Human Immunodeficiency Virus Induces a Dual Regulation of Bcl-2, Resulting in Persistent Infection of CD4⁺T- or Monocytic Cell Lines

Abstract

This work aims at characterizing the interplay between human immunodeficiency virus type 1 (HIV-1) and the antiapoptotic cellular protein Bcl-2 responsible for a persistent infection in lymphoblastoid T (J.Jhan) or monocytic (U937) cells. We report that the kinetics of Bcl-2 protein 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 kinetics of Bcl-2 levels in J.Jhan or U937 clones exhibiting different levels of Bcl-2. Using these clones, we also showed that Bcl-2 downregulates HIV-1 replication. Therefore, the cells overexpressing Bcl-2 are characterized 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 upregulation at the transcriptional level of the bcl-2 gene concomitant with a downregulation at the protein level. Convergent data suggest that this downregulation is caused by the oxidative stress induced by the infection itself as shown by the associated modulations of glutathione and thioredoxin levels and by the prevention of these dysregulations byN-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 proceeds, the replication is negatively controlled by Bcl-2 to reach a balance characterized by low virus production and a level of Bcl-2 compatible with cell survival. We suggest that the basal level of Bcl-2, together with infection-inducible transcription factors able to activate bcl-2 gene transcription, is a critical cellular determinant in the tendency toward an acute or a persistent infection.

Human Coronaviruses: A Review of Virus–Host Interactions

“…For example, some viruses encode for viral proteins that act as Bcl2 family protein homologues [59]. Alternatively, viruses might develop mechanisms to regulate Bcl2 family proteins or caspase activation either directly or indirectly through other molecular pathways such as mitogen-activated protein (MAPK) and nuclear factor kappa B (NF-κB) pathways [60][61][62][63][64][65]. Interestingly, some viruses may engage the apoptotic machineries for efficient viral infection.…”

Thioredoxins, Glutaredoxins, and Peroxiredoxins—Molecular Mechanisms and Health Significance: from Cofactors to Antioxidants to Redox Signaling

“…[12] Peroxynitrite can (metal catalyzed) lead to the nitration of, for instance, protein tyrosyl residues. [13] Peroxynitrite and carbon dioxide react spontaneously to nitrosoperoxycarbonate. [14] Spontaneous decay of nitrosoperoxycarbonate to carbonate radical anions and nitrite radicals.…”

“…Decreased expression of the Trx system correlated with a decreased rate of activated macrophages and DCs and a general higher apoptosis rate of CD4 + cells (22,238), thereby preventing an effective immune mounting against virus-infected cells. An initial down-regulation of the proapoptotic Bcl-2 and Trx allows a replication boost; subsequent up-regulation might reflect a way of inducing a persistent infection (13). Innate immune mechanisms are further compromised by elevated Trx serum levels that impair CD4 + cell survival by blocking pathogen-induced chemotaxis (542).…”

Galectin‐3 promotes caspase‐independent cell death of HIV‐1‐infected macrophages

“…For example, Guillemard et al [34] detected increased Bcl-2 and Bcl-xL expression and decreased Bax and Bad expression in HIV-1infected human macrophages. Aillet et al [35] observed increased Bcl-2 gene expression at the transcriptional level concomitant with decreased expression at the protein level in HIV-1-infected U937 cells, suggesting the existence of infection-inducible transcription factors that are able to activate Bcl-2 gene transcription in these cells. Swingler et al [36] found that the viral envelope protein induced the pro-survival cytokine macrophage colony-stimulating factor, which decreased the expression of the TRAIL receptor TRAIL-R1/DR4 and increased the expression of the anti-apoptotic genes Bfl-1 and Mcl-1 in HIV-1-infected macrophages.…”