Reducing the CNS reservoir through myeloid cell depletion

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PROJECT SUMMARY/ABSTRACT HIV infection results in CNS comorbidities, with nearly 75% of patients with advanced HIV disease showing neurological manifestations. The blood-brain barrier prevents antiretroviral drugs from entering the CNS, and thus a reservoir occurs. Macrophage and microglia remain at least latently infected, awaiting an insult to reawaken. A recently FDA-approved drug, Pexidartinib, has been used to safely deplete microglia and macrophages. These microglia are believed to repopulate from the subventricular zone, with initial cells being CD4-ve. This could render these cells impervious to infection. Further, SIV infection makes macrophages resistant to apoptosis: Pexidartinib restores this apoptotic sensitivity. This could provide an avenue to examining the depletion of latently infected cells from the CNS, with the potential for diminishing later neurological disorders, including the major CNS comorbidity: HAND. There is debate that latently-infected microglia and macrophages can be a source of viral rebound to the periphery. Removing those microglia after viral setpoint, with macaques on stable cART, and determining if the CNS reservoir can return, could answer this very question. The effects of transiently depleting microglia from the CNS, especially in the context of SIV infection, represent a significant gap in our knowledge. Therefore, there is a critical need to understand the effects of transiently removing latently-infected microglia from the CNS in SIV neuropathology. This R21 application seeks to address how removing microglia from the CNS influences neuroinflammation both positively and negatively in the context of SIV infection.