{ "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.", "abstract_shown": true, "affiliations": [ "Research Unit Genomics of Retroviral Infections, Leibniz Institute of Virology, Hamburg, Germany.", "Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.", "Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.", "Gladstone Institutes, University of California San Francisco (UCSF), San Francisco, California, United States of America.", "Department of Urology, University of California San Francisco (UCSF), San Francisco, CaliforniaUnited States of America.", "Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.", "Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.", "Research Department Integrative Virology, Leibniz Institute of Virology, Hamburg, Germany.", "Research Department Virus Genomics, Leibniz Institute of Virology, Hamburg, Germany.", "Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany.", "Department of Infectious Diseases, Virology, Heidelberg University, Heidelberg, Germany.", "German Center for Infection Research (DZIF), Braunschweig, Germany.", "Institute for Infection Research and Vaccine Development, University Medical Center Hamburg-Eppendorf, Hamburg, Germany." ], "article_type": "Research Article", "arxiv": null, "author_total": 18, "authors": [ { "affs": [ 0 ], "name": "Martin V Hamann" }, { "affs": [ 0 ], "name": "Lisa Brauckmann" }, { "affs": [ 0 ], "name": "Christoph Schwarz" }, { "affs": [ 1 ], "name": "Michael Spohn" }, { "affs": [ 0 ], "name": "Ramon Stoeck" }, { "affs": [ 0, 2 ], "name": "Sabrina M Leddy" }, { "affs": [ 3, 4 ], "name": "Julie Frouard" }, { "affs": [ 0 ], "name": "Maisha Adiba" }, { "affs": [ 5, 6 ], "name": "Riekje Winzer" }, { "affs": [ 7 ], "name": "Fabian Hausmann", "orcid": "0000-0001-6110-5824" }, { "affs": [ 8 ], "name": "Sanamjeet Virdi" }, { "affs": [ 8 ], "name": "Adam Grundhoff" }, { "affs": [ 2 ], "name": "Cedric Feschotte" }, { "affs": [ 9 ], "name": "Daniel Sauter", "orcid": "0000-0001-7665-0040" }, { "affs": [ 10, 11 ], "name": "Frauke Muecksch" }, { "affs": [ 3, 4 ], "name": "Nadia R Roan" }, { "affs": [ 5, 6 ], "name": "Eva Tolosa" }, { "affs": [ 0, 11, 12 ], "name": "Ulrike C Lange", "orcid": "0009-0002-5274-3108" } ], "bibtex": "https://research.draconitic.com/paper/9716tbvc2ebc8.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014618", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014618", "id": "9716tbvc2ebc8", "issns": [ "1553-7374", "1553-7366" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014618", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2406|HIV Research and Treatment" ], [ "plos", "/Biology and life sciences/Evolutionary biology/Evolutionary processes/Evolutionary adaptation" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/DNA transcription" ], [ "plos", "/Biology and life sciences/Genetics/Genetic loci" ], [ "plos", "/Biology and life sciences/Immunology/Vaccination and immunization/Antiviral therapy/Antiretroviral therapy" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Immunodeficiency viruses/HIV" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Immunodeficiency viruses/HIV/HIV-1" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Retroviruses/Lentivirus/HIV" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Retroviruses/Lentivirus/HIV/HIV-1" ], [ "plos", "/Biology and life sciences/Molecular biology/Molecular biology techniques/Cloning" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Immunodeficiency viruses/HIV" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Immunodeficiency viruses/HIV/HIV-1" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/RNA viruses/Retroviruses/Lentivirus/HIV" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/RNA viruses/Retroviruses/Lentivirus/HIV/HIV-1" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Immunodeficiency viruses/HIV" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Immunodeficiency viruses/HIV/HIV-1" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Retroviruses/Lentivirus/HIV" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Retroviruses/Lentivirus/HIV/HIV-1" ], [ "plos", "/Medicine and health sciences/Immunology/Vaccination and immunization/Antiviral therapy/Antiretroviral therapy" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Immunodeficiency viruses/HIV" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Immunodeficiency viruses/HIV/HIV-1" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Retroviruses/Lentivirus/HIV" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Retroviruses/Lentivirus/HIV/HIV-1" ], [ "plos", "/Medicine and health sciences/Public and occupational health/Preventive medicine/Vaccination and immunization/Antiviral therapy/Antiretroviral therapy" ], [ "plos", "/Research and analysis methods/Molecular biology techniques/Cloning" ] ], "openalex": "W7223053455", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014618&type=printable", "pmcid": "PMC13682663", "pmid": "42900669", "published": "2026-10-20", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/9716tbvc2ebc8.ris", "sources": [ { "first_seen": "2026-10-30T12:17:23Z", "native_id": "10.1371/journal.ppat.1014618", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014618" }, { "first_seen": "2026-10-30T12:19:32Z", "native_id": "MED:42900669", "source": "europepmc", "url": "https://europepmc.org/article/MED/42900669" } ], "subjects": [ { "field": "biochemistry", "origin": "plos:gene expression", "subfield": "molecular-biology" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "biology", "origin": "plos:microbiology", "subfield": "microbiology" } ], "title": "Selective persistence of HIV-1-infected T cell clones can occur through immune reprogramming driven by defective, transcriptionally active proviruses", "title_text": "Selective persistence of HIV-1-infected T cell clones can occur through immune reprogramming driven by defective, transcriptionally active proviruses", "type": "peer-reviewed", "updated_at": "2026-10-30T12:19:32Z", "url": "https://research.draconitic.com/paper/9716tbvc2ebc8", "venue": "PLOS Pathogens", "versions": [] }