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

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 3

Rapamycin treatment does not reduce CTL killing.

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Rapamycin treatment does not reduce CTL killing. (A) Rapamycin does not ...
(A) Rapamycin does not affect viral peptide production and presentation of epitopes to CTLs (n = 3). Activated CD4+ T cells were infected with NL4-3-Δenv-GFP and cultured in media alone, or with rapamycin for 24 hours before coculture. Infected CD4+ T cells were cocultured at a 1:1 E/T ratio with CD8+ T cells prestimulated with IL-2 alone or Gag and IL-2. After 72 hours, reduction in infected cells was measured by flow cytometry. (B) CTL-mediated killing of HIV-1–infected cells is impaired by the presence of cyclosporin, but not rapamycin (n = 8). As above, CD4+ T cells were infected with NL4-3-Δenv-GFP. Infected CD4+ T cells were cultured alone, or cocultured at a 1:1 E/T ratio with CD8+ T cells. As indicated, some CD8+ T cells were pretreated with rapamycin for 3 days before coculture, or cocultured in the presence of rapamycin or cyclosporin. Data points are the average of duplicate experiment conditions. Two-tailed paired Student’s t test was used to determine statistical significance (*P < 0.05).