Brain microglia serve as a persistent HIV reservoir despite durable antiretroviral therapy
Yuyang Tang, … , David M. Margolis, Guochun Jiang
Yuyang Tang, … , David M. Margolis, Guochun Jiang
Published June 15, 2023
Citation Information: J Clin Invest. 2023;133(12):e167417. https://doi.org/10.1172/JCI167417.
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Research Article AIDS/HIV

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

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.

Authors

Yuyang Tang, Antoine Chaillon, Sara Gianella, Lilly M. Wong, Dajiang Li, Theresa L. Simermeyer, Magali Porrachia, Caroline Ignacio, Brendon Woodworth, Daniel Zhong, Jiayi Du, Eduardo de la Parra Polina, Jennifer Kirchherr, Brigitte Allard, Matthew L. Clohosey, Matt Moeser, Amy L. Sondgeroth, Gregory D. Whitehill, Vidisha Singh, Amir Dashti, Davey M. Smith, Joseph J. Eron, Katherine J. Bar, Ann Chahroudi, Sarah B. Joseph, Nancie M. Archin, David M. Margolis, Guochun Jiang

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Figure 6

Outgrowth HIV reestablished its infection in both myeloid cells and PBMC PHA blasts.

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Outgrowth HIV reestablished its infection in both myeloid cells and PBMC...
Supernatant HIV from day 7 after CM272- and SAHA-stimulated reinfected MG culture (as shown in Figure 4A) (A and B) or CD8-depleted PBMC PHA blasts isolated from HIV– donors (C and D). The same sources of target MG cultures or PHA blasts without addition of HIV (No HIV) were used as negative infection controls. HIV production was measured by HIV RT-ddPCR (A–C) or HIV p24 ELISA (D). HIV infection in MG was suppressed by the CCR5 inhibitor MVC (B), while ART (raltegravir/darunavir/nevirapine) treatment blocked HIV infection in PBMC PHA blasts (C and D) (n = 3). DPI, days post infection.