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Sirolimus reduces T cell cycling, immune checkpoint marker expression, and HIV-1 DNA in people with HIV
- Henrich, Timothy J;
- Bosch, Ronald J;
- Godfrey, Catherine;
- Mar, Hanna;
- Nair, Apsara;
- Keefer, Michael;
- Fichtenbaum, Carl;
- Moisi, Daniela;
- Clagett, Brian;
- Buck, Amanda M;
- Deitchman, Amelia N;
- Aweeka, Francesca;
- Li, Jonathan Z;
- Kuritzkes, Daniel R;
- Lederman, Michael M;
- Hsue, Priscilla Y;
- Deeks, Steven G;
- Team, the ACTG A5337;
- Campbell, Danielle;
- Cutler, Corey;
- Dorosh, Michael;
- Ha, Belinda;
- Hawkins, Elizabeth;
- Hensel, Christopher;
- Khairalla, Nayri;
- Knowles, Kevin;
- Lee, Sulggi A;
- Pedersen, Susan;
- Ritz, Justin;
- Ryder, Dylan;
- Sekaly, Rafick;
- Shugarts, David L;
- Straub, Becky;
- Zolopa, Andrew
Published Web Location
https://doi.org/10.1016/j.xcrm.2024.101745Abstract
Key HIV cure strategies involve reversing immune dysfunction and limiting the proliferation of infected T cells. We evaluate the safety of sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in people with HIV (PWH) and study the impact of sirolimus on HIV-1 reservoir size and HIV-1-specific immunity in a single-arm study of 20 weeks of treatment in PWH on antiretroviral therapy (ART). Sirolimus treatment does not impact HIV-1-specific CD8 T cell responses but leads to a significant decrease in CD4+ T cell-associated HIV-1 DNA levels at 20 weeks of therapy in the primary efficacy population (n = 16; 31% decline, p = 0.008). This decline persists for at least 12 weeks following cessation of the study drug. Sirolimus treatment also leads to a significant reduction in CD4+ T cell cycling and PD-1 expression on CD8+ lymphocytes. These data suggest that homeostatic proliferation of infected cells, an important mechanism for HIV persistence, is an intriguing therapeutic target.
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