ID: 139: Reactivation of latent HIV-1 by iron-mediated redox stress

Abstract

HIV pathogenesis includes dysregulated immune responses and cytokines production, resulting in an increased redox stress. Cytokines, namely TNF-alpha, and redox-stress promote replication of HIV-1. We have previously observed that heme arginate, a drug approved for human use in treatment of hepatic porphyria, can reactivate the latent provirus in synergism with PKC inducers like TNF-alpha, phorbol myristate acetate (PMA), prostratin or bryostatin-1, while inhibiting HIV-1 replication during the acute infection. Heme is physiologically decomposed by action of heme oxygenases into 3 degradation products: iron (Fe2+), carbon monoxide (CO) and biliverdin that is further converted to bilirubin by biliverdin reductase. Therefore, we have studied the effects of heme degradation products on latent HIV-1 reactivation when added individually to ACH-2 cells harboring integrated HIV-1 provirus or to a clone of Jurkat cells harboring HIV-minivirus expressing EGFP. Addition of iron increased expression of both HIV-1 p24 Ag and EGFP, while addition of a CO-donor or bilirubin decreased the PMA-stimulated p24 and EGFP expression. The reactivation was inhibited by antioxidants N-acetyl cysteine and vitamin E or by an iron chelator desferrioxamine, decreasing iron-induced redox stress. Desferrioxamine also inhibited the effect of heme arginate on latent HIV-1 reactivation. Redox stress was shown to affect epigenetic mechanisms regulating gene expression as well as to activate redox-sensitive transcription factors. Therefore, we propose a model in which redox-modulating agents induce chromatin remodeling, affect binding of specific transcription factors to HIV-LTR and allow HIV-1 expression. These results may point towards a new direction in the latent HIV-1 reactivation and therapy.