title: 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.forename: Alyssa R
authors.initials: AR
authors.lastname: Martin
authors.forename: Ross A
authors.initials: RA
authors.lastname: Pollack
authors.forename: Adam
authors.initials: A
authors.lastname: Capoferri
authors.forename: Richard F
authors.initials: RF
authors.lastname: Ambinder
authors.forename: Christine M
authors.initials: CM
authors.lastname: Durand
authors.forename: Robert F
authors.initials: RF
authors.lastname: Siliciano
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008297:Male; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D014775:Virus Activation / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D016207:Cytokines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus