Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension

Mark G. Lewis, Sandrina Dafonseca, Nicolas Chomont, Anna T. Palamara, Maria Tardugno, Antonello Mai, Matt Collins, Wendeline L. Wagner, Jake Yalley-Ogunro, Jack Greenhouse, Barbara Chirullo, Sandro Norelli, Enrico Garaci, Andrea Savarino

Research output: Contribution to journalArticle

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Abstract

Objectives: A small pool of long-lived memory CD4 T cells harboring the retroviral genome is one main obstacle to HIV eradication. We tested the impact of the gold compound, auranofin, on phenotype and viability of CD4 + T cells in vitro, and on persistence of lentiviral reservoir cells in vivo. Design: In-vitro and in-vivo study. The pro-differentiating effect of auranofin was investigated in human primary CD4 + T cells, and its capacity to deplete the viral DNA (vDNA) reservoir was tested in a pilot study involving six SIVmac251-infected macaques with viral loads stably suppressed by antiretroviral therapy (ART) (tenofovir/emtricitabine/raltegravir). The study was then amplified by intensifying ART using darunavir/r and including controls under intensified ART alone. All therapies were eventually suspended and viro-immunological parameters were monitored over time. METHODS:: Cell subpopulations were quantitated by flow cytometry following proper hematological analyses. Viral load and cell-associated vDNA were quantitated by Taqman real-time PCR. Results: In naïve, central memory and transitional memory CD4 + T cells, auranofin induced both phenotype changes and cell death which were more pronounced in the memory compartment. In the pilot study in vivo, auranofin transiently decreased the cell-associated vDNA reservoir in peripheral blood. When ART was intensified, a sustained decrease in vDNA was observed only in auranofin-treated monkeys but not in controls treated with intensified ART alone. After therapy suspension, only monkeys that had received auranofin showed a deferred and subsequently blunted viral load rebound. Conclusion: These findings represent a first step towards a remission of primate lentiviral infections.

Original languageEnglish
Pages (from-to)1347-1356
Number of pages10
JournalAIDS (London, England)
Volume25
Issue number11
DOIs
Publication statusPublished - Jul 17 2011

Fingerprint

Auranofin
Viral Load
Gold
Haplorhini
Suspensions
Acquired Immunodeficiency Syndrome
Viral DNA
Pharmaceutical Preparations
T-Lymphocytes
Tenofovir
Therapeutics
Gold Compounds
Phenotype
Macaca
Primates
Real-Time Polymerase Chain Reaction
Flow Cytometry
Cell Death
HIV
Genome

Keywords

  • central memory
  • eradication
  • remission
  • reservoir
  • SIVmac251
  • therapy suspension
  • viral DNA

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension. / Lewis, Mark G.; Dafonseca, Sandrina; Chomont, Nicolas; Palamara, Anna T.; Tardugno, Maria; Mai, Antonello; Collins, Matt; Wagner, Wendeline L.; Yalley-Ogunro, Jake; Greenhouse, Jack; Chirullo, Barbara; Norelli, Sandro; Garaci, Enrico; Savarino, Andrea.

In: AIDS (London, England), Vol. 25, No. 11, 17.07.2011, p. 1347-1356.

Research output: Contribution to journalArticle

Lewis, MG, Dafonseca, S, Chomont, N, Palamara, AT, Tardugno, M, Mai, A, Collins, M, Wagner, WL, Yalley-Ogunro, J, Greenhouse, J, Chirullo, B, Norelli, S, Garaci, E & Savarino, A 2011, 'Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension', AIDS (London, England), vol. 25, no. 11, pp. 1347-1356. https://doi.org/10.1097/QAD.0b013e328347bd77
Lewis, Mark G. ; Dafonseca, Sandrina ; Chomont, Nicolas ; Palamara, Anna T. ; Tardugno, Maria ; Mai, Antonello ; Collins, Matt ; Wagner, Wendeline L. ; Yalley-Ogunro, Jake ; Greenhouse, Jack ; Chirullo, Barbara ; Norelli, Sandro ; Garaci, Enrico ; Savarino, Andrea. / Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension. In: AIDS (London, England). 2011 ; Vol. 25, No. 11. pp. 1347-1356.
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AU - Lewis, Mark G.

