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Updated: Jul 26, 2025
A Rat Model of EcoHIV Brain Infection
Published on: January 21, 2021
Brain microglia serve as a persistent HIV reservoir despite durable antiretroviral therapy
Yuyang Tang1,2, Antoine Chaillon3, Sara Gianella3
1University of North Carolina (UNC) HIV Cure Center, and.
Abstract:
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.
Insights
Brain microglia (MG) are confirmed to harbor replication-competent human immunodeficiency virus (HIV). This discovery reveals MG as a persistent HIV reservoir in the brain, potentially igniting viral rebound after treatment cessation.
Area of Science:
- Neuroscience
- Virology
- Immunology
Background:
- Microglia (MG) are implicated as a potential human immunodeficiency virus (HIV) reservoir.
- Rebound viremia after antiretroviral therapy (ART) cessation suggests a persistent viral source.
- Replication-competent HIV within brain microglia has not been definitively proven.
Purpose of the Study:
- To investigate if brain myeloid cells (BrMCs), predominantly microglia, harbor replication-competent HIV.
- To identify the role of microglia in persistent HIV infection and potential viral rebound.
Main Methods:
- Isolation of BrMCs from nonhuman primates and HIV-positive individuals on ART.
- Detection of total and integrated SIV/HIV DNA and cell-associated viral RNA in microglia.
- Epigenetic inhibition assays to assess provirus sensitivity.
- Viral outgrowth assays from brain microglia to determine replication competence.
- Phenotyping of brain-derived virus for tropism (e.g., CD4 expression).
Main Results:
- BrMCs were confirmed as primarily microglia (TMEM119+).
- Detectable HIV DNA and low levels of viral RNA were found in microglia.
- Provirus in microglia showed sensitivity to epigenetic inhibition.
- Replication-competent, inducible HIV was successfully cultured from parietal cortex microglia.
- Brain-derived HIV exhibited macrophage tropism and low genetic diversity, suggesting rapid colonization.
Conclusions:
- Brain microglia serve as a persistent reservoir for replication-competent HIV.
- Inducible HIV in microglia can lead to viral rebound.
- Brain-associated HIV displays distinct characteristics, including macrophage tropism.
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