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Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity
Alyssa R. Martin, … , Christine M. Durand, Robert F. Siliciano
Alyssa R. Martin, … , Christine M. Durand, Robert F. Siliciano
Published January 17, 2017
Citation Information: J Clin Invest. 2017;127(2):651-656. https://doi.org/10.1172/JCI89552.
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Brief Report AIDS/HIV

Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity

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Abstract

Current strategies for HIV-1 eradication require the reactivation of latent HIV-1 in resting CD4+ T cells (rCD4s). Global T cell activation is a well-characterized means of inducing HIV-1 transcription, but is considered too toxic for clinical applications. Here, we have explored a strategy that involves a combination of immune activation and the immunosuppressive mTOR inhibitor rapamycin. In purified rCD4s from HIV-1–infected individuals on antiretroviral therapy, rapamycin treatment downregulated markers of toxicity, including proinflammatory cytokine release and cellular proliferation that were induced after potent T cell activation using αCD3/αCD28 antibodies. Using an ex vivo assay for HIV-1 mRNA, we demonstrated that despite this immunomodulatory effect, rapamycin did not affect HIV-1 gene expression induced by T cell activation in these rCD4s. In contrast, treating activated rCD4s with the immunosuppressant cyclosporin, a calcineurin inhibitor, robustly inhibited HIV-1 reactivation. Importantly, rapamycin treatment did not impair cytotoxic T lymphocyte (CTL) recognition and killing of infected cells. These findings raise the possibility of using rapamycin in conjunction with T cell–activating agents in HIV-1 cure strategies.

Authors

Alyssa R. Martin, Ross A. Pollack, Adam Capoferri, Richard F. Ambinder, Christine M. Durand, Robert F. Siliciano

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Figure 1

Immunosuppressant mechanisms and dose-response inhibition of HIV-1 or cytokine expression by rapamycin or cyclosporin treatment.

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Immunosuppressant mechanisms and dose-response inhibition of HIV-1 or cy...
(A) Accepted mechanisms of action and downstream effects of rapamycin and cyclosporin. (B) qRT-PCR measurements of intracellular HIV-1 mRNA from rCD4s derived from infected individuals, shown as percentage inhibition of αCD3/αCD28–induced HIV-1 expression by rapamycin or cyclosporin cotreatment. (C) Dose-dependent inhibition of αCD3/αCD28–induced supernatant IL-2 by increasing concentrations of rapamycin or cyclosporin. (D) Effects of rapamycin or cyclosporin viability of rCD4s stimulated with αCD3/αCD28, compared with αCD3/αCD28 treatment alone or unstimulated cells. Data points are the average of duplicate experiment conditions.
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