Investigating intercellular interactions between astrocytes and microglia in HIV infection and latency

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HIV currently infects over 38 million people worldwide. Despite the high efficacy of antiretroviral therapies, HIV persists via transcriptionally silent latent infection and long-lived viral reservoirs in tissue sites such as the central nervous system. Viral persistence in the central nervous system leads to sustained neuroinflammation, which in turn causes neuronal injury. As a result, a spectrum of deficits in memory, learning, and/or motor functions referred to as HIV-associated neurocognitive disorders can be observed in 40- 50% of people living with HIV. The largest population of central nervous system resident cells that are susceptible to HIV infection is microglia, the resident macrophages of the brain. Astrocytes are also impacted by HIV infection both through abortive integration of the viral genome and through indirect activation by proinflammatory cytokines produced by infected cells. Because microglia are challenging to model in vitro and rarely obtainable from HIV patients, the dynamics of HIV infection in microglia as well as the immune response of both microglia and astrocytes to HIV infection remain poorly understood. This proposal seeks to deepen our understanding of the neuroinflammatory response to HIV infection using IPSC models of human microglia (iMg) and astrocytes (iAst). Recent studies have shown that peripheral macrophages respond to HIV infection by producing IL-1β and my preliminary data suggests that HIV infected iMg also secrete IL-1β. Additionally, coculture of iAst and iMg leads to increased HIV replication, suggesting that iAst act to augment HIV infection. I hypothesize that IL-1β produced by infected iMg induces TNFa production by iAst, which acts on iMg to increase productive HIV infection and decrease latent infection. I will test this hypothesis in two aims: (1) Define the impact of intercellular interactions between astrocytes and microglia on HIV-induced inflammation and HIV infection, and (2) define the influence of astrocytes on HIV latency in microglia using single cell transcriptomics. These studies will increase our understanding of HIV infection in the CNS and the intercellular interactions that cause neuroinflammation in HIV associated neurocognitive disorders.