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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)651-656
Number of pages6
JournalJournal of Clinical Investigation
Volume127
Issue number2
DOIs
StatePublished - Feb 1 2017

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Sirolimus
HIV-1
Cytokines
T-Lymphocytes
Immunosuppressive Agents
Poisons
Cytotoxic T-Lymphocytes
Cyclosporine
Down-Regulation
Cell Proliferation
Gene Expression
Messenger RNA
Antibodies

ASJC Scopus subject areas

  • Medicine(all)

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Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity. / Martin, Alyssa R.; Pollack, Ross A.; Capoferri, Adam; Ambinder, Richard F; Durand, Christine; Siliciano, Robert F.

In: Journal of Clinical Investigation, Vol. 127, No. 2, 01.02.2017, p. 651-656.

Research output: Contribution to journalArticle

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