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: 10251333
• 负责人: JACOB D ESTES
• 金额: $ 78.57万
• 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/10251333
• 关键词: Achievement; Acquired Immunodeficiency Syndrome; Address; Adherence; Age; Anatomy; Autopsy; Biological Markers; Blood; Brain; CCR5 gene; CD4 Positive T Lymphocytes; CXCR4 gene; Cell physiology; Cells; Clinical Trials; Collection; Controlled Study; Cues; DNA; Data; Development; Disease Progression; Disease remission; Enrollment; Equilibrium; Fingerprint; Genetic Fingerprintings; Goals; HIV; HIV Infections; In Vitro; Individual; Infection; Inflammation; Interruption; Intervention; Kinetics; Location; Longevity; Macaca mulatta; Mediating; Modeling; Nature; Neuraxis; Neuropathogenesis; Phagocytosis; Primates; Recording of previous events; Regimen; Research; Research Personnel; Residual state; Resistance; Rest; Role; SIV; Specimen; T-Cell Depletion; 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; macrophage; 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，但它无法根除艾滋病毒感染。这 治愈艾滋病毒感染的主要障碍是病毒在抑制性抗逆转录病毒治疗下在宿主体内持续存在的能力 潜伏感染细胞，在感染后早期建立并支持反弹至治疗前水平 如果 ART 被中断。尽管持久性病毒储存库面临巨大挑战，但仍有少数病例 最近证明，分析治疗中断（ATI）后延长病毒缓解是可能的。 不幸的是，人们对调节艾滋病毒反弹的具体机制仍然知之甚少，因此， 限制了旨在根除或缓解艾滋病毒感染的新治疗策略的开发。在 在这个项目中，我们组建了一个多学科研究小组，直接解决体内如何 CD4 T 细胞和巨噬细胞中储库的大小和相对分布控制 (i) 解剖学 持久性病毒储存库的位置； (ii) 残余炎症和神经病变的程度； (iii) ATI 后病毒反弹的时间和程度。具体来说，我们建议直接在体内改变 在与 HIV 感染高度相关的模型（即恒河猴的 SIV 感染；RM）中， 病毒库及其在 CD4 T 细胞和巨噬细胞之间的分布。这些目标将通过 (i) 实现 使用经过 ART 治疗、感染 SIV 的 RM 的成熟模型； (ii) 通过使用 SIV 群，允许 追踪多种病毒变种； (iii) 在 SIV 之前进行体内 Ab 介导的 CD4 T 细胞耗竭 感染以及抑制性 ART 期间 SIV 感染后。我们将确定如何计划体内消耗 干预措施改变 CD4 T 细胞和巨噬细胞之间病毒库的分布；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 反弹的病毒。最后，我们将研究有利于 SIV 感染和持续存在的机制。 CD4 T 细胞耗尽时的巨噬细胞。 我们相信，互补的、全面的、高度协同的、严格对照的研究 我们建议将提供前所未有的、新颖的见解：（i）了解病毒的细胞性质如何 储库调节 ART 中的残余炎症和病毒持续性以及 ATI 后的病毒反弹，以及 (2) 巨噬细胞在长期 ART 期间隐藏具有复制能力的病毒并有助于 ATI 后病毒反弹。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库有贡献，而且在收集的大量组织中也对病毒库有贡献 纵向和尸检时，包括脑脊液和脑组织。这些成就将为以下方面的努力提供信息： 设计新的治疗策略，旨在实现艾滋病毒感染的长期病毒缓解。