Selective persistence of HIV-1-infected T cell clones can occur through immune reprogramming driven by defective, transcriptionally active proviruses
13 affiliations
- 1Research Unit Genomics of Retroviral Infections, Leibniz Institute of Virology, Hamburg, Germany.
- 2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- 3Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
- 4Gladstone Institutes, University of California San Francisco (UCSF), San Francisco, California, United States of America.
- 5Department of Urology, University of California San Francisco (UCSF), San Francisco, CaliforniaUnited States of America.
- 6Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- 7Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- 8Research Department Integrative Virology, Leibniz Institute of Virology, Hamburg, Germany.
- 9Research Department Virus Genomics, Leibniz Institute of Virology, Hamburg, Germany.
- 10Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany.
- 11Department of Infectious Diseases, Virology, Heidelberg University, Heidelberg, Germany.
- 12German Center for Infection Research (DZIF), Braunschweig, Germany.
- 13Institute for Infection Research and Vaccine Development, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Abstract
People living with HIV (PLWH) on antiretroviral therapy (ART) accumulate primarily defective proviral sequences in genomes of often clonally expanded CD4 + HIV-1 target cells. The majority of viral-derived DNA is transcriptionally active and preferentially found at distinct genomic loci suggesting a selective process driven by integration site-specific crosstalk between viral and host sequences. Focusing on one of the most prominent selected integration loci, the BTB Domain and CNC Homolog 2 (BACH2) gene, we here show mechanistic insights how CD4 + T cells are functionally reprogrammed via exaptation of provirus-derived regulatory sequences during long-term ART. Using a cellular model of BACH2-integrated proviruses, we find that proviral transcription drives aberrant BACH2 protein levels that escape autoregulatory feedback and impose BACH2-dependent transcriptomic changes. By mimicking these changes in primary CD4 + T lymphocytes, we observe that BACH2 drives reprogramming of cells toward a proliferative, precursor memory-like type. These reprogrammed CD4 + T cells possess traits of immune evasion and cellular survival that are signatures of persistent HIV reservoir cells in PLWH. Inhibition of provirus transcriptional activity can mitigate exaptation, suggesting a strategy to offset HIV-driven differentiation and expansion of CD4 + T cells. Finally, our data suggest that provirus exaptation at a second prominently selected proviral integration gene, the Signal Transducer And Activator of Transcription 5B (STAT5B) gene, drives a contrary, effector-like T cell fate, suggesting a multifaceted impact of exaptation on immune homeostasis. Overall, our data suggest that transcriptionally active proviruses, even if structurally defective, modulate target cells through insertional activation of integration genes, a process which we postulate to contribute to the complex immune modulation and dysregulation experienced by ART-suppressed PLWH. Author summary: Although antiretroviral therapy (ART) effectively suppresses HIV, it cannot eliminate the virus from the body. HIV persists as genetic material integrated into the DNA of infected immune cells, where many viral copies are defective and unable to produce new virus. Our study shows that these defective viral sequences are not necessarily biologically inactive. Instead, they can alter the activity of nearby human genes and change how infected immune cells behave. We found that this can promote the survival and persistence of cells with features resembling the long-lived HIV reservoir. Integration at different genes can thereby have distinct effects on cell function. Importantly, we found that reducing viral transcription can potentially diminish these changes, suggesting a possible strategy to limit HIV-driven effects on immune cells. Overall, our findings indicate that defective HIV genomes may actively contribute to ongoing immune disturbances in people living with HIV, despite successful antiviral treatment.
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BibTeX
@article{hamann2026selective,
title = {{Selective persistence of HIV-1-infected T cell clones can occur through immune reprogramming driven by defective, transcriptionally active proviruses}},
author = {Martin V Hamann and Lisa Brauckmann and Christoph Schwarz and Michael Spohn and Ramon Stoeck and Sabrina M Leddy and Julie Frouard and Maisha Adiba and Riekje Winzer and Fabian Hausmann and Sanamjeet Virdi and Adam Grundhoff and Cedric Feschotte and Daniel Sauter and Frauke Muecksch and Nadia R Roan and Eva Tolosa and Ulrike C Lange},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014618},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014618},
note = {CC BY},
}
RIS
TY - JOUR
TI - Selective persistence of HIV-1-infected T cell clones can occur through immune reprogramming driven by defective, transcriptionally active proviruses
AU - Martin V Hamann
AU - Lisa Brauckmann
AU - Christoph Schwarz
AU - Michael Spohn
AU - Ramon Stoeck
AU - Sabrina M Leddy
AU - Julie Frouard
AU - Maisha Adiba
AU - Riekje Winzer
AU - Fabian Hausmann
AU - Sanamjeet Virdi
AU - Adam Grundhoff
AU - Cedric Feschotte
AU - Daniel Sauter
AU - Frauke Muecksch
AU - Nadia R Roan
AU - Eva Tolosa
AU - Ulrike C Lange
PY - 2026
DA - 2026/10/20
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014618
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014618
AB - People living with HIV (PLWH) on antiretroviral therapy (ART) accumulate primarily defective proviral sequences in genomes of often clonally expanded CD4 + HIV-1 target cells. The majority of viral-derived DNA is transcriptionally active and preferentially found at distinct genomic loci suggesting a selective process driven by integration site-specific crosstalk between viral and host sequences. Focusing on one of the most prominent selected integration loci, the BTB Domain and CNC Homolog 2 (BACH2) gene, we here show mechanistic insights how CD4 + T cells are functionally reprogrammed via exaptation of provirus-derived regulatory sequences during long-term ART. Using a cellular model of BACH2-integrated proviruses, we find that proviral transcription drives aberrant BACH2 protein levels that escape autoregulatory feedback and impose BACH2-dependent transcriptomic changes. By mimicking these changes in primary CD4 + T lymphocytes, we observe that BACH2 drives reprogramming of cells toward a proliferative, precursor memory-like type. These reprogrammed CD4 + T cells possess traits of immune evasion and cellular survival that are signatures of persistent HIV reservoir cells in PLWH. Inhibition of provirus transcriptional activity can mitigate exaptation, suggesting a strategy to offset HIV-driven differentiation and expansion of CD4 + T cells. Finally, our data suggest that provirus exaptation at a second prominently selected proviral integration gene, the Signal Transducer And Activator of Transcription 5B (STAT5B) gene, drives a contrary, effector-like T cell fate, suggesting a multifaceted impact of exaptation on immune homeostasis. Overall, our data suggest that transcriptionally active proviruses, even if structurally defective, modulate target cells through insertional activation of integration genes, a process which we postulate to contribute to the complex immune modulation and dysregulation experienced by ART-suppressed PLWH. Author summary: Although antiretroviral therapy (ART) effectively suppresses HIV, it cannot eliminate the virus from the body. HIV persists as genetic material integrated into the DNA of infected immune cells, where many viral copies are defective and unable to produce new virus. Our study shows that these defective viral sequences are not necessarily biologically inactive. Instead, they can alter the activity of nearby human genes and change how infected immune cells behave. We found that this can promote the survival and persistence of cells with features resembling the long-lived HIV reservoir. Integration at different genes can thereby have distinct effects on cell function. Importantly, we found that reducing viral transcription can potentially diminish these changes, suggesting a possible strategy to limit HIV-driven effects on immune cells. Overall, our findings indicate that defective HIV genomes may actively contribute to ongoing immune disturbances in people living with HIV, despite successful antiviral treatment.
SN - 1553-7374
SN - 1553-7366
ER -