Determining the relative contribution of CD4 T cells and macrophages to HIV persistence and rebound

确定 CD4 T 细胞和巨噬细胞对 HIV 持续存在和反弹的相对贡献

• 批准号: 10673779
• 负责人: JACOB D ESTES
• 金额: $ 78.31万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673779
• 关键词: Achievement; Acquired Immunodeficiency Syndrome; Address; Adherence; Age; Anatomy; Autopsy; Binding; Biological Markers; Blood; Brain; CCR5 gene; CD4 Positive T Lymphocytes; CXCR4 gene; Cell physiology; Cells; Central Nervous System; Clinical Trials; Collection; Controlled Study; Cues; DNA; Data; Development; Disease Progression; Disease remission; Enrollment; Equilibrium; Fingerprint; Genetic Fingerprintings; Genetic Transcription; Goals; HIV; HIV Infections; In Vitro; Individual; Infection; Inflammation; Interruption; Intervention; Kinetics; Location; Longevity; Macaca mulatta; Macrophage; Mediating; Modeling; Nature; Neuropathogenesis; Persons; Phagocytosis; Predisposition; Primates; Productivity; Recording of previous events; Regimen; Research; Research Personnel; Residual state; Resistance; Rest; Role; SIV; Specimen; T-Cell Depletion; T-Lymphocyte; Time; Tissues; Variant; Viral; Viral Genome; Viral Load result; Viral reservoir; Virion; Virus; Virus Latency; Virus Replication; Work; animal resource; antiretroviral therapy; brain tissue; clinically relevant; cost; design; detection limit; in vivo; insight; memory CD4 T lymphocyte; multidisciplinary; novel; novel strategies; novel therapeutic intervention; peer; side effect; social stigma; success; synergism; viral DNA; viral RNA; viral rebound

Abstract Despite its success at suppressing viral loads, antiretroviral therapy (ART) cannot eradicate HIV infection. The main obstacle to curing HIV infection is the ability of the virus to persist under suppressive ART in reservoirs of latently infected cells, which are established early after infection and supports rebound to pre-treatment levels if ART is interrupted. Despite the extraordinary challenge of persistent virus reservoirs, a few cases have recently proved that prolonged viral remission after analytical therapy interruption (ATI) is possible. Unfortunately, the specific mechanisms regulating HIV rebound remain very poorly understood, thus critically limiting the development of novel therapeutic strategies aimed at eradication or remission of HIV infection. In this project, we have assembled a multidisciplinary team of investigators to address directly in vivo how the size and relative distribution of the reservoir in CD4 T cells and macrophages govern (i) the anatomic location of persistent viral reservoirs; (ii) the exent of residual inflammation and neuropathogenesis; and (iii) the time and extent of viral rebound after ATI. Specifically, we propose to alter directly in vivo and in a highly relevant model for HIV infection (i.e., the SIV infection of rhesus macaques; RMs) the overall size of virus reservoirs and its distribution between CD4 T cells and macrophages. These goals will be achieved (i) by using the well-established model of ART-treated, SIV-infected RMs; (ii) by using a SIV swarm that allows tracking of multiple viral variants; and (iii) by performing in vivo Ab-mediated CD4 T cell depletion before SIV infection and after SIV-infection during suppressive ART. We will determine how the planned in vivo depleting interventions alter the distribution of viral reservoirs between CD4 T cells and macrophages; impact the kinetics and extent of viral rebound following ATI; and influence the cellular nature and genetic fingerprinting of the rebounding virus. Finally, we will investigate the mechanisms favoring SIV infection and persistence in macrophages when CD4 T cells are depleted. We believe that the complementary, comprehensive, highly synergistic, and rigourosly controlled studies that we propose will provide unprecedented, novel insights into (i) understanding how the cellular nature of the viral reservoir regulate residual inflammation and viral persistence on ART and viral rebound after ATI, and (2) the direct role of macrophages in harboring replication competent virus during long-term ART and contributing to viral rebound after ATI. Critical for our aims, the SIV/RM model allows for investigating the CD4 T cells versus macrophages contribution to viral reservoir not only in blood, but also in a large number of tissues collected longitudinally and at necropsy, including CSF and brain tissues. These achievements will inform efforts to design novel therapeutic strategies aimed at achieving prolonged viral remission of HIV infection.

抽象的 尽管抗逆转录病毒疗法（ART）在抑制病毒载量方面取得了成功，但仍无法消除HIV感染。这 治愈艾滋病毒感染的主要障碍是病毒在抑制性艺术中持续的能力 潜在感染的细胞，这些细胞是在感染后尽早建立的，并支持反弹到预处理水平 如果艺术被中断。尽管持续的病毒水库面临非凡的挑战，但有一些情况有 最近证明，分析疗法中断后长时间的病毒缓解是可能的。 不幸的是，调节HIV反弹的特定机制仍然非常了解，因此很严格 限制旨在消除或减轻HIV感染的新型治疗策略的发展。在 这个项目，我们组建了一个多学科的调查员团队，直接在体内解决如何处理 CD4 T细胞和巨噬细胞中储层的大小和相对分布控制（i）解剖学 持续病毒储存的位置； （ii）残留炎症和神经病发生的外部； （iii）ATI后病毒反弹的时间和程度。具体而言，我们建议直接改变体内和 在高度相关的HIV感染模型中（即恒河猕猴的SIV感染） 病毒储层及其在CD4 T细胞和巨噬细胞之间的分布。这些目标将通过 使用良好的艺术处理，SIV感染的RMS模型； （ii）使用允许的SIV群 跟踪多种病毒变体； （iii）通过在SIV之前进行体内AB介导的CD4 T细胞耗竭 抑制性艺术期间感染和SIV感染后。我们将确定计划的体内耗竭 干预措施改变了CD4 T细胞和巨噬细胞之间病毒储量的分布。影响 ATI后病毒反弹的动力学和程度；并影响细胞性质和遗传指纹识别 反弹病毒。最后，我们将研究有利于SIV感染和持久性的机制 当CD4 T细胞耗尽时，巨噬细胞。 我们认为，互补，全面，高度协同和严格控制的研究 我们建议将为（i）了解病毒的细胞性质如何提供前所未有的新颖见解 水库调节ATI后的ART和病毒反弹的残留炎症和病毒持续性，（2） 巨噬细胞在长期艺术期间携带复制能力病毒中的直接作用，并有助于 ATI后的病毒反弹。对于我们的目标至关重要，SIV/RM模型允许研究CD4 T细胞与 巨噬细胞不仅在血液中对病毒储存库有贡献，而且还在收集的大量组织中 纵向和尸检，包括CSF和脑组织。这些成就将为 设计新型治疗策略，旨在实现艾滋病毒感染的长期病毒缓解。