Single-cell analyses identify monocyte gene expression profiles that influence HIV-1 reservoir size in acutely treated cohorts

Philip K. Ehrenberg, Aviva Geretz, Meta Volcic, Taisuke Izumi, Lauren K. Yum, Adam Waickman, Shida Shangguan, Dominic Paquin-Proulx, Matthew Creegan, Meera Bose, Kawthar Machmach, Aidan McGraw, Akshara Narahari, Jeffrey R. Currier, Carlo Sacdalan, Nittaya Phanuphak, Richard Apps, Michael Corley, Lishomwa C. Ndhlovu, Bonnie Slike, Shelly J. Krebs, Jintanat Anonworanich, Sodsai Tovanabutra, Merlin L. Robb, Michael A. Eller, Gregory M. Laird, Joshua Cyktor, Eric S. Daar, Trevor A. Crowell, John W. Mellors, Sandhya Vasan, Nelson L. Michael, Frank Kirchhoff and Rasmi Thomas ()
Additional contact information
Philip K. Ehrenberg: Walter Reed Army Institute of Research
Aviva Geretz: Walter Reed Army Institute of Research
Meta Volcic: Ulm University Medical Center
Taisuke Izumi: Walter Reed Army Institute of Research
Lauren K. Yum: Walter Reed Army Institute of Research
Adam Waickman: Walter Reed Army Institute of Research
Shida Shangguan: Walter Reed Army Institute of Research
Dominic Paquin-Proulx: Walter Reed Army Institute of Research
Matthew Creegan: Walter Reed Army Institute of Research
Meera Bose: Walter Reed Army Institute of Research
Kawthar Machmach: Walter Reed Army Institute of Research
Aidan McGraw: American University
Akshara Narahari: Saint Joseph’s University
Jeffrey R. Currier: Walter Reed Army Institute of Research
Carlo Sacdalan: SEARCH Research Foundation
Nittaya Phanuphak: Institute of HIV Research and Innovation
Richard Apps: National Institutes of Health
Michael Corley: Weill Cornell Medicine
Lishomwa C. Ndhlovu: Weill Cornell Medicine
Bonnie Slike: Walter Reed Army Institute of Research
Shelly J. Krebs: Walter Reed Army Institute of Research
Jintanat Anonworanich: Walter Reed Army Institute of Research
Sodsai Tovanabutra: Walter Reed Army Institute of Research
Merlin L. Robb: Walter Reed Army Institute of Research
Michael A. Eller: Walter Reed Army Institute of Research
Gregory M. Laird: Accelevir Diagnostics
Joshua Cyktor: University of Pittsburgh
Eric S. Daar: Lundquist Institute at Harbor-UCLA Medical Center
Trevor A. Crowell: Walter Reed Army Institute of Research
John W. Mellors: University of Pittsburgh
Sandhya Vasan: Walter Reed Army Institute of Research
Nelson L. Michael: Walter Reed Army Institute of Research
Frank Kirchhoff: Ulm University Medical Center
Rasmi Thomas: Walter Reed Army Institute of Research

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Eliminating latent HIV-1 is a major goal of AIDS research but host factors determining the size of these reservoirs are poorly understood. Here, we investigate the role of host gene expression on HIV-1 reservoir size during suppressive antiretroviral therapy (ART). Peripheral blood cells of fourteen males initiating ART during acute infection and demonstrating effective viral suppression but varying magnitudes of total HIV-1 DNA were characterized by single-cell RNA sequencing. Differential expression analysis demonstrates increased CD14+ monocyte activity in participants having undetectable HIV-1 reservoirs, with IL1B expression inversely associating with reservoir size. This is validated in another cohort of 38 males comprised of different ancestry and HIV-1 subtypes, and with intact proviral DNA assay (IPDA®) measurements. Modeling interactions show monocyte IL1B expression associates inversely with reservoir size at higher frequencies of central memory CD4+ T cells, linking monocyte IL1B expression to cell types known to be reservoirs for persistent HIV-1. Functional analyses reveal that IL1B activates NF-κB, thereby promoting productive HIV-1 infection while simultaneously suppressing viral spread, suggesting a natural latency reversing activity to deplete the reservoir in ART-treated individuals. Altogether, scRNA-seq analyses reveal that monocyte IL1B expression could decrease HIV-1 proviral reservoirs in individuals initiating ART during acute infection.

Date: 2025
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DOI: 10.1038/s41467-025-59833-9

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