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：
10224629
负责人：
Richard D'Aquila
金额：
$ 151.18万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224629
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.

项目摘要该计划项目将增加以长期理解SIV/HIV病毒血症反弹的发病机理创新的治疗策略的目标，能够在“最佳案例”中持续缓解艾滋病毒感染设想。这种情况涉及感染后不久（“早期艺术”）和在定义的持续时间之后停止它 - 以及短期使用新的辅助治疗策略，该策略将在停止早期艺术后，显着增加了受试者的比例。这个建议将定义粘膜中的细胞，而其他时候SIV/HIV感染后持续感染了SIV/HIV；表征T细胞激活触发的机制，假设两者都早点启动病毒产生艺术停止以及引起一系列靶细胞敏感性和病毒感染，导致病毒血症反弹；并开始测试信息的基于细胞的干预措施，以中断这些“恶性周期”。目标解决了以下三个关于停止早期艺术后反弹的假设。 1。持续病毒感染后不久，在粘膜细胞中建立了储层，并启动病毒血症反弹。我们将确定 SIV最初在结肠和雌性复制道粘膜中建立潜伏期的细胞类型/亚型猕猴粘膜感染后的头几天；确定那些“病毒储层”细胞是否保留在在体内抑制艺术期间的粘膜；从细胞 /组织模型中研究这些细胞的病毒生产 Ex Vivo，人性化的拖曳小鼠和猕猴在体内；设计/执行试点观察研究人类。 2。暂时抑制雷帕霉素的机械靶标（MTOR）将降低两种病毒的产生从细胞储层以及新靶细胞感染的敏感性。我们将表征蜂窝 MTOR活性下游的机制，从储层细胞引发病毒，并增加通过T细胞受体（TCR）激活，髓样产物激活靶细胞感染的靶细胞敏感性细胞和T细胞通过髓样细胞衍生的细胞因子激活。将研究催化MTOR抑制剂的作用在猕猴的体内，已建立的延迟/重新激活的离体细胞模型以及使用新模型结肠粘膜活检，切除的扁桃体组织和人源性拖曳小鼠。 3。暂时增加病毒体 APOBEC3G（A3G）将降低病毒感染。在离体模型和人性化小鼠中，我们将测试假设T表达VIF之前，T细胞储层的A3G水平较低。该工具化合物（“ A3G-）助推器”）将增加从中产生的VIF阳性病毒中的A3G水平；这增加了A3G介导的病毒扩散减少会增加MTOR抑制剂效应，以降低未感染的靶T细胞易感性反弹感染； MTOR抑制作用将增强对病毒粒子A3G含量的A3G增强作用。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo.

DOI：
10.1172/jci.insight.162290
发表时间：
2022-11-08
期刊：
JCI INSIGHT
影响因子：
8
作者：
Samer, Sadia;Thomas, Yanique;Arainga, Mariluz;Carter, Crystal;Shirreff, Lisa M.;Arif, Muhammad S.;Avita, Juan M.;Frank, Ines;McRaven, Michael D.;Thuruthiyil, Christopher T.;Heybeli, Veli B.;Anderson, Meegan R.;Owen, Benjamin;Gaisin, Arsen;Bose, Deepanwita;Simons, Lacy M.;Hultquist, Judd F.;Arthos, James;Cicala, Claudia;Sereti, Irini;Santangelo, Philip J.;Lorenzo-Redondo, Ramon;Hope, Thomas J.;Villinger, Francois J.;Martinelli, Elena
通讯作者：
Martinelli, Elena

HIV-1 infected humanized DRAGA mice develop HIV-specific antibodies despite lack of canonical germinal centers in secondary lymphoid tissues.