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

Abstract

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.

Keywords: HIV curative strategies; HIV immunology; HIV persistence; HIV reservoirs; HIV-1; antiproliferative medications; immunotherapy; intact proviral HIV-1 DNA; mTOR inhibition; sirolimus.

Graphical abstract

Figure 1

ACTG A5337 study schema and enrollment Study and treatment weeks are shown with the number of participants enrolled and completing trial milestones. Sixteen participants completed the full 20 weeks of planned oral sirolimus and are defined as the primary analysis population, and 13 participants completed 6 to 16 weeks of sirolimus (median 12 weeks) and are defined as the secondary analysis population. Twenty-nine participants completed at least 6 weeks of study drug and comprise the secondary analysis population.

Figure 2

Changes in CD4⁺ T cell counts, CD4⁺ T cell-associated HIV-1 DNA, and low-level residual plasma HIV-1 RNA in response to sirolimus treatment Transient decreases in CD4⁺ T cell counts (A) and sustained and significant reduction in CD4⁺ T cell-associated HIV-1 DNA (B) in the primary analysis population are shown. CD4⁺ T cell-associated HIV-1 DNA at baseline and week 4 time points in the secondary analysis population is shown in (C). HIV-1 DNA levels remain significantly decreased 12 weeks after discontinuation of sirolimus in the primary efficacy population. The proportion of participants with undetectable low-level residual HIV-1 plasma RNA measured by iSCA for the primary analysis population is shown in (D). 95% confidence intervals and means at each time point are presented. p values from two-tailed, paired t tests. Baseline values were defined as the average of measures from treatment weeks −12 and 0 in statistical analyses.

Figure 3

Changes in soluble markers of inflammation in response to sirolimus treatment Significant increases in circulating IL-6, sCD14, and D-Dimer are shown in (A)–(C). Levels returned to baseline 12 weeks after the cessation of treatment. A significant decrease in interferon gamma-induced protein 10 (IP-10) levels was observed at treatment week 20, which return to baseline 12 weeks after cessation of sirolimus therapy (D). IL-7 levels for the primarily analysis population are shown in (E). 95% confidence intervals and geometric means at each time point are presented. p values are from two-tailed, paired t tests. Baseline values were defined as the average of measures from treatment weeks −12 and 0 in statistical analyses.