Gene expression from the HIV-1 genomic RNA

HIV-1 gRNA PT control

From its birth during transcription to nuclear export, translation and decay, an mRNA molecule is always associated to a large number of proteins to form a messenger ribonucleoprotein complex (mRNP). It has been shown that the protein composition or nuclear imprinting acquired by a given mRNA can impact its cytoplasmic localization, translation and even its decay rates.
HIV transcription depends on the activity of the host RNAP II and, as a classical cellular mRNA, viral transcripts associate with several host RNA binding proteins in the nucleus. Interestingly, a single viral mRNA molecule, the so called full-length 9-kb unspliced genomic RNA (gRNA), is first processed by alternative splicing (fully or partially spliced transcripts) to give rise more than 40 transcripts coding for different regulatory and accessory proteins as well as the surface glycoproteins. However the unspliced form, the 9-kb gRNA, is also used as an mRNA coding for the major structural protein (Gag) and the proteins containing the viral enzymatic activities (Pol). This viral transcript exhibits features that are,
a priori, not compatible with efficient gene expression including i) the presence of functional introns, an aspect incompatible with efficient nuclear export and translation; ii) AU-rich sequences that strongly interferes with gRNA stability, nuclear export and translation; iii) a 5’-untranslated region (5´-UTR) composed of several highly structured RNA motifs, which are expected to interfere with the ribosome recruitment by the canonical cap-dependent translation initiation mechanism and iv) a trimethylated cap structure that is expected to be inefficiently recognized by any of the canonical cellular cap-binding proteins associated to translation initiation. However, and despite all these constraints, the HIV-1 gRNA is efficiently exported to the cytoplasm by the viral protein Rev through the CRM1-RanGTP pathway to then reach the cytoplasm and recruit the host translational machinery giving rise to the large amounts of Gag that are required during viral replication. Once translated, the gRNA do not undergoes turnover as it is used as the genome that is incorporated into the viral particles. In the lab, we are mostly interested in study all these processes involved in the post-transcriptional control of the HIV-1 gRNA, specially on how nuclear events such as mRNP composition impact cytoplasmic localization and translation.