after mucosal infection of macaques; determine if those “virus reservoir” cells remain in the mucosa during suppressive ART in vivo; study virus production from those cells off-ART in cell / tissue models ex vivo, humanized DRAG mice, and macaques in vivo; and design/perform a pilot observational study of humans. 2. Temporarily inhibiting mechanistic target of rapamycin (mTOR) will decrease both virus production from cellular reservoirs and susceptibility of new target cells to infection. We will characterize cellular mechanisms downstream of mTOR activity that initiate virus production from reservoir cells, and increase target cell susceptibility to infection, via T cell receptor (TCR) activation, microbial product activation of myeloid cells, and T cell activation by myeloid cell-derived cytokines. Effects of catalytic mTOR inhibitors will be studied in macaques in vivo, established ex vivo cellular models of latency/reactivation, as well as new models using colon mucosal biopsies, excised tonsil tissue, and humanized DRAG mice. 3. Temporarily increasing virion APOBEC3G (A3G) will decrease virus infectivity. In the ex vivo models and humanized mice, we will test the hypotheses that T cell reservoirs have low A3G levels before Vif is expressed; that tool compounds (”A3G- boosters”) will increase A3G levels in Vif-positive virions produced from them; that boosted A3G-mediated decreased virus spread will add to mTOR inhibitor effects to diminish uninfected target T cell susceptibility to rebounding infection; and that mTOR inhibition will enhance A3G booster effects on virion A3G content.

项目摘要 该项目将有助于了解SIV/HIV病毒血症反弹的发病机制， 目标是创新治疗策略，在“最佳情况”下持续缓解艾滋病毒感染 场景这种情况涉及在感染后不久开始抗逆转录病毒治疗（ART）（“早期ART”）， 在规定的持续时间后停止--沿着短期使用一种新的、持续的治疗策略， 显著增加停止早期ART后持续缓解的受试者比例。 将确定SIV/HIV感染后早期持续感染的粘膜和其他组织中的细胞; 表征T细胞激活触发的机制，假设在早期 抗逆转录病毒疗法停止，以及引起级联的靶细胞易感性和病毒感染性，导致病毒血症 反弹;并开始测试机制通知，基于细胞的干预，以中断这些“恶性循环”。 目的是解决以下3个关于早期停止ART后反弹的假设。持续的病毒 感染后不久，在粘膜细胞中建立了储库，并启动病毒血症反弹。我们将确定 SIV最初在结肠和女性生殖道粘膜中潜伏的细胞类型/亚型 在猕猴粘膜感染后的第一天;确定那些“病毒储存库”细胞是否留在粘膜中， 在细胞/组织模型中研究来自那些非ART细胞的病毒产生 离体、人源化DRAG小鼠和体内猕猴;并设计/进行一项初探性观察研究 人类2.暂时抑制雷帕霉素的机制靶点（mTOR）将减少两种病毒的产生， 从细胞储库和新靶细胞对感染的易感性。我们将描述细胞 mTOR活性下游的机制，启动从储库细胞产生病毒，并增加 靶细胞对感染易感性，通过T细胞受体（TCR）活化、微生物产物活化髓样 细胞，以及通过骨髓细胞衍生的细胞因子的T细胞活化。将研究催化mTOR抑制剂的作用 在猕猴体内，建立了潜伏期/再激活的离体细胞模型，以及使用 结肠粘膜活组织检查、切除的扁桃体组织和人源化DRAG小鼠。3.暂时增加的病毒体 APOBEC 3G（A3 G）可降低病毒的感染性。在离体模型和人源化小鼠中，我们将测试 假设T细胞库在Vif表达之前具有较低A3 G水平;工具化合物（“A3 G- 增强剂”）将增加由其产生的Vif阳性病毒体中的A3 G水平;增强A3 G介导的 减少的病毒传播将增加mTOR抑制剂的作用，以减少未感染的靶T细胞对 并且mTOR抑制将增强A3 G对病毒体A3 G含量的加强作用。