Effects of heme degradation products on reactivation of latent HIV-1

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.

Bromodomains in Human-Immunodeficiency Virus-Associated Neurocognitive Disorders: A Model of Ferroptosis-Induced Neurodegeneration

“…In addition, virus or cART-induced lysosomal dysfunction can activate microglial cells that often eliminate healthy neurons and synapses, further contributing to neurodegeneration ( Tripathi et al, 2019 ; Kapralov et al, 2020 ; Cao et al, 2021 ; Miyanishi et al, 2021 ). Microglia are highly susceptible to ferroptosis and harbor latent HIV-1, therefore ferroptotic disintegration of these cells release DAMPs, triggering neuroinflammation ( Lisi et al, 2016 ; Chivero et al, 2017 ; Shankaran et al, 2017 ; Wallet et al, 2019 ; Borrajo et al, 2021 ). Indeed, iron-activated microglia and macrophages, documented in HIV-1 infection, are believed to drive HAND pathology ( Boelaert et al, 1996 ; Kenkhuis et al, 2021 ).…”

Contemporary Antiretroviral Therapy Dysregulates Iron Transport and Augments Mitochondrial Dysfunction in HIV-Infected Human Microglia and Neural-Lineage Cells

“…We observed dysregulated expression of ferritin, Fth1, TfR and ferroportin in hµglia following ARV exposure and an iron-avid phenotype in SH-SY5Y cells, particularly at 48 h. Both SH-SY5Y cells and hµglia exhibited significantly increased cellular iron content and excess cytosolic and/or mtROS. Such alterations in cellular iron status may also lead to changes in provirus transcription in hµglia and drive metabolic reprogramming during HIV infection [53,54]. In human microglia, increased cellular iron is associated with a more inflammatory phenotype [41,43] and could therefore promote neuroinflammation, despite viral suppression.…”

Role of Divalent Cations in HIV-1 Replication and Pathogenicity

“…When Tat-TAR interaction problems occur, HIV-1 transcription prematurely terminates and HIV-1 can reside inside cells in the latent phase [91,92]. However, HIV-1 can exhibit latency breakthrough resulting from modulation of Tat and TAR interactions by stimulatory factors generally [93,94] and specifically by divalent cations [95,96].…”