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

摘要 尽管有效的抗逆转录病毒疗法(ART)的发展成功地抑制了病毒的复制 对于大多数艾滋病毒携带者(PLWH)来说，没有可以完全治愈这种感染的治疗方法。这个 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)，具有产生传染性病毒的能力，并在 艺术停止后的一小段时间，几乎没有例外情况。因此，开发新的干预措施 旨在减少或消除VRS是艾滋病毒研究的关键优先事项之一。为了回应RFA-MH- 20-701，我们的申请提出了SIV感染恒河猴(RMS)的基础科学和临床前研究 建立PLWH中枢神经系统髓系细胞VR的模型，并探讨新型VR的疗效。 防止艾滋病毒在中枢神经系统内持续存在的药理学策略。因此，基于 在本申请中概述的观察我们假设，在急性期PMC形成的中断 感染将限制VR的播种和维持，因此，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 在感染急性期全身性破坏PMC的形成，调节病毒在中枢神经系统的持续；(2) 目的：研究感染急性期全身性破坏PMC的形成是否调节了 ATI后病毒反弹的动力学和程度；以及(3)调查PMC的全身破坏是否 感染急性期的形成，调节神经炎症和突触树突状细胞的损伤 与长期的ART和ATI有关。这些目标将通过以下方式实现：(I)使用成熟的 抑制性ART治疗SIV感染的RMS，以及(Ii)体内抗体介导的PMC破坏 在未经治疗的感染的急性期形成。揭示了血小板调节的机制 HIV在髓系细胞中的持续存在将提供对这些细胞如何相互作用的关键理解 在哺乳动物细胞中的功能，并洞察如何在PLWH实现潜在的艾滋病毒治愈。

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.