Extensive uORF translation from HIV-1 transcripts conditions DDX3 dependency for expression of main ORFs and elicits specific T cell immune responses in infected individuals

Labaronne, E.; Decimo, D.; Bertrand, L.; Guiguettaz, L.; Sohier, T. J.; Cluet, D.; Vivet-Boubou, V.; Dahoui, C.; Francois, P.; Hatin, I.; Lambotte, O.; Samri, A.; Autran, B.; Etienne, L.; Goujon, C.; Paillart, J.-C.; Namy, O.; Ramirez, B. C.; Ohlmann, T.; Moris, A.; Ricci, E.

doi:10.1101/2022.04.29.489990

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bioRxiv · 10.1101/2022.04.29.489990

Extensive uORF translation from HIV-1 transcripts conditions DDX3 dependency for expression of main ORFs and elicits specific T cell immune responses in infected individuals

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Abstract

Human immunodeficiency virus type-1 (HIV-1) is a complex retrovirus which relies on alternative splicing, translational and post-translational mechanisms to produce more than 15 functional proteins from its single [~]10kb transcriptional unit. Here, we have applied ribosome profiling and nascent protein labeling at different time points during infection of CD4+ T lymphocytes to characterize the translational landscape of cellular and viral transcripts during the course of infection. Our results indicate a strong impact of viral infection on host cellular transcript levels but a modest impact on global translation rates. Analysis of ribosome profiling reads from viral transcripts reveals extensive and productive non-AUG translation of small peptides from multiple upstream open reading-frames (uORFs) located in the 5 long terminal repeat. Remarkably, these uORFs derived peptides elicit specific T cell responses in HIV-infected individuals. uORFs are conserved among other retroviruses and, together with the TAR sequence, condition the dependency on DDX3 for efficient translation of the main viral open-reading frames.

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Labaronne, E., Decimo, D., Bertrand, L., Guiguettaz, L., Sohier, T. J., Cluet, D., Vivet-Boubou, V., Dahoui, C., Francois, P., Hatin, I., Lambotte, O., Samri, A., Autran, B., Etienne, L., Goujon, C., Paillart, J.-C., Namy, O., Ramirez, B. C., Ohlmann, T., Moris, A., Ricci, E.. 2022-04-29. Extensive uORF translation from HIV-1 transcripts conditions DDX3 dependency for expression of main ORFs and elicits specific T cell immune responses in infected individuals. https://doi.org/10.1101/2022.04.29.489990

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