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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该计划项目将有助于了解 SIV/HIV 病毒血症长期反弹的发病机制。创新治疗策略的目标是在“最佳情况”下实现艾滋病毒感染的持续缓解这种情况涉及感染后立即开始抗逆转录病毒治疗（“早期 ART”）和在规定的持续时间后停止治疗 - 同时短期使用新的辅助治疗策略显着增加停止早期 ART 后持续缓解的受试者比例。将定义 SIV/HIV 在感染后早期持续感染的粘膜和其他组织中的细胞；表征 T 细胞激活触发机制阻碍了早期病毒产生 ART 停止并导致靶细胞易感性和病毒感染性级联，从而导致病毒血症反弹；并开始测试基于机制的、基于细胞的干预措施，以中断这些“恶性循环”。目的是解决以下 3 个关于停止早期 ART 后反弹的假设： 1. 病毒持续存在。感染后很快就会在粘膜细胞中建立储库，并引发病毒血症反弹。 SIV 最初在结肠和女性生殖道粘膜中建立潜伏期的细胞类型/亚型在猕猴粘膜感染后的最初几天内，确定这些“病毒库”细胞是否仍保留在体内体内抑制性 ART 期间的粘膜；在细胞/组织模型中研究非 ART 细胞的病毒产生离体、人源化 DRAG 小鼠和体内猕猴；并设计/进行试点观察研究 2. 暂时抑制雷帕霉素的机械靶点 (mTOR) 将减少两种病毒的产生。从细胞储存库和新靶细胞对感染的易感性我们将表征细胞。 mTOR 活性的下游机制，启动储存细胞的病毒生产，并增加通过 T 细胞受体 (TCR) 激活、骨髓微生物产物激活，靶细胞对感染的易感性将研究催化 mTOR 抑制剂的作用。在猕猴体内，建立了潜伏/重新激活的离体细胞模型，以及使用结肠粘膜活检、切除的扁桃体组织和人源化 DRAG 小鼠 3. 暂时增加病毒颗粒。 APOBEC3G (A3G) 将降低病毒感染性在离体模型和人源化小鼠中，我们将测试。假设在 Vif 表达之前，T 细胞储存库的 A3G 水平较低（“A3G-”）增强剂”）将增加由它们产生的 Vif 阳性病毒体中的 A3G 水平，从而增强 A3G 介导的能力；病毒传播的减少将增加 mTOR 抑制剂的效果，从而降低未感染的靶 T 细胞对病毒的敏感性感染反弹；并且 mTOR 抑制将增强对病毒颗粒 A3G 含量的 A3G 增强作用。