Impact of drugs of abuse on HIV brain reservoirs and HAND in humanized microglia mice

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ABSTRACT Since the start of the HIV/AIDS epidemic, it has been recognized that drug abuse is strongly linked to contracting and transmitting HIV, as well as more severe consequences. Factors influencing the susceptibility and disease progression are still unclear. Viral reservoir establishment occurs early in acute HIV infection and reaches a set point within the first two months of infection, which in turn determines the size of the reservoir in the chronic stage. HIV enters the brain right after infection and replicates in macrophages, microglia, and to a small extent in astrocytes. Increased susceptibility in substance use could affect the size of the central nervous system (CNS) reservoir, which may influence spontaneous virological remission and viral rebound kinetics. CNS viral reservoir size may also determine the HIV- associated neurocognitive disorder (HAND) severity, viral recurrence, and rebound. Until now, there was no means to study the viral dynamics, CNS viral invasion, susceptibility to MP infection in the brain, and the reservoirs of HIV infection so that interventions can be developed effectively. A small animal model, like the humanized mouse, provides great advantages due to manipulations using host/human cells, as well as the possibility of establishing chronic infection by HIV itself. The humanized microglial (hMGL) mouse model is reconstituted with the human immune system and human glial cells, which allows natural progression of CNS infection and disease in relation to peripheral HIV infection. Herein, we propose to deploy our hMGL mouse to elucidate the mechanisms of HIV-1 invasion, persistence, and neuropathogenesis for substance use. Our objective is to define the CNS viral reservoir and investigate changes in the brain viral reservoir as a consequence of substances of abuse with an overarching goal of viral eradication. Our aims are, 1. to investigate the effect of cocaine on the CNS viral invasion, reservoir establishment, and viral latency during chronic infection in humanized microglial mice, 2. to determine the host genetic signatures that accelerate the CNS viral reservoir and assess the influence of antiretroviral therapy (ART) on glial homeostasis, and 3. to study HIV and SUD-induced neuropathology using a multimodal approach. The complete characterization of this humanized mouse model in establishing linkages to human disease, and demonstrating a comprehensive evaluation of the CNS reservoir during cART, HIV infection, and drug abuse will prove to be a significant value to the neuroHIV field.