Brain Myeloid Cells are Sources of HIV-associated Damage and Viral Dispersal

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SUMMARY HIV infects the brain soon after transmission, but it is unknown how infected brain cells contribute to HIV persistence and whether these cells release viable virus that can seed cells outside the brain. It is also unclear how HIV persistence leads to local cellular damage, although inflammatory and external factors (like antiretroviral [ARV] penetration and opioids) likely impact such damage. Such new knowledge could be important for HIV cure strategies and ways to improve brain health in persons with HIV (PWH). This project will address stated objectives of RFA-MH-20-701, Role of Myeloid Cells in Persistence and Eradication of HIV-1 Reservoirs from the Brain, by: (i) mapping HIV reservoir size, composition, and activity in brain myeloid cells (BMC) in relation to cellular density and levels of ARV and opioids, (ii) determining the role of BMC in HIV dispersal within the central nervous system (CNS) and across the body in the setting of ARV treatment (ART) and after treatment interruption, and (iii) defining how HIV reservoir size and activity in BMC is associated with local inflammation and cell damage. Our goal is to examine the role of BMC in HIV persistence, local inflammatory-induced damage and as a source of viruses that can egress from the CNS to re-seed peripheral organs. The rationale for this project is supported by literature demonstrating that brain macrophages and microglia can harbor HIV that persists during modern ART. The low turnover of these macrophages and microglial cells (from months to years) make them unique reservoirs for HIV. While HIV in resting T cells has been extensively characterized, the role of BMC as a source of rebound upon cessation of ART is yet to be determined. Further, HIV in BMC likely triggers immune responses, even during ART, causing local damage. Our overall hypothesis is that BMC (primarily microglial cells) contribute to HIV persistence in the CNS with regional heterogeneity. HIV harbored in these BMC likely also causes inflammation-associated brain damage and contributes to viral dispersal when ART is stopped. We also hypothesize that HIV persistence, local damage and viral dispersal are influenced by local ARV and opioid levels. To address these open questions, our study will collect and analyze tissues throughout the CNS (white and grey matters of frontal cortex, thalamus, hippocampus, basal ganglia, cerebellum, spinal cord), ileum, spleen, blood and cerebrospinal fluid (CSF) of altruistic PWH enrolled in the Last Gift cohort, an ongoing rapid autopsy study. Some participants (n=15) will remain virally suppressed until the time of death, while others (n=5) will want to stop their ART before death. Half of the population will use prescription opioids. These studies will be important for PWH because they will provide new insights for the development of strategies to clear HIV infection and lessen inflammatory-dependent microglial-induced neurological damage.