Despite suppressive antiretroviral therapy (ART), HIV persists in the central nervous system (CNS) and contributes to HIV-associated neurocognitive disorder (HAND), but cell type-specific effects remain poorly defined. Using fluorescence-activated nuclei sorting of postmortem brain tissue of aviremic and viremic deceased people with HIV (DPWH) and HIV-negative individuals, we quantified the size of the HIV CNS reservoir and transcriptional alterations. Microglia were identified as the dominant CNS reservoir, harboring 10^3-10^4 HIV DNA copies per million cells by ddPCR-LTR assay in both aviremic and viremic DPWH. Bulk RNA-sequencing revealed immune pathway upregulation specifically in microglia, and downregulation of synaptic and homeostatic pathways across cell-types in viremic compared to aviremic individuals. ART partially mitigated microglial transcriptional dysregulation, but transcriptional profiles did not restore profiles to HIV-negative levels. Notably, persistent microglial infection was associated with transcriptional changes in other cell-types, underscoring microglia as a key therapeutical target for CNS-directed HIV cure strategies.
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