HUMAN-IMMUNODEFICIENCY-VIRUS INDUCES A DUAL REGULATION OF BCL-2, RESULTING IN PERSISTENT INFECTION OF CD4(-CELL OR MONOCYTIC CELL-LINES() T)

This work aims at characterizing the interplay between human immunodef iciency virus type 1 (HIV-1) and the antiapoptotic cellular protein Bc l-2 responsible for a persistent infection in lymphoblastoid T (J.Jhan ) or monocytic (U937) cells. We report that the kinetics of Bcl-2 prot ein level during the establishment of a chronic infection is biphasic, characterized by a transient decrease followed by restoration to the initial level. The extent and duration of this transient decrease were inversely correlated with the basal level of Bcl-2 as shown by kineti cs of Bcl-2 levels in J.Jhan or U937 clones exhibiting different level s of Bcl-2. Using these clones, we also showed that Bcl-2 downregulate s HIV-I replication. Therefore, the cells overexpressing Bcl-2 are cha racterized by a low viral burden which, in turn, has little effect on the level of this protein. The observed bipasic kinetics is the result of a dual regulation of Bcl-2 induced by HIV-1 infection itself: an u pregulation at the transcriptional level of the bcl-2 gene concomitant with a downregulation at the protein level. Convergent data suggest t hat this downregulation is caused by the oxidative stress induced by t he infection itself as shown by the associated modulations of glutathi one and thioredoxin levels and by the prevention of these dysregulatio ns by N-acetylcysteine. Altogether, these data indicate that infection first results in a decrease of Bcl-2, permitting an initial boost of replication. Then, as the synthesis at the transcriptional level proce eds, the replication is negatively controlled by Bcl-2 to reach a bala nce characterized by low virus production and a level of Bcl-2 compati ble with cell survival. We suggest that the basal level of Bcl-2, toge ther with infection-inducible transcription factors able to activate b cl-2 gene transcription, is a critical cellular determinant in the ten dency toward an acute or a persistent infection.