Department of Medicine, University of California San Francisco, San Francisco, CA 94110, USA.
Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Cell Rep Med. 2024 Oct 15;5(10):101745. doi: 10.1016/j.xcrm.2024.101745. Epub 2024 Sep 24.
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.
关键的 HIV 治愈策略包括逆转免疫功能障碍和限制受感染 T 细胞的增殖。我们评估了雷帕霉素（mTOR 抑制剂）在 HIV 感染者（PWH）中的安全性，并在一项单臂研究中研究了雷帕霉素对 HIV-1 储存库大小和 HIV-1 特异性免疫的影响，该研究对接受抗逆转录病毒治疗（ART）的 PWH 进行了 20 周的治疗。雷帕霉素治疗不会影响 HIV-1 特异性 CD8 T 细胞反应，但会导致主要疗效人群（n = 16）在治疗 20 周时 CD4 T 细胞相关 HIV-1 DNA 水平显著下降（下降 31%，p = 0.008）。这种下降在研究药物停止后至少 12 周内持续存在。雷帕霉素治疗还导致 CD4 T 细胞循环和 CD8 淋巴细胞上 PD-1 表达显著减少。这些数据表明，受感染细胞的稳态增殖是 HIV 持续存在的一个重要机制，这是一个有趣的治疗靶点。
