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

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.

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Publication Details

Journal
Nature Communications
Published
2025-02-18
DOI
https://doi.org/10.1038/s41467-025-56772-3
Citations
3
Primary Topic
HIV Research and Treatment
Type
article
Field-Weighted Citation Impact
3.11

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article

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

Lisa Bertrand, Théophile Ohlmann, Valérie Vivet‐Boudou, David Cluet et al.
3 citations
Nature Communications
HIV Research and Treatment
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article

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

Lisa Bertrand, Théophile Ohlmann, Valérie Vivet‐Boudou, David Cluet, Olivier Namy, Emiliano P. Ricci, Isabelle Hatin, Assia Samri, Brigitte Autran, Jean‐Christophe Paillart, Lucie Etienne, Laura Guiguettaz, Caroline Goujon, Ana Luiza Chaves Valadão, Didier Décimo, Thibault J. M. Sohier, Bertha Cecilia Ramírez, Olivier Lambotte, Arnaud Moris, Clara Dahoui, Emmanuel Labaronne, Pauline François
article en
3 citations

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.

Nature CommunicationsVol. 16(1)
Université Claude Bernard Lyon 1 (FR), École Normale Supérieure de Lyon (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université de Montpellier (FR), Université Paris Cité (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), Sorbonne Université (FR), CEA Paris-Saclay - Etablissement de Fontenay-aux-roses (FR), Assistance Publique – Hôpitaux de Paris (FR), Institut de Biologie Intégrative de la Cellule (FR), CEA Paris-Saclay (FR), Infectious Disease Models and Innovative Therapies (FR), Architecture et Réactivité de l'arN (FR), Centre d'Immunologie et des Maladies Infectieuses (FR), Institut de Recherche en Infectiologie de Montpellier (FR), Institut Cochin (FR), Centre International de Recherche en Infectiologie (FR), Bicêtre Hospital (FR), Université de Strasbourg (FR)
Styrelsen för Internationellt Utvecklingssamarbete, Fondation Innovations en Infectiologie, Sidaction, European Commission, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Centre National de la Recherche Scientifique, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, National Institutes of Health, Centre International de Mathématiques et Informatique de Toulouse
Openalex Percentile: Top 11%
HIV Research and Treatment
3.11
DOIOpen Access PDFOpenAlex
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