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

B. Chirullo, R. Sgarbanti, D. Limongi, I. L. Shytaj, D. Alvarez, B. Das, A. Boe, S. DaFonseca, N. Chomont, L. Liotta, E. Petricoin, S. Norelli, E. Pelosi, E. Garaci, A. Savarino, A. T. Palamara

Research output: Contribution to journalArticle

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 T CM/TTM lymphocyte subsets, which encompass the HIV reservoir, by affecting redox-sensitive cell death pathways.

Original languageEnglish
Article numbere944
JournalCell Death and Disease
Volume4
Issue number12
DOIs
Publication statusPublished - Dec 2013

Fingerprint

Auranofin
HIV
Lymphocytes
Peroxides
Pyruvic Acid
T-Lymphocytes
Lymphocyte Subsets
Viral DNA
p38 Mitogen-Activated Protein Kinases
Gold
Pharmaceutical Preparations
Oxidation-Reduction
Immune System
Reactive Oxygen Species
Acquired Immunodeficiency Syndrome
Cell Death
Down-Regulation
Antioxidants
Apoptosis

Keywords

  • apoptosis
  • auranofin
  • differentiation effect
  • HIV cure
  • memory compartment
  • oxidative stress

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

A candidate anti-HIV reservoir compound, auranofin, exerts a selective 'anti-memory' effect by exploiting the baseline oxidative status of lymphocytes. / Chirullo, B.; Sgarbanti, R.; Limongi, D.; Shytaj, I. L.; Alvarez, D.; Das, B.; Boe, A.; DaFonseca, S.; Chomont, N.; Liotta, L.; Petricoin, E.; Norelli, S.; Pelosi, E.; Garaci, E.; Savarino, A.; Palamara, A. T.

In: Cell Death and Disease, Vol. 4, No. 12, e944, 12.2013.

Research output: Contribution to journalArticle

Chirullo, B, Sgarbanti, R, Limongi, D, Shytaj, IL, Alvarez, D, Das, B, Boe, A, DaFonseca, S, Chomont, N, Liotta, L, Petricoin, E, Norelli, S, Pelosi, E, Garaci, E, Savarino, A & Palamara, AT 2013, 'A candidate anti-HIV reservoir compound, auranofin, exerts a selective 'anti-memory' effect by exploiting the baseline oxidative status of lymphocytes', Cell Death and Disease, vol. 4, no. 12, e944. https://doi.org/10.1038/cddis.2013.473
Chirullo, B. ; Sgarbanti, R. ; Limongi, D. ; Shytaj, I. L. ; Alvarez, D. ; Das, B. ; Boe, A. ; DaFonseca, S. ; Chomont, N. ; Liotta, L. ; Petricoin, E. ; Norelli, S. ; Pelosi, E. ; Garaci, E. ; Savarino, A. ; Palamara, A. T. / A candidate anti-HIV reservoir compound, auranofin, exerts a selective 'anti-memory' effect by exploiting the baseline oxidative status of lymphocytes. In: Cell Death and Disease. 2013 ; Vol. 4, No. 12.
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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 T CM/TTM lymphocyte subsets, which encompass the HIV reservoir, by affecting redox-sensitive cell death pathways.",
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AU - Shytaj, I. L.

AU - Alvarez, D.

AU - Das, B.

AU - Boe, A.

AU - DaFonseca, S.

AU - Chomont, N.

AU - Liotta, L.

AU - Petricoin, E.

AU - Norelli, S.

AU - Pelosi, E.

AU - Garaci, E.

AU - Savarino, A.

AU - Palamara, A. T.

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