Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, USA.
Biochem Pharmacol. 2021 Dec;194:114816. doi: 10.1016/j.bcp.2021.114816. Epub 2021 Oct 26.
The presence of latent human immunodeficiency virus 1 (HIV-1) in quiescent memory CD4 + T cells represents a major barrier to viral eradication. Proliferation of memory CD4 + T cells is the primary mechanism that leads to persistence of the latent reservoir, despite effective antiretroviral therapy (ART). Memory CD4 + T cells are long-lived and can proliferate through two mechanisms: homeostatic proliferation via γc-cytokine stimulation or antigen-driven proliferation. Therefore, therapeutic modalities that perturb homeostatic and antigen-driven proliferation, combined with ART, represent promising strategies to reduce the latent reservoir. In this study, we investigated a library of FDA-approved oncology drugs to determine their ability to inhibit homeostatic and/or antigen-driven proliferation. We confirmed potential hits by evaluating their effects on proliferation in memory CD4 + T cells from people living with HIV-1 on ART (PLWH) and interrogated downstream signaling of γc-cytokine stimulation. We found that dasatinib and ponatinib, tyrosine kinase inhibitors, and trametinib, a MEK inhibitor, reduced both homeostatic and antigen-driven proliferationby >65%, with a reduction in viability <45%, ex vivo. In memory CD4 + T cells from PLWH, only dasatinib restricted both homeostatic and antigen-driven proliferation and prevented spontaneous rebound, consistent with promoting a smaller reservoir size. We show that dasatinib restricts IL-7 induced proliferation through STAT5 phosphorylation inhibition. Our results establish that the anti-cancer agent dasatinib is an exciting candidate to be used as an anti-proliferative drug in a clinical trial, since it efficiently blocks proliferation and iswell tolerated in patients with chronic myeloid leukemia (CML).
潜伏的人类免疫缺陷病毒 1（HIV-1）存在于静止记忆 CD4+T 细胞中，这是病毒根除的主要障碍。尽管有有效的抗逆转录病毒疗法（ART），但记忆 CD4+T 细胞的增殖是导致潜伏储库持续存在的主要机制。记忆 CD4+T 细胞寿命长，可以通过两种机制增殖：通过 γc-细胞因子刺激的稳态增殖或抗原驱动的增殖。因此，扰乱稳态和抗原驱动增殖的治疗方式，结合 ART，代表了减少潜伏储库的有前途的策略。在这项研究中，我们研究了一组 FDA 批准的肿瘤药物，以确定它们抑制稳态和/或抗原驱动增殖的能力。我们通过评估它们对接受 ART 的 HIV-1 感染者（PLWH）记忆 CD4+T 细胞增殖的影响来确认潜在的命中，并研究 γc-细胞因子刺激的下游信号。我们发现，达沙替尼和波那替尼，两种酪氨酸激酶抑制剂，以及曲美替尼，一种 MEK 抑制剂，均能使稳态和抗原驱动的增殖减少 >65%，而体外细胞活力降低 <45%。在 PLWH 的记忆 CD4+T 细胞中，只有达沙替尼限制了稳态和抗原驱动的增殖，并防止了自发反弹，这与促进较小的储库大小一致。我们表明，达沙替尼通过抑制 STAT5 磷酸化来限制 IL-7 诱导的增殖。我们的结果表明，抗癌药物达沙替尼是一种令人兴奋的候选药物，可作为临床试验中的抗增殖药物，因为它能有效地阻止增殖，并且在慢性髓性白血病（CML）患者中耐受性良好。
