Enhanced latency reversal and reservoir clearance in macaques

增强猕猴的潜伏期逆转和储库清除能力

基本信息

批准号：
10626131
负责人：
Ann M Chahroudi
金额：
$ 86.85万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-23 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626131
关键词：
Adherence Anatomy Animal Model Antibodies Apoptosis BCL1 Oncogene Bar Codes Binding Biological Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Caspase Cells Clinical Collaborations Combined Modality Therapy Data Ensure Event FDA approved Family Future HIV HIV Infections Immune Immune system Immunologics Impairment In Vitro Induction of Apoptosis Infusion procedures Interruption Intervention Knowledge Macaca Macaca mulatta Measurement Methodology Mitochondria Modeling Morbidity - disease rate Pathway interactions Patients Pharmaceutical Preparations Plasma Predictive Factor Proteins Proviruses RNA Recording of previous events Recrudescences Regimen Reporting Research Research Personnel Rest SIV Safety Shock Signal Pathway Signal Transduction Sorting Source T cell response T-Cell Activation T-Lymphocyte Subsets Testing Therapeutic Tissues Viral Viral reservoir Viremia Virus Virus Latency Work antiretroviral therapy arm curative treatments design exhaust experimental study humanized mouse in vivo inhibitor innovation mathematical model memory CD4 T lymphocyte mimetics mortality nonhuman primate novel novel strategies response small molecule success synergism therapeutic target transcriptomics viral RNA viral rebound

项目摘要

PROJECT SUMMARY Current treatment for HIV infection requires strict adherence to daily antiretroviral therapy (ART). ART has greatly reduced mortality and morbidity but is not a cure. The main barrier to a cure is the pool of latently infected CD4+ T cells that carry integrated HIV provirus and are capable of reactivating and causing recrudescence of viremia if ART is stopped. A leading strategy to eliminate this persistent reservoir is termed “shock and kill” or “kick and kill” and consists of two interventions used with continued ART: first, a latency reversal agent (LRA) to reactivate latent virus and second, an approach to enhance clearance of infected cells. In this proposal, we will build upon our preliminary data indicating that activation of the non-canonical (nc) NF- κB signaling pathway with a mimetic of the second mitochondrial-derived activator of caspases (SMACm) results in systemic latency reversal in animal models. Using the highly relevant SIV/RM/ART model, we will answer three important questions regarding the biologic effects of SMACm treatment. First (Aim 1), we will determine the anatomic and cellular origin of the viremia produced during ART upon treatment with SMACm and its relationship with rebound viremia after ART interruption. In this study, we will utilize barcoded SIVmac239M to extensively sequence SIV RNA in sorted CD4+ T cell subsets from blood and tissues in comparison to plasma virus. We will also apply single cell transcriptomic methodologies to answer this question. Second (Aim 2), we test a novel “kick and kill” approach that combines latency reversal with SMACm plus venetoclax, a selective BCL-2 inhibitor, that has been shown to cause preferential apoptosis of HIV- expressing cells. We will determine whether this combined treatment reduces total, intact, and replication competent reservoirs in memory CD4+ T cells from multiple tissues and/or modulates viral recrudescence after ART interruption. Third (Aim 3), we will model the immunovirologic factors predictive of virus reactivation on ART with SMACm treatment and during ART interruption following therapeutic targeting of the ncNF-κB and BCL-2 pathways. This model will further reveal the potential of this cure approach and inform the design of future “kick and kill” studies. This work will allow us to elucidate the full potential of targeting the ncNF-κB pathway for latency reversal and to evaluate an innovative strategy to reduce virus persistence. We hope these results will contribute to a cure for HIV infection.

项目概要目前治疗 HIV 感染需要严格遵守日常抗逆转录病毒治疗 (ART)。大大降低了死亡率和发病率，但不是治愈方法治愈的主要障碍是潜在的病毒库。感染的 CD4+ T 细胞携带整合的 HIV 原病毒，能够重新激活并引起如果停止抗逆转录病毒治疗，病毒血症就会复发，消除这种持续性病毒库的主要策略被称为病毒血症。 “电击杀戮”或“踢杀”，包括与持续 ART 一起使用的两种干预措施：首先，潜伏期其次，是一种增强感染细胞清除率的方法。在本提案中，我们将基于初步数据表明非规范（nc）NF-的激活 κB 信号通路与第二种线粒体衍生的半胱天冬酶激活剂 (SMACm) 的模拟物使用高度相关的 SIV/RM/ART 模型，我们将在动物模型中导致系统性潜伏期逆转。首先（目标 1），我们将回答有关 SMACm 治疗的生物学效应的三个重要问题。确定 SMACm 治疗后 ART 期间产生的病毒血症的解剖学和细胞起源及其与 ART 中断后病毒血症反弹的关系在本研究中，我们将利用条形码。 SIVmac239M 主要对来自血液和组织的分选 CD4+ T 细胞亚群中的 SIV RNA 进行测序我们还将应用单细胞转录组学方法来回答这个问题。第二个问题（目标 2），我们测试了一种新颖的“踢杀”方法，该方法将延迟反转与 SMACm 相结合。再加上 Venetoclax，一种选择性 BCL-2 抑制剂，已被证明可导致 HIV- 我们将确定这种联合治疗是否会减少表达细胞的总数、完整度和复制。来自多个组织的记忆 CD4+ T 细胞中的有效储存库和/或调节病毒复发第三（目标 3），我们将对预测病毒重新激活的免疫病毒学因素进行建模。 ART 与 SMACm 治疗以及 ART 期间中断治疗靶向 ncNF-κB 和该模型将进一步揭示这种治疗方法的潜力并为设计提供信息。未来的“踢杀”研究。这项工作将使我们能够阐明靶向 ncNF-κB 通路用于延迟逆转和评估减少病毒持久性的创新策略，我们希望这些结果将有助于治愈疾病。用于艾滋病毒感染。