Persistent type I interferon signaling within the brain of people with HIV on ART with cognitive impairment

Year: 2025

Type: article

Abstract: To better understand the molecular mechanism that drives neuroinflammation, we analyzed the protein profiles of 27 brains from HIV with HIV (PWH) on antiretroviral therapy (ART), including various stages of HIV-associated neurocognitive disorders (HAND), and compared them to 9 HAND-negative controls. We found that most of the proteins that were increased-about 66.7%-were involved in immune response pathways. Of these, 23.3% were specifically related to type I interferon (IFN-I) signaling, which remains active in the brain through both HIV-related and unrelated mechanisms. Using single-cell RNA sequencing (scRNA-seq) on brain tissues collected during rapid autopsies from participants in the Last Gift cohort, we found that IFN-I signaling was especially strong in astrocytes, microglia (MG), and endothelial cells. In a mini-brain organoid model of acute HIV infection, IFN-I signaling was also highly active in astrocytes but less so in MG. Interestingly, IFN-I activation can happen without HIV being present-expression of human endogenous retrovirus-W1 (HERV-W1) Env can directly trigger this response in astrocytes, and it continues in glial cells even with effective ART. Together, our findings point to persistent IFN-I activation in glial and endothelial cells in the brain, which may contribute to neuroinflammation and cognitive disorders in PWH on ART.

Source: PLoS Pathogens

DOI: 10.1371/journal.ppat.1013411

Authors: Yuyang Tang, Ling Xie, Ciniso Sylvester Shabangu, Dajiang Li, Gabriela da Silva Prates, Ashokkumar Manickam, Lilly M. Wong, Antoine Chaillon, Edward P. Browne, Sara Gianella, Wenzhe Ho, David M. Margolis, Xian Chen, Wenhui Hu, Guochun Jiang

Institutions: University of North Carolina at Chapel Hill, University of California San Diego, Temple University, Virginia Commonwealth University

Language: English

Topic: HIV Research and Treatment

Subfield: Virology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,043

Funders: James B. Pendleton Charitable Trust, National Institutes of Health, Center for AIDS Research, University of Washington, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of Allergy and Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill

OpenAlex ID: W4413367240