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.
View: Text | PDF
Brief Report AIDS/HIV

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

×

Figure 3

Rapamycin treatment does not reduce CTL killing.

Options: View larger image (or click on image) Download as PowerPoint
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).