AU - Dafonseca, Sandrina

AU - Chomont, Nicolas

AU - Palamara, Anna T.

AU - Tardugno, Maria

AU - Mai, Antonello

AU - Collins, Matt

AU - Wagner, Wendeline L.

AU - Yalley-Ogunro, Jake

AU - Greenhouse, Jack

AU - Chirullo, Barbara

AU - Norelli, Sandro

AU - Garaci, Enrico

AU - Savarino, Andrea

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N2 - Objectives: A small pool of long-lived memory CD4 T cells harboring the retroviral genome is one main obstacle to HIV eradication. We tested the impact of the gold compound, auranofin, on phenotype and viability of CD4 + T cells in vitro, and on persistence of lentiviral reservoir cells in vivo. Design: In-vitro and in-vivo study. The pro-differentiating effect of auranofin was investigated in human primary CD4 + T cells, and its capacity to deplete the viral DNA (vDNA) reservoir was tested in a pilot study involving six SIVmac251-infected macaques with viral loads stably suppressed by antiretroviral therapy (ART) (tenofovir/emtricitabine/raltegravir). The study was then amplified by intensifying ART using darunavir/r and including controls under intensified ART alone. All therapies were eventually suspended and viro-immunological parameters were monitored over time. METHODS:: Cell subpopulations were quantitated by flow cytometry following proper hematological analyses. Viral load and cell-associated vDNA were quantitated by Taqman real-time PCR. Results: In naïve, central memory and transitional memory CD4 + T cells, auranofin induced both phenotype changes and cell death which were more pronounced in the memory compartment. In the pilot study in vivo, auranofin transiently decreased the cell-associated vDNA reservoir in peripheral blood. When ART was intensified, a sustained decrease in vDNA was observed only in auranofin-treated monkeys but not in controls treated with intensified ART alone. After therapy suspension, only monkeys that had received auranofin showed a deferred and subsequently blunted viral load rebound. Conclusion: These findings represent a first step towards a remission of primate lentiviral infections.

AB - Objectives: A small pool of long-lived memory CD4 T cells harboring the retroviral genome is one main obstacle to HIV eradication. We tested the impact of the gold compound, auranofin, on phenotype and viability of CD4 + T cells in vitro, and on persistence of lentiviral reservoir cells in vivo. Design: In-vitro and in-vivo study. The pro-differentiating effect of auranofin was investigated in human primary CD4 + T cells, and its capacity to deplete the viral DNA (vDNA) reservoir was tested in a pilot study involving six SIVmac251-infected macaques with viral loads stably suppressed by antiretroviral therapy (ART) (tenofovir/emtricitabine/raltegravir). The study was then amplified by intensifying ART using darunavir/r and including controls under intensified ART alone. All therapies were eventually suspended and viro-immunological parameters were monitored over time. METHODS:: Cell subpopulations were quantitated by flow cytometry following proper hematological analyses. Viral load and cell-associated vDNA were quantitated by Taqman real-time PCR. Results: In naïve, central memory and transitional memory CD4 + T cells, auranofin induced both phenotype changes and cell death which were more pronounced in the memory compartment. In the pilot study in vivo, auranofin transiently decreased the cell-associated vDNA reservoir in peripheral blood. When ART was intensified, a sustained decrease in vDNA was observed only in auranofin-treated monkeys but not in controls treated with intensified ART alone. After therapy suspension, only monkeys that had received auranofin showed a deferred and subsequently blunted viral load rebound. Conclusion: These findings represent a first step towards a remission of primate lentiviral infections.

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KW - viral DNA

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