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

Initiation of translation of most eukaryotic cellular messenger RNAs (mRNAs) occurs by a cap-dependent mechanism that requires ribosomal scanning of their 5 0 UTR. The 40S ribosomal subunit bearing the initiator tRNA, Met-tRNA Met i , interacts with the initiation factors bound at the cap (m 7 GpppG) at the 5 0 end of the mRNA, and then scans the mRNA in the 5 0 -3 0 direction until it encounters an initiation codon in an appropriate context. The 60S ribosomal subunit joins the 40S subunit and translation of the mRNA begins (1) (2) (3) . However, several groups of viruses and a minority of cellular mRNAs initiate translation in a cap-independent manner, using internal ribosome entry sites (IRESes) (3, 4, (5) (6) (7) (8) . IRESes are structured RNA regions that are able to directly recruit the 40S ribosomal subunit at or near an initiation codon. This mode of initiation usually requires the participation of some canonical initiation factors and of host cell factors called IRES trans-acting factors (ITAFs). The structure, the molecular mechanism and the requirement for ITAFs of different IRESes vary greatly, reflecting their functional diversity (9) (10) (11) . IRESes were first discovered in picornaviruses (12, 13) , and have since been found in several other groups of viruses, including retroviruses (14) such as simian immunodeficiency virus (15, 16) , human immunodeficiency virus type 1 (HIV-1) (17, 18) , human immunodeficiency virus type 2 (19, 20) , murine leukemia virus (21, 22) , Rous sarcoma virus (23) , feline immunodeficiency virus (FIV) (24) and mouse mammary tumor virus (25) .