Sirolimus reduces T cell cycling, immune checkpoint marker expression, and HIV-1 DNA in people with HIV

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. • Sirolimus treatment decreases cell-associated HIV-1 levels in people with HIV on ART • The reduction in HIV DNA persists for at least 12 weeks following sirolimus treatment • Sirolimus reduces CD4 + T cell cycling and CD8 + T cell PD-1 expression • Sirolimus does not impact HIV-1-specific CD8 T cell responses or HIV-1 RNA levels Henrich et al. show that sirolimus (rapamycin) reduces HIV-1 proviral DNA, perhaps through decreased cell cycling that limits the homeostatic proliferation of infected CD4 + T cells. Conceptually, these data suggest that homeostatic proliferation of infected cells, an important mechanism for HIV persistence, might be targeted therapeutically.