The activity of the HIV-1 IRES is stimulated by oxidative stress and controlled by a negative regulatory element

Gendron, Karine; Ferbeyre, Gerardo; Heveker, Nikolaus; Brakier-Gingras, Léa

Translation of HIV-1 full-length mRNA produces the precursor of structural proteins, Gag (p55), and, through a programmed À1 ribosomal frameshift (26, 27) , it produces the precursor of viral enzymes, Gag-Pol (p220). This full-length RNA also serves as a genomic RNA that is encapsidated in viral particles as a dimer. The HIV-1 full-length mRNA is capped and polyadenylated, but the long structured 5 0 UTR of this mRNA could interfere with ribosomal scanning from the cap and decrease the efficiency of the cap-dependent translation initiation (28, 29) . Indeed, the 5 0 UTR of HIV-1 RNA contains several structural elements that are required for the replication cycle (30) , such as the transactivation response domain (TAR), the poly(A) hairpin, the primer binding site (PBS), the dimerization initiation site (DIS), the major splicing donor site (SD) and the packaging signal (c) (see Figure 1A ). Various models for the 5 0 UTR region of HIV-1 full-length RNA encompassing the IRES have been proposed, based on phylogenetic, chemical mapping and mutagenesis approaches (31) . Among them, Huthoff and Berkhout (32) had described two mutually exclusive conformations for the 5 0 UTR of HIV-1 RNA, the branched multiple hairpin (BMH) and the long-distance interaction (LDI). Recently, using the powerful SHAPE (selective 2 0 hydroxyl acylation analyzed by primer extension) technology, the Weeks group found that the 5 0 UTR of HIV-1 full-length mRNA exists inside and outside the virus particles in a single predominant conformation, which we refer to as the Weeks conformation (see Figure 1A ) (31, 33) . The BMH conformation has several similarities with the Weeks conformation, but the existence of the LDI conformation, which has never been detected in infected cells or in viral particles, has been challenged (31, 34) .