HIV infection in microglia leads to senescence, triggering activation of neurotoxicity pathways.

HIV-associated neurocognitive disorders (HAND) persist in milder forms despite anti-retroviral therapy, leading to premature and exacerbated aging-related cognitive disorders. We investigated the interplay between HAND and aging in microglia, which constitute the main brain HIV reservoir. We compared the transcriptomic patterns associated with normal aging in healthy humans to those observed following HIV infection in both ex vivo and in vivo models. Single cell and bulk transcriptomic patterns revealed that HIV infection induces a pattern of cellular senescence, with strong parallels to the transcriptomic signature of normal aging. Both processes were characterized by p53 pathway activation, upregulation of inflammatory genes and downregulation of proliferative genes while maintaining mTOR signaling, a pattern characteristic of cellular senescence. Importantly, both actively HIV infected and bystander microglia showed the cellular senescence patterns. Our results provide a mechanistic basis for the observed premature brain aging in HAND, and identify senescence-associated pathways as potential therapeutic targets.