While modern therapy has transformed HIV into a manageable chronic disease and enabled people with HIV to expect a near-normal lifespan, neurocognitive impairment remains an unresolved clinical concern. Mounting evidence links chronic infection and immune activation with persistent neuroinflammation, a hallmark of neurodegeneration. The long-term objective of this project is to identify therapeutic targets to alleviate neuroinflammation and neurodegeneration associated with chronic infection. A potential factor linking neuroinflammation, neurodegeneration, and antimicrobial immunity is the immune kinase leucine-rich repeat kinase 2 (LRRK2). Mutated LRRK2 is the most common monogenetic cause of Parkinson’s disease, and LRRK2 has been heavily implicated in conferring susceptibility to mycobacterial infection and modulating antiviral cytokine activity. Based on our observation that LRRK2 modulates antiviral immunity during mycobacterial infection, the goals of this project are to 1) determine the function of LRRK2 in viral pathogenesis and neuroinflammation and 2) assess its therapeutic potential during viral infection. Using a macaque SIV infection model of HIV, this proposal seeks to address the fundamental questions of whether SIV infection promotes LRRK2 expression and how loss of LRRK2 impacts SIV pathogenesis and the host immune response. We hypothesize that LRRK2 contributes to HIV pathogenesis through regulation of antiviral immunity. In Aim 1, we will use a non-human primate (NHP) model to assess the impact of SIV infection on LRRK2 gene expression and protein levels longitudinally in immune populations and the gastrointestinal tract and at a single time point in the brain, as LRRK2 is dynamically expressed in these tissues. In Aim 2, we will use an NHP model to determine the consequences of LRRK2 inhibition on host response to SIV using both in vivo and ex vivo approaches. The data obtained from this project will shed light on the function of LRRK2 in antiviral immune activation and generate preliminary data for future studies investigating factors contributing to viral-induced neuroinflammation.