Biology subjects

Autran, B.

Publications and source records attributed to Autran, B..

3 recordsLinked to original sources

bioRxiv2024

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

The development of ribosomal profiling (Riboseq) revealed the immense coding capacity of human and viral genomes. Here, we used Riboseq to delineate the first 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 observed 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 HIV-infected individuals, 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.

immunology↗

bioRxiv2023

A truncated HIV Tat demonstrates potent and specific latency reversal activity

A major barrier to HIV-1 cure is caused by the pool of latently infected CD4 T-cells that persist under combination antiretroviral therapy (cART). This latent reservoir is capable of producing replication-competent infectious virus once prolonged suppressive cART is withdrawn. Inducing the reactivation of HIV-1 gene expression in T-cells harboring a latent provirus in people living with HIV-1 under cART will likely result in depletion of this latent reservoir due to cytopathic effects or immune clearance. Studies have investigated molecules that reactivate HIV-1 gene expression but to date no latency reversal agent has been identified to eliminate latently infected cells harboring replication-competent HIV in cART treated individuals. Stochastic fluctuations in HIV-1 tat gene expression have been described and hypothesized to allow the progression into proviral latency. We hypothesized that exposing latently infected CD4+ T-cells to Tat would result in effective latency reversal. Our results indicate the capacity of a truncated Tat protein and mRNA to reactivate HIV-1 in latently infected T-cells ex vivo to a similar degree as the protein kinase C agonist: Phorbol 12-Myristate 13-Acetate, without T-cell activation nor any significant transcriptome perturbation.

cell biology↗

bioRxiv2022

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

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.

microbiology↗