Pharmacologic control of homeostatic and antigen-driven proliferation to target HIV-1 persistence.
Pharmacologic control of homeostatic and antigen-driven proliferation to target HIV-1 persistence.
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DOI：
10.1016/j.bcp.2021.114816
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发表时间：
2021-12
影响因子：
5.8
通讯作者：
Planelles V
中科院分区：
文献类型：
--
作者：
Innis EA;Levinger C;Szaniawski MA;Williams ESCP;Alcamí J;Bosque A;Schiffer JT;Coiras M;Spivak AM;Planelles V
潜伏的人类免疫缺陷病毒1 （HIV-1）在静止记忆CD4+ T细胞中的存在是病毒根除的主要障碍。尽管有有效的抗逆转录病毒治疗（ART），记忆性CD4+ T细胞的增殖是导致潜伏库持续存在的主要机制。记忆性CD4+ T细胞寿命长，可通过两种机制增殖：通过γ -c细胞因子刺激的稳态增殖或抗原驱动的增殖。因此，扰乱体内平衡和抗原驱动增殖的治疗方式，结合抗逆转录病毒治疗，代表了减少潜伏库的有希望的策略。在这项研究中，我们调查了fda批准的肿瘤药物库，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抗逆转录病毒治疗（PLWH）中HIV-1感染者记忆性CD4+ T细胞增殖的影响，并询问γ -c细胞因子刺激的下游信号，确认了潜在的撞击。我们发现，达沙替尼和波纳替尼（酪氨酸激酶抑制剂）以及曲美替尼（MEK抑制剂）可使体内稳态和抗原驱动的增殖降低65%，体外生存能力降低不到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，并阻止了自发反弹，这与促进更小的储存库大小一致。我们发现达沙替尼通过STAT5磷酸化抑制IL-7诱导的增殖。我们的研究结果表明，抗癌药物达沙替尼是一种令人兴奋的候选药物，可用于临床试验中的抗增殖药物，因为它能有效地阻断增殖，并且在慢性髓性白血病（CML）患者中具有良好的耐受性。达沙替尼可以阻断抗原驱动和稳态增殖，扰乱HIV-1潜伏库
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, MEK inhibitor, reduced both homeostatic and antigen-driven proliferation by 65%, with a reduction in viability less than 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 is well tolerated in patients with chronic myeloid leukemia (CML). Dasatinib can block both antigen-driven and homeostatic proliferation to perturb the HIV-1 latent reservoir
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影响因子：
8.8
作者：
Bosque A;Nilson KA;Macedo AB;Spivak AM;Archin NM;Van Wagoner RM;Martins LJ;Novis CL;Szaniawski MA;Ireland CM;Margolis DM;Price DH;Planelles V
通讯作者：
Planelles V
影响因子：
3.3
作者：
Fujii, Hodaka
通讯作者：
Fujii, Hodaka
影响因子：
6.4
作者：
Crooks, Amanda M.;Bateson, Rosalie;Archin, Nancie M.
通讯作者：
Archin, Nancie M.
影响因子：
64.5
作者：
Ho YC;Shan L;Hosmane NN;Wang J;Laskey SB;Rosenbloom DI;Lai J;Blankson JN;Siliciano JD;Siliciano RF
通讯作者：
Siliciano RF
影响因子：
16.6
作者：
Jaafoura, S.;de Herve, M. G. de Goer;Hernandez-Vargas, E. A.;Hendel-Chavez, H.;Abdoh, M.;Mateo, M. C.;Krzysiek, R.;Merad, M.;Seng, R.;Tardieu, M.;Delfