The translational landscape of HIV-1 infected cells reveals novel gene regulatory principles

ABSTRACT: Human Immunodeficiency Virus-1 (HIV-1) uses a number of strategies to modulate viral and host gene expression during its lifecycle. To characterize the transcriptional and translational landscape of HIV-1 infected cells, we used a combination of ribosome profiling, disome sequencing and RNA sequencing. We found that the initial host response to viral infection is translationally regulated, and subsequently gives way to transcriptomic changes as the infection progresses. We show that HIV-1 mRNAs are efficiently translated at all stages of infection, despite evidence for a substantial decrease in translational efficiency of host genes that are implicated in host cell translation. Our data also reveal novel upstream open reading frames (uORFs) within the HIV-1 5'UTR as well as internal ORFs (iORFs) within the Vif and Pol coding domains. We observed ribosomal collisions in Gag-Pol upstream of the ribosome frameshift site that we attributed to a novel RNA structural fold using RNA structural probing and single molecule optical tweezers. Antisense oligos designed to break this structure decreased frameshifting efficiency. Overall, our data highlight the complexity of HIV-1 gene regulation and provide a key resource for decoding of host-pathogen interactions upon HIV-1 infection. Furthermore, we provide evidence for a novel RNA structural fold including the frameshift site that might be promising as target for antiviral therapy.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Andreas Schlosser  

LAB HEAD: Andreas Schlosser

PROVIDER: PXD058232 | Pride | 2025-05-26

REPOSITORIES: Pride