Restoring a homeostatic microglia state by combination antiretroviral therapy in SIV-infected rhesus macaques

Although modern therapies like cART have transformed HIV from a lethal disease to a manageable condition, associated neurocognitive consequences remain a concern. Paradoxically, microglia and macrophages, which comprise the innate defense system in the brain and are crucial for CNS homeostasis, are targets for HIV and key players in its neuropathogenesis. In addition, these infected cells can serve as viral reservoirs even in effectively treated infection. Here using an scRNA-seq approach in the SIV-NHP model, we demonstrate differential transcriptional programs in brain myeloid cells from monkeys under four conditions: uninfected, chronically SIV-infected, chronically SIV-infected treated with combination antiretroviral therapy (cART), and SIVE. Our study reveals alterations in composition (both lineage and gene expression profiles) of the cell populations between groups. Importantly, treatment with cART largely restored the homeostatic microglia profile present in uninfected animals that was disrupted in SIV-infected untreated animals Overall design: Microglia/Macrophages were isolated and cryopreserved from the rhesus monkey brains of 3 saline-treated (control), 3 saline-treated SIV-infected, 3 saline-treated SIV-infected treated with cART and 1 saline-treated SIV-infected with encephalitis. They were subsequently thawed and immunomagnetically enriched for CD11b+ cells, and further purified by flow cytometry, sorted for CD11b positive, live events, and processed for scRNA by the 10xGenomics platform.