Effects of heme degradation products on reactivation of latent HIV-1.
Human immunodeficiency virus (HIV-1) infection can be currently controlled by combined antiretroviral therapy, but a sterilizing cure is not achievable as this therapy does not target persistent HIV-1 in latent reservoirs. Therefore, different latency reversal agents are intensively explored in various models. We have previously observed that heme arginate, a drug approved for human use, reveals a strong synergism with PKC inducers in reactivation of the latent provirus. Heme is physiologically decomposed by heme oxygenases into 3 degradation products: iron (Fe2+), carbon monoxide (CO) and biliverdin which is further converted to bilirubin by biliverdin reductase. In this paper, we have studied the effects of individual heme-degradation products on latent HIV-1 reactivation in ACH-2 cells harboring integrated HIV-1 provirus and in H12 clone of Jurkat cells harboring HIV-minivirus expressing EGFP. We employed addition of ascorbate to generate Fe2+, resulting in increased expression of both HIV-1 p24 Ag and EGFP in PMA-stimulated ACH-2 and H12 cells, respectively, as characterized on RNA and protein levels. On the other hand, addition of a CO-donor or bilirubin decreased the p24 expression. The reactivation of latent HIV-1 by iron or heme arginate was inhibited by antioxidant N-acetyl cysteine, or by an iron chelator desferrioxamine, suggesting that the effects were mediated by iron- or heme-induced redox stress. Finally, we demonstrated the stimulatory effects of heme arginate and PMA on HIV-1 expression in peripheral blood mononuclear cells of HIV-infected patients cultured ex vivo. These results may constitute a new direction in the latent HIV-1 reactivation and therapy.
P
P
Shankaran
M
M
Madlenakova
V
V
Hajkova
D
D
Jilich
I
I
Svobodova
A
A
Horinek
Y
Y
Fujikura
Z
Z
Melkova
D001120:Arginine / Q000494:pharmacology*; D001663:Bilirubin / Q000494:pharmacology*; D002248:Carbon Monoxide; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006418:Heme / Q000494:pharmacology*; D006801:Humans; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D017735:Virus Latency / Q000502:physiology*
D012367:RNA, Viral; D006418:Heme; D002248:Carbon Monoxide; D001120:Arginine; D013755:Tetradecanoylphorbol Acetate; C048849:heme arginate; D001663:Bilirubin
HIV-1 reactivation; iron; heme arginate; carbon monoxide; bilirubin; redox stress.