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: 10645038
• 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/10645038
• 关键词: Acute; Anatomy; Basic Science; Blood - brain barrier anatomy; Blood Platelets; Blood Vessels; Brain; CCL2 gene; CD14 gene; Cells; Central Nervous System; Cerebrospinal Fluid; Complex; Data; Development; Event; FCGR3B gene; HIV; HIV Infections; HIV-1; Immune; Infection; Interruption; Intervention; Kinetics; Learning; Macaca mulatta; Macrophage; Maintenance; Mammalian Cell; Mediating; Microglia; Modeling; Myeloid Cells; Peripheral; Persons; Phase; Phenotype; Predisposition; Productivity; Research; Resistance; Role; SIV; Testing; Viral; Viral reservoir; Virus; Virus Replication; antiretroviral therapy; in vivo; innovation; insight; migration; monocyte; neuroinflammation; novel; permissiveness; pharmacologic; pre-clinical research; prevent; response; trafficking; transmission process; 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.

总结