BPS2026 – Mechanisms of translation initiation on the structured HIV-1 5’ UTR

The beginning of eukaryotic translation is the most regulated step. In this process, human ribosomes must load onto and scan the 5’ untranslated region (5’ UTR) of messenger RNA (mRNA) to locate the start codon. Viruses, like HIV-1, have highly structured 5’ UTRs which are important for regulating many processes of their viral lifecycles. However, little is known how the 5’ UTR structure impacts the molecular mechanisms of translation initiation. To elucidate the role of the 5’ UTR structure in translation, we used single-molecule fluorescence (smFRET) in a reconstituted human translation initiation system to quantify ribosomal subunit and eukaryotic initiation factor dynamics on HIV-1 RNA in real time. Mechanistic data were utilized to guide structural targets for cryo-electron microscopy (cryo-EM). Understanding how HIV-1 uses this region of its genome to modulate translation initiation will be informative for characterizing translation initiation in other viral systems and potentially reveal new therapeutic targets. This work will also shed light on how RNA structure broadly mediates eukaryotic translational control.