The HIV-1 Rev protein substitutes the positive effects of splicing on nuclear export and translation to promote efficient Gag synthesis from the unspliced genomic mRNA

Abstract

Human Immunodeficiency Virus type-1 (HIV-1) gene expression involves the synthesis of a complex transcriptome including a subset of completely and incompletely spliced transcripts and one unspliced mRNA molecule. As cellular mRNAs, completely spliced transcripts follow the classical gene expression pathway in which nuclear export and translation are strongly stimulated by splicing. In contrast, the HIV-1 unspliced mRNA does not benefit from splicing and it is retained and degraded in the cell nucleus unless the viral protein Rev is present. Here, we confirm that the recruitment of Rev to the unspliced mRNA is sufficient to substitute the effects of splicing on nuclear export and translation. Interestingly, these functions of Rev are interconnected since no effect of Rev on translation was observed when the unspliced mRNA is exported through NXF1. We also demonstrate that Rev interacts with the DEAD-box RNA helicase eIF4A favouring the recruitment of the RNA helicase to the unspliced mRNA. Together our data reveal a novel mechanism by which Rev interconnects nuclear export and translation of the unspliced mRNA in order to ensure efficient Gag synthesis during viral replication.