Implications of HIV persistence and pathogenesis in microglia

This review summarizes recent advances in understanding HIV infection of the brain, focusing on viral persistence in microglia and associated pathogenesis during viremia and viral suppression. We highlight key findings in microglial research that inform the next steps toward therapeutic strategies and cure approaches addressing the brain as a viral reservoir.

Microglia can contain intact, replication-competent inducible proviruses, even during antiretroviral therapy (ART). The microglial chromatin context and HIV integration site landscape during HIV infection are reportedly distinct from peripheral lymphocytes. Upon infection, both infected and bystander microglia exhibit pro-inflammatory and senescent phenotypes that closely resemble those observed in aging microglia and play a central role in neuropathogenesis. ART mitigates these effects but does not fully restore to levels observed in HIV-uninfected conditions.

Microglial HIV infection and persistence of this reservoir play a central and detrimental role in HIV pathogenesis in the brain. Given their role in neurodegeneration during HIV infection, closer characterization of the microglial (latent) reservoir and careful monitoring of neurodegeneration during treatment and cure interventions are essential. Treatment and cure strategies should prioritize minimizing viral transcription and protein expression within the brain reservoir to mitigate neuroinflammation and neuropathogenesis.