Unveiling conserved HIV-1 open reading frames encoding T cell antigens using ribosome profiling

Lisa Bertrand, Annika Nelde, Bertha Cecilia Ramirez, Isabelle Hatin, Hugo Arbes, Pauline François, Stéphane Demais, Emmanuel Labaronne, Didier Decimo, Laura Guiguettaz, Sylvie Grégoire, Anne Bet, Guillaume Beauclair, Antoine Gross, Maja C. Ziegler, Mathias Pereira, Raphaël Jeger-Madiot, Yann Verdier, Joelle Vinh, Sylvain Cardinaud, Stéphanie Graff-Dubois, Audrey Esclatine, Cécile Gouttefangeas, Marcus Altfeld, Laurent Hocqueloux, Assia Samri, Brigitte Autran, Olivier Lambotte, Hans-Georg Rammensee, Emiliano P. Ricci, Juliane Walz, Olivier Namy (olivier.namy@i2bc.paris-saclay.fr) and Arnaud Moris (arnaud.moris@i2bc.paris-saclay.fr)
Additional contact information
Lisa Bertrand: Institute for Integrative Biology of the Cell (I2BC)
Annika Nelde: University and University Hospital Tübingen
Bertha Cecilia Ramirez: Institute for Integrative Biology of the Cell (I2BC)
Isabelle Hatin: Institute for Integrative Biology of the Cell (I2BC)
Hugo Arbes: Institute for Integrative Biology of the Cell (I2BC)
Pauline François: Institute for Integrative Biology of the Cell (I2BC)
Stéphane Demais: Institute for Integrative Biology of the Cell (I2BC)
Emmanuel Labaronne: 46 allée d’Italie F-69364
Didier Decimo: ENS de Lyon
Laura Guiguettaz: 46 allée d’Italie F-69364
Sylvie Grégoire: Institute for Integrative Biology of the Cell (I2BC)
Anne Bet: Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris)
Guillaume Beauclair: Institute for Integrative Biology of the Cell (I2BC)
Antoine Gross: Université de Montpellier
Maja C. Ziegler: Leibniz Institute of Virology
Mathias Pereira: Institute for Integrative Biology of the Cell (I2BC)
Raphaël Jeger-Madiot: Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris)
Yann Verdier: Spectrométrie de Masse Biologique et Protéomique
Joelle Vinh: Spectrométrie de Masse Biologique et Protéomique
Sylvain Cardinaud: Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris)
Stéphanie Graff-Dubois: Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris)
Audrey Esclatine: Institute for Integrative Biology of the Cell (I2BC)
Cécile Gouttefangeas: University of Tübingen
Marcus Altfeld: Leibniz Institute of Virology
Laurent Hocqueloux: Centre Hospitalier Universitaire d’Orléans
Assia Samri: Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris)
Brigitte Autran: Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris)
Olivier Lambotte: Le Kremlin-Bicêtre
Hans-Georg Rammensee: University of Tübingen
Emiliano P. Ricci: 46 allée d’Italie F-69364
Juliane Walz: University and University Hospital Tübingen
Olivier Namy: Institute for Integrative Biology of the Cell (I2BC)
Arnaud Moris: Institute for Integrative Biology of the Cell (I2BC)

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract The development of ribosomal profiling (Riboseq) revealed the immense coding capacity of human and viral genomes. Here, we used Riboseq to delineate the translatome of HIV-1 in infected CD4+ T cells. In addition to canonical viral protein coding sequences (CDSs), we identify 98 alternative open reading frames (ARFs), corresponding to small Open Reading Frames (sORFs) that are distributed across the HIV genome including the UTR regions. Using a database of HIV genomes, we observe that most ARF amino-acid sequences are likely conserved among clade B and C of HIV-1, with 8 ARF-encoded amino-acid sequences being more conserved than the overlapping CDSs. Using T cell-based assays and mass spectrometry-based immunopeptidomics, we demonstrate that ARFs encode viral polypeptides. In the blood of people living with HIV, ARF-derived peptides elicit potent poly-functional T cell responses mediated by both CD4+ and CD8+ T cells. Our discovery expands the list of conserved viral polypeptides that are targets for vaccination strategies and might reveal the existence of viral microproteins or pseudogenes.

Date: 2025
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DOI: 10.1038/s41467-025-56773-2

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