title: A candidate anti-HIV reservoir compound, auranofin, exerts a selective 'anti-memory' effect by exploiting the baseline oxidative status of lymphocytes.
abstract: Central memory (T(CM)) and transitional memory (T(TM)) CD4(+) T cells are known to be the major cellular reservoirs for HIV, as these cells can harbor a transcriptionally silent form of viral DNA that is not targeted by either the immune system or current antiretroviral drug regimens. In the present study, we explored the molecular bases of the anti-HIV reservoir effects of auranofin (AF), a pro-oxidant gold-based drug and a candidate compound for a cure of AIDS. We here show that T(CM) and T(TM) lymphocytes have lower baseline antioxidant defenses as compared with their naive counterpart. These differences are mirrored by the effects exerted by AF on T-lymphocytes: AF was able to exert a pro-differentiating and pro-apoptotic effect, which was more pronounced in the memory subsets. AF induced an early activation of the p38 mitogen-activated protein kinase (p38 MAPK) followed by mitochondrial depolarization and a final burst in intracellular peroxides. The pro-differentiating effect was characterized by a downregulation of the CD27 marker expression. Interestingly, AF-induced apoptosis was inhibited by pyruvate, a well-known peroxide scavenger, but pyruvate did not inhibit the pro-differentiating effect of AF, indicating that the pro-apoptotic and pro-differentiating effects involve different pathways. In conclusion, our results demonstrate that AF selectively targets the T(CM)/T(TM) lymphocyte subsets, which encompass the HIV reservoir, by affecting redox-sensitive cell death pathways.
authors: Istituto Superiore di Sanità, Viale Regina Elena, 299, Rome, Italy.
authors: B
authors: B
authors: Chirullo
authors: R
authors: R
authors: Sgarbanti
authors: D
authors: D
authors: Limongi
authors: I L
authors: IL
authors: Shytaj
authors: D
authors: D
authors: Alvarez
authors: B
authors: B
authors: Das
authors: A
authors: A
authors: Boe
authors: S
authors: S
authors: DaFonseca
authors: N
authors: N
authors: Chomont
authors: L
authors: L
authors: Liotta
authors: E Iii
authors: EI
authors: Petricoin
authors: S
authors: S
authors: Norelli
authors: E
authors: E
authors: Pelosi
authors: E
authors: E
authors: Garaci
authors: A
authors: A
authors: Savarino
authors: A T
authors: AT
authors: Palamara
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001310:Auranofin / Q000494:pharmacology*; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D013438:Sulfhydryl Compounds; D001310:Auranofin; D005978:Glutathione