Revealing the role of platelets in promoting HIV reservoir seeding and persistence in the CNS-resident myeloid cells

揭示血小板在促进中枢神经系统驻留骨髓细胞中 HIV 储存库播种和持久性中的作用

• 批准号: 10463824
• 负责人: SANJAY B. MAGGIRWAR
• 金额: $ 81.85万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463824
• 关键词: Acute; Anatomy; Basic Science; Blood - brain barrier anatomy; Blood Platelets; Brain; CCL2 gene; CD14 gene; Cells; Cerebrospinal Fluid; Complex; Data; Development; Event; FCGR3B gene; HIV; HIV Infections; HIV-1; Immune; Infection; Interruption; Intervention; Kinetics; Learning; Macaca mulatta; Maintenance; Mammalian Cell; Mediating; Microglia; Modeling; Myeloid Cells; Neuraxis; Peripheral; Persons; Pharmacology; Phase; Phenotype; Research; Resistance; Role; SIV; Testing; Viral; Viral reservoir; Virus; Virus Replication; antiretroviral therapy; base; in vivo; innovation; insight; macrophage; migration; monocyte; neuroinflammation; novel; pre-clinical research; prevent; response; trafficking; viral rebound

Summary Despite the development of potent anti-retroviral therapy (ART) that successfully suppresses virus replication in the majority of people living with HIV (PLWH), there is no treatment that can cure this infection entirely. The major obstacle in eradicating HIV is the persistence of various anatomical viral reservoirs (VRs), including the central nervous system (CNS), that have the capacity to produce infectious virus and systemically spread within a short period upon cessation of ART in all, with few exceptional cases. Therefore, developing novel interventions aimed at reducing or eliminating the VRs is one of the key priorities for HIV research. In response to RFA-MH- 20-701, our application proposes basic science and preclinical research in SIV-infected rhesus macaques (RMs) to model aspects of VR in the CNS-resident myeloid cells of PLWH, and to investigate the efficacy of the novel pharmacologic strategy to prevent establishment of HIV persistence in the CNS. Thus, based on the observations outlined in this application we hypothesize that the disruption of PMC formation during acute phase of infection will limit the seeding and maintenance of VR and, as a consequence, the extent of viral rebound in the CNS following analytical therapy interruption (ATI). Three aims are proposed: (1) To investigate whether the systemic disruption of PMC formation during acute phase of infection, regulates viral persistence in the CNS; (2) To investigate whether the systemic disruption of PMC formation during acute phase of infection, regulates the kinetics and extent of viral rebound after ATI; and (3) To investigate whether the systemic disruption of PMC formation during acute phase of infection, regulates the neuroinflammation and synaptodendritic damages associated with long-term ART and ATI. These aims will be achieved by (i) using a well-established model of SIV-infected RMs treated with suppressive ART, and (ii) performing in vivo Ab-mediated disruption of PMC formation during acute phase of untreated infection. Revealing the mechanisms through which platelets regulate the persistence of HIV in myeloid cells will provide a critical understanding of how these cellular interactions function in mammalian cells, and an insight into how a potential HIV cure can be achieved in PLWH.

概括 尽管开发了有效的抗逆转录病毒疗法（ART），可以成功抑制病毒复制 对于大多数艾滋病毒感染者（PLWH）来说，没有任何治疗方法可以完全治愈这种感染。这 根除艾滋病毒的主要障碍是各种解剖病毒库（VR）的持续存在，包括 中枢神经系统（CNS），有能力产生传染性病毒并在体内系统性传播 除极少数例外情况外，所有情况均在停止抗逆转录病毒治疗后持续很短的时间内。因此，开发新的干预措施 旨在减少或消除 VR 是 HIV 研究的重点之一。回应 RFA-MH- 20-701，我们的申请提出了感染 SIV 的恒河猴 (RM) 的基础科学和临床前研究 对 PLWH 中枢神经系统驻留髓样细胞中 VR 的各个方面进行建模，并研究新型药物的功效 预防艾滋病毒在中枢神经系统中持续存在的药理学策略。因此，基于 本申请中概述的观察结果我们假设急性期 PMC 形成的破坏 感染的增加将限制 VR 的传播和维持，从而限制病毒反弹的程度 分析治疗中断（ATI）后的中枢神经系统。提出了三个目标： (1) 调查是否 感染急性期 PMC 形成的系统性破坏，调节中枢神经系统中病毒的持续存在； (2) 研究感染急性期 PMC 形成的系统性破坏是否调节 ATI 后病毒反弹的动力学和程度； (3) 调查 PMC 是否受到系统性破坏 在感染急性期形成，调节神经炎症和突触树突损伤 与长期 ART 和 ATI 相关。这些目标将通过以下方式实现：(i) 使用完善的模型 用抑制性 ART 治疗感染 SIV 的 RM，以及 (ii) 进行体内 Ab 介导的 PMC 破坏 在未经治疗的感染急性期形成。揭示血小板调节机制 HIV 在骨髓细胞中的持续存在将提供对这些细胞如何相互作用的批判性理解 哺乳动物细胞中的功能，并深入了解如何在感染者身上实现潜在的艾滋病毒治愈。