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

As mentioned in the 'Introduction' section, HIV-1 IRES is activated during viral infection (38) . Oxidative stress, one of the pleiotropic effects caused by HIV infection, increases the activity of the wild-type IRES but not of the M4.stem143 mutant. Since the effect of oxidative stress is not additive to that of the M4 mutation, this result strongly suggests that oxidative stress increases the IRES activity via an effect on IRENE. A model can be proposed to describe the role of IRENE and oxidative stress in the increase in HIV-1 IRES activity, which is illustrated in Figure 6 . The IRES could initially adopt a weakly active conformation that is stabilized by the binding of a repressor cellular protein to IRENE, as suggested above. In the course of the viral infection, a decrease in global protein synthesis would decrease the level of repressor. This could make IRENE available for interacting with a stimulatory ITAF that could act as a chaperone and help the IRES to adopt a more active conformation, such as that we artificially induced by mutating the upper stem of IRENE ( Figure 5D ). The ITAF could be a cellular protein which would be relocalized in the cytoplasm or whose expression would be induced by oxidative stress following viral infection. This hypothetical model thus suggests that IRENE controls the IRES activity through the conformation it adopts. Although this model is attractive, it is presently speculative and relies strongly on the structures of IRENE obtained with the folding algorithm. Further study of the effect of IRENE on HIV-1 IRES activity requires a characterization of the proteins that interact with this structure.