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

• Authors: Yuyang Tang, University of North Carolina (UNC); Antoine Chaillon, University of California San Diego, La Jolla; Sara Gianella, University of California San Diego, La Jolla; Lilly M Wong, University of North Carolina (UNC); Dajiang Li, University of North Carolina (UNC); Theresa L Simermeyer, University of North Carolina (UNC); Magali Porrachia, University of California San Diego, La Jolla; Caroline Ignacio, University of California San Diego, La Jolla; Brendon Woodworth, University of California San Diego, La Jolla; Daniel Zhong, University of North Carolina (UNC); Jiayi Du, University of North Carolina (UNC); Eduardo de la Parra Polina, University of North Carolina (UNC); Jennifer Kirchherr, University of North Carolina (UNC); Brigitte Allard, University of North Carolina (UNC); Matthew L Clohosey, University of North Carolina (UNC); Matt Moeser, University of North Carolina Chapel Hill; Amy L Sondgeroth, University of North Carolina Chapel Hill; Gregory D Whitehill, University of Pennsylvania; Vidisha Singh, Emory University; Amir Dashti, Emory University; Davey M Smith, University of California San Diego, La Jolla; Joseph J Eron, University of North Carolina Chapel Hill; Katherine J Bar, University of Pennsylvania; Ann Chahroudi, Emory University; Sarah B Joseph, University of North Carolina (UNC); Nancie M Archin, University of North Carolina (UNC); David M Margolis, University of North Carolina (UNC); Guochun Jiang, University of North Carolina (UNC)
• Journal Title: JOURNAL OF CLINICAL INVESTIGATION
• Volume: Volume 133, Number 12
• Publisher: AMER SOC CLINICAL INVESTIGATION INC | 2023-06-15
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1172/JCI167417
• Subjects: Health Sciences, Epidemiology; Health Sciences, Medicine and Surgery; Biology, Microbiology; Health Sciences, Immunology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, Research & Experimental; Research & Experimental Medicine; T-CELLS; MONOCYTE DIFFERENTIATION; ENTRY PHENOTYPES; LATENT HIV-1; MACROPHAGES; TARGET; MOUSE; CNS; TRANSCRIPTION; QUANTITATION

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.