A new type of IRES within gag coding region recruits three initiation complexes on HIV-2 genomic RNA

Abstract

Genomic RNA of primate lentiviruses serves both as an mRNA that encodes Gag and Gag-Pol polyproteins and as a propagated genome. Translation of this RNA is initiated by standard cap dependant mechanism or by internal entry of the ribosome. Two regions of the genomic RNA are able to attract initiation complexes, the 5′ untranslated region and the gag coding region itself. Relying on probing data and a phylogenetic study, we have modelled the secondary structure of HIV-1, HIV-2 and SIVMac coding region. This approach brings to light conserved secondary-structure elements that were shown by mutations to be required for internal entry of the ribosome. No structural homologies with other described viral or cellular IRES can be identified and lentiviral IRESes show many peculiar properties. Most notably, the IRES present in HIV-2 gag coding region is endowed with the unique ability to recruit up to three initiation complexes on a single RNA molecule. The structural and functional properties of gag coding sequence define a new type of IRES. Although its precise role is unknown, the conservation of the IRES among fast evolving lentiviruses suggests an important physiological role.

The yellow fever 17D virus as a platform for new live attenuated vaccines

“…Actually, we attributed the genetic instability of a recombinant YF virus expressing a fragment of the SIV Gag precursor protein to the presence of an IRES element localized at the 3′end of gene encoding the SIV Matrix protein. 69 We managed to substantially improve the genetic stability of this recombinant YF17D virus by introducing mutations in the IRES element. 70 The foreign antigens expressed by the recombinant YF17D virus in the E/NS1 region appear to remain cell-associated as described elsewhere.…”

Viral SELEX reveals individual and cooperative roles of the C-box and G-box in HIV-2 replication

“…Previous studies on HIV-2 translation have suggested that the genomic RNA contains an IRES located downstream from the gag AUG1 initiation codon (Herbreteau et al 2005;Weill et al 2010). According to this model, HIV-2 IRES recruits ribosomes for translational initiation at AUG1 and farther downstream at AUG2 and AUG3 to generate the three Gag isoforms.…”

“…Ohlmann and coworkers have shown that these three isoforms of Gag are expressed during HIV-2 infection, which they attributed to alternative initiation events (Herbreteau et al 2005;Weill et al 2010). The first isoform, p58, initiates synthesis from a start codon located at nucleotides 546-548 (AUG1).…”

Design and Production of mRNA-based Gene Vectors for Therapeutic Reprogramming of Cell Fate

“…Some researchers consider such 5'-UTR IRESes as sufficiently different from the bona fide inter-cistron IRESes to warrant them a special name, cap-independent translational enhancers (CITEs) [17]. Some CITEs appear to be reasonably efficient, attracting up to three translation initiation complexes on a single mRNA [18]. It is difficult to define a specific sequence motif for CITEs and they are presumed to act through secondary structures.…”