Programmed Frameshift Recoding of HIV-1 mRNA

HIV-1 uses a single mRNA to encode Gag (viral structure proteins) and Pol (viral enzymes protease, reverse transcriptase, and integrase). The pol gene is positioned downstream of and slightly overlapping with the gag gene, but does not have its own translational start codon and is in a different reading frame (−1 nucleotide) relative to gag. To achieve the synthesis of Pol, HIV-1 has developed a mechanism named Programmed Frameshift Recoding (PFR), by which ribosomes slip backward one nucleotide (-1 frameshift) to leave the gag reading frame and shift to the pol reading frame to produce the Gag-Pol fusion protein. Within HIV-1 mRNA, PFR occurs on a highly conserved slippery sequence (U UUU UUA), and a downstream pseudoknot structure is required for efficient frameshifting. While the cis-acing RNA sequences and elements that mediate HIV-1 PFR have been intensively investigated, the trans-acting cellular factors regulating PFR remain relatively unexplored. We are conducting a systematic search for host factors regulating HIV-1 PFR by genome-wide CRISPR-Cas9 knockout (KO) and transcriptional activation screening.

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