A candidate anti-HIV reservoir compound, auranofin, exerts a selective ‘anti-memory’ effect by exploiting the baseline oxidative status of lymphocytes

Abstract

Central memory (TCM) and transitional memory (TTM) 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 TCM and TTM 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 TCM/TTM lymphocyte subsets, which encompass the HIV reservoir, by affecting redox-sensitive cell death pathways.

Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

“…The mechanism of action of auranofin and BSO is likely three-fold (Figures 2 and 3). First, auranofin causes a reduction in the viral reservoir as a direct consequence of the proapoptotic and prodifferentiating effects of auranofin on memory T cells (26,27) harboring the bulk of latent virus (ref. 104 and Figure 2).…”

“…Trx upregulation is observed in murine splenic B lymphocytes following the initial oxidative burst (24). Conversely, inhibition of the Trx system impairs the mitogenic response of mouse splenocytes (25), favors ASK1-mediated cell death of CD4 + T lymphocytes (26), and downregulates costimulatory CD27 and CD28 molecules in T cells (26,27). The GSH system is also necessary for efficient lymphocyte proliferation.…”

“…Antioxidant defenses gradually decrease during lymphocyte differentiation, with memory T cells showing lower levels of intracellular GSH than do naive cells (26). Accordingly, the memory T cell subsets are most vulnerable to Trx inhibition and the resultant apoptosis (in this case, p38 MAP kinase-mediated apoptosis) (26); senescent CD27 − CD28…”

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

“…It showed good activities against multidrug‐resistant bacteria, including methicillin‐resistant Staphylococcus aureus (MRSA) and K. pneumoniae (Harbut et al , 2015; Sun et al , 2016b). Auranofin also exhibited activities against other diseases including HIV/AIDS (Chirullo et al , 2013), and some parasitic diseases (Debnath et al , 2012), as well as Alzheimer's disease, Parkinson's disease (Madeira et al , 2013; Madeira et al , 2014) and cancer (Fiskus et al , 2014). Notably, auranofin was evaluated in human clinical studies for gastrointestinal protozoa, HIV, and cancer.…”

Novel Prospective Treatment Options

“…The memory T-cells with low antioxidant defenses are highly vulnerable to the oxidative stress induced by auranofin and perish along with the integrated provirus. Combination of auranofin and buthionine sulfoximine, an inhibitor of glutathione synthesis is found to act synergistically by causing further imbalance in the redox pathways [133].…”