Brain microglia serve as a persistent HIV reservoir despite durable antiretroviral therapy

Brain microglia (MG) may serve as a human immunodeficiency virus 1 (HIV) reservoir and ignite rebound viremia following cessation of antiretroviral therapy (ART), but they have yet to be proven to harbor replication-competent HIV. Here, we isolated brain myeloid cells (BrMCs) from nonhuman primates and rapid autopsy of people with HIV (PWH) on ART and sought evidence of persistent viral infection. BrMCs predominantly displayed microglial markers, in which up to 99.9% of the BrMCs were TMEM119+ MG. Total and integrated SIV or HIV DNA was detectable in the MG, with low levels of cell -associated viral RNA. Provirus in MG was highly sensitive to epigenetic inhibition. Outgrowth virus from parietal cortex MG in an individual with HIV productively infected both MG and PBMCs. This inducible, replication-competent virus and virus from basal ganglia proviral DNA were closely related but highly divergent from variants in peripheral compartments. Phenotyping studies characterized brain-derived virus as macrophage tropic based on the ability of the virus to infect cells expressing low levels of CD4. The lack of genetic diversity in virus from the brain suggests that this macrophage-tropic lineage quickly colonized brain regions. These data demonstrate that MG harbor replication-competent HIV and serve as a persistent reservoir in the brain.

Automated summary

Reservoirs of human immunodeficiency virus 1 (HIV) may exist in brain microglia, which can cause rebound viremia after antiretroviral therapy cessation, but the presence of replication-competent HIV in these cells has not been proven yet. In this study, brain myeloid cells (BrMCs) isolated from nonhuman primates and HIV-infected individuals were found to contain detectable levels of SIV or HIV DNA, indicating persistent viral infection. These findings suggest that brain microglia serve as a long-term reservoir for replication-competent HIV in the brain.