IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-56772-3.html
   My bibliography  Save this article

Non-AUG HIV-1 uORF translation elicits specific T cell immune response and regulates viral transcript expression

Author

Listed:
  • Emmanuel Labaronne

    (46 allee d’Italie F-69364
    ADLIN Science)

  • Didier Décimo

    (F-69007)

  • Lisa Bertrand

    (Institute for Integrative Biology of the Cell (I2BC))

  • Laura Guiguettaz

    (46 allee d’Italie F-69364)

  • Thibault J. M. Sohier

    (46 allee d’Italie F-69364)

  • David Cluet

    (46 allee d’Italie F-69364)

  • Valérie Vivet-Boudou

    (UPR9002)

  • Ana Luiza Chaves Valadão

    (Montpellier University)

  • Clara Dahoui

    (F-69007)

  • Pauline François

    (Institute for Integrative Biology of the Cell (I2BC))

  • Isabelle Hatin

    (Institute for Integrative Biology of the Cell (I2BC))

  • Olivier Lambotte

    (Le Kremlin Bicêtre
    IDMIT)

  • Assia Samri

    (Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris))

  • Brigitte Autran

    (Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris))

  • Lucie Etienne

    (F-69007)

  • Caroline Goujon

    (Montpellier University)

  • Jean-Christophe Paillart

    (UPR9002)

  • Olivier Namy

    (Institute for Integrative Biology of the Cell (I2BC))

  • Bertha Cecilia Ramirez

    (Institute for Integrative Biology of the Cell (I2BC)
    Université de Paris Cité)

  • Théophile Ohlmann

    (F-69007)

  • Arnaud Moris

    (Institute for Integrative Biology of the Cell (I2BC))

  • Emiliano P. Ricci

    (46 allee d’Italie F-69364)

Abstract

Human immunodeficiency virus type-1 (HIV-1) is a complex retrovirus that relies on alternative splicing, translational, and post-translational mechanisms to produce over 15 functional proteins from its single ~10 kb transcriptional unit. Using ribosome profiling, nascent protein labeling, RNA sequencing, and whole-proteomics of infected CD4 + T lymphocytes, we characterized the transcriptional, translational, and post-translational landscape during infection. While viral infection exerts a significant impact on host transcript abundance, global translation rates are only modestly affected. Proteomics data reveal extensive transcriptional and post-translational regulation, with many genes showing opposing trends between transcript/ribosome profiling and protein abundance. These findings highlight a complex regulatory network orchestrating gene expression at multiple levels. Viral ribosome profiling further uncovered extensive non-AUG translation of small peptides from upstream open reading frames (uORFs) within the 5’ long terminal repeat, which elicit specific T cell responses in people living with HIV. Conservation of uORF translation among retroviruses, along with TAR sequences, shapes DDX3 dependency for efficient translation of the main viral open reading frames.

Suggested Citation

  • Emmanuel Labaronne & Didier Décimo & Lisa Bertrand & Laura Guiguettaz & Thibault J. M. Sohier & David Cluet & Valérie Vivet-Boudou & Ana Luiza Chaves Valadão & Clara Dahoui & Pauline François & Isabel, 2025. "Non-AUG HIV-1 uORF translation elicits specific T cell immune response and regulates viral transcript expression," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56772-3
    DOI: 10.1038/s41467-025-56772-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-56772-3
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-56772-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Philippe E. Mangeot & Valérie Risson & Floriane Fusil & Aline Marnef & Emilie Laurent & Juliana Blin & Virginie Mournetas & Emmanuelle Massouridès & Thibault J. M. Sohier & Antoine Corbin & Fabien Aub, 2019. "Genome editing in primary cells and in vivo using viral-derived Nanoblades loaded with Cas9-sgRNA ribonucleoproteins," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    2. Mathieu Ringeard & Virginie Marchand & Etienne Decroly & Yuri Motorin & Yamina Bennasser, 2019. "FTSJ3 is an RNA 2′-O-methyltransferase recruited by HIV to avoid innate immune sensing," Nature, Nature, vol. 565(7740), pages 500-504, January.
    3. Caroline Goujon & Olivier Moncorgé & Hélène Bauby & Tomas Doyle & Christopher C. Ward & Torsten Schaller & Stéphane Hué & Wendy S. Barclay & Reiner Schulz & Michael H. Malim, 2013. "Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection," Nature, Nature, vol. 502(7472), pages 559-562, October.
    4. Ulf-Peter Guenther & David E. Weinberg & Meghan M. Zubradt & Frank A. Tedeschi & Brittany N. Stawicki & Leah L. Zagore & Gloria A. Brar & Donny D. Licatalosi & David P. Bartel & Jonathan S. Weissman &, 2018. "The helicase Ded1p controls use of near-cognate translation initiation codons in 5′ UTRs," Nature, Nature, vol. 559(7712), pages 130-134, July.
    5. Shringar Rao & Cynthia Lungu & Raquel Crespo & Thijs H. Steijaert & Alicja Gorska & Robert-Jan Palstra & Henrieke A. B. Prins & Wilfred Ijcken & Yvonne M. Mueller & Jeroen J. A. Kampen & Annelies Verb, 2021. "Selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    6. Manqing Li & Elaine Kao & Xia Gao & Hilary Sandig & Kirsten Limmer & Mariana Pavon-Eternod & Thomas E. Jones & Sebastien Landry & Tao Pan & Matthew D. Weitzman & Michael David, 2012. "Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11," Nature, Nature, vol. 491(7422), pages 125-128, November.
    7. Olivier Namy & Stephen J. Moran & David I. Stuart & Robert J. C. Gilbert & Ian Brierley, 2006. "A mechanical explanation of RNA pseudoknot function in programmed ribosomal frameshifting," Nature, Nature, vol. 441(7090), pages 244-247, May.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. James C. Murphy & Elena M. Harrington & Sophie Schumann & Elton J. R. Vasconcelos & Timothy J. Mottram & Katherine L. Harper & Julie L. Aspden & Adrian Whitehouse, 2023. "Kaposi’s sarcoma-associated herpesvirus induces specialised ribosomes to efficiently translate viral lytic mRNAs," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Yifei Gu & Yuanhui Mao & Longfei Jia & Leiming Dong & Shu-Bing Qian, 2021. "Bi-directional ribosome scanning controls the stringency of start codon selection," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    3. Michael Kugler & Felix J. Metzner & Gregor Witte & Karl-Peter Hopfner & Katja Lammens, 2024. "Phosphorylation-mediated conformational change regulates human SLFN11," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Chris H. Hill & Lukas Pekarek & Sawsan Napthine & Anuja Kibe & Andrew E. Firth & Stephen C. Graham & Neva Caliskan & Ian Brierley, 2021. "Structural and molecular basis for Cardiovirus 2A protein as a viral gene expression switch," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    5. Omar M. Hedaya & Kadiam C. Venkata Subbaiah & Feng Jiang & Li Huitong Xie & Jiangbin Wu & Eng-Soon Khor & Mingyi Zhu & David H. Mathews & Chris Proschel & Peng Yao, 2023. "Secondary structures that regulate mRNA translation provide insights for ASO-mediated modulation of cardiac hypertrophy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Lisa Bertrand & Annika Nelde & Bertha Cecilia Ramirez & Isabelle Hatin & Hugo Arbes & Pauline François & Stéphane Demais & Emmanuel Labaronne & Didier Decimo & Laura Guiguettaz & Sylvie Grégoire & Ann, 2025. "Unveiling conserved HIV-1 open reading frames encoding T cell antigens using ribosome profiling," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    7. Daniel Strebinger & Chris J. Frangieh & Mirco J. Friedrich & Guilhem Faure & Rhiannon K. Macrae & Feng Zhang, 2023. "Cell type-specific delivery by modular envelope design," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    8. Myung Chung & Katsutoshi Imanaka & Ziyan Huang & Akiyuki Watarai & Mu-Yun Wang & Kentaro Tao & Hirotaka Ejima & Tomomi Aida & Guoping Feng & Teruhiro Okuyama, 2024. "Conditional knockout of Shank3 in the ventral CA1 by quantitative in vivo genome-editing impairs social memory in mice," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    9. Agnieszka Dorman & Maryam Bendoumou & Aurelija Valaitienė & Jakub Wadas & Haider Ali & Antoine Dutilleul & Paolo Maiuri & Lorena Nestola & Monika Bociaga-Jasik & Gilbert Mchantaf & Coca Necsoi & Stéph, 2025. "Nuclear retention of unspliced HIV-1 RNA as a reversible post-transcriptional block in latency," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    10. Shuting Yan & Qiyao Zhu & Swati Jain & Tamar Schlick, 2022. "Length-dependent motions of SARS-CoV-2 frameshifting RNA pseudoknot and alternative conformations suggest avenues for frameshifting suppression," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    11. Simon Zenke & Mauricio P. Sica & Florian Steinberg & Julia Braun & Alicia Zink & Alina Gavrilov & Alexander Hilger & Aditya Arra & Monika Brunner-Weinzierl & Roland Elling & Niklas Beyersdorf & Tim Lä, 2022. "Differential trafficking of ligands trogocytosed via CD28 versus CTLA4 promotes collective cellular control of co-stimulation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    12. Felix J. Metzner & Simon J. Wenzl & Michael Kugler & Stefan Krebs & Karl-Peter Hopfner & Katja Lammens, 2022. "Mechanistic understanding of human SLFN11," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    13. Eric M. Patrick & Rajeev Yadav & Kasun Senanayake & Kyle Cotter & Andrea A. Putnam & Eckhard Jankowsky & Matthew J. Comstock, 2025. "High-resolution fleezers reveal duplex opening and stepwise assembly by an oligomer of the DEAD-box helicase Ded1p," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    14. Jie Chen & Nan Liu & Yinpin Huang & Yuanxun Wang & Yuxing Sun & Qingcui Wu & Dianrong Li & Shuanhu Gao & Hong-Wei Wang & Niu Huang & Xiangbing Qi & Xiaodong Wang, 2021. "Structure of PDE3A–SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    15. Chen Bao & Mingyi Zhu & Inna Nykonchuk & Hironao Wakabayashi & David H. Mathews & Dmitri N. Ermolenko, 2022. "Specific length and structure rather than high thermodynamic stability enable regulatory mRNA stem-loops to pause translation," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    16. Thibaut Halegua & Valérie Risson & Julien Carras & Martin Rouyer & Laurent Coudert & Arnaud Jacquier & Laurent Schaeffer & Théophile Ohlmann & Philippe Emmanuel Mangeot, 2025. "Delivery of Prime editing in human stem cells using pseudoviral NanoScribes particles," Nature Communications, Nature, vol. 16(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56772-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.