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Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity
- Source :
- Journal of Clinical Investigation. February, 2017, Vol. 127 Issue 2, p651, 6 p.
- Publication Year :
- 2017
-
Abstract
- Current strategies for HIV-1 eradication require the reactivation of latent HIV-1 in resting [CD4.sup.+] 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.<br />Introduction HIV-1 persists in a latent reservoir in resting memory [CD4.sup.+] T cells despite combination antiretroviral therapy (cART) (1-3). Latently infected cells represent a major barrier to eradication. Integrated proviruses [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 127
- Issue :
- 2
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.480385920
- Full Text :
- https://doi.org/10.1172/JCI89552