Barcoded HIV-1 reveals viral persistence driven by clonal proliferation and distinct epigenetic patterns

Tian-hao Zhang, Yuan Shi, Natalia L. Komarova, Dominik Wordaz, Matthew Kostelny, Alexander Gonzales, Izra Abbaali, Hongying Chen, Gabrielle Bresson-Tan, Melanie Dimapasoc, William Harvey, Christopher Oh, Camille Carmona, Christopher Seet, Yushen Du, Ren Sun, Jerome A. Zack and Jocelyn T. Kim ()
Additional contact information
Tian-hao Zhang: University of California
Yuan Shi: University of California
Natalia L. Komarova: University of California San Diego
Dominik Wordaz: University of California San Diego
Matthew Kostelny: Los Angeles
Alexander Gonzales: Los Angeles
Izra Abbaali: Los Angeles
Hongying Chen: Los Angeles
Gabrielle Bresson-Tan: Los Angeles
Melanie Dimapasoc: Los Angeles
William Harvey: Los Angeles
Christopher Oh: Los Angeles
Camille Carmona: Los Angeles
Christopher Seet: Los Angeles
Yushen Du: Zhejiang University School of Medicine
Ren Sun: University of California
Jerome A. Zack: Los Angeles
Jocelyn T. Kim: Los Angeles

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The HIV reservoir consists of infected cells in which the HIV-1 genome persists as provirus despite effective antiretroviral therapy (ART). Studies exploring HIV cure therapies often measure intact proviral DNA levels, time to rebound after ART interruption, or ex vivo stimulation assays of latently infected cells. This study utilizes barcoded HIV to analyze the reservoir in humanized mice. Using bulk PCR and deep sequencing methodologies, we retrieve 890 viral RNA barcodes and 504 proviral barcodes linked to 15,305 integration sites at the single RNA or DNA molecule in vivo. We track viral genetic diversity throughout early infection, ART, and rebound. The proviral reservoir retains genetic diversity despite cellular clonal proliferation and viral seeding by rebounding virus. Non-proliferated cell clones are likely the result of elimination of proviruses associated with transcriptional activation and viremia. Elimination of proviruses associated with viremia is less prominent among proliferated cell clones. Proliferated, but not massively expanded, cell clones contribute to proviral expansion and viremia, suggesting they fuel viral persistence. This approach enables comprehensive assessment of viral levels, lineages, integration sites, clonal proliferation and proviral epigenetic patterns in vivo. These findings highlight complex reservoir dynamics and the role of proliferated cell clones in viral persistence.

Date: 2025
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DOI: 10.1038/s41467-025-56771-4

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