Home CONTACT Acta Virologica 2017 Acta Virologica Vol.61, No.1, p.86-96, 2017

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ISSN 0001-723X
E-ISSN 1336-2305

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Acta Virologica Vol.61, No.1, p.86-96, 2017

Title: Effects of heme degradation products on reactivation of latent HIV-1
Author: P. SHANKARAN, M. MADLENAKOVA, V. HAJKOVA, D. JILICH, I. SVOBODOVA, A. HORINEK, Y. FUJIKURA, Z. MELKOVA

Abstract: 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.

Keywords: HIV-1 reactivation; iron; heme arginate; carbon monoxide; bilirubin; redox stress
Published online: 28-Feb-2017
Year: 2017, Volume: 61, Issue: 1 Page From: 86, Page To: 96
doi:10.4149/av_2017_01_86


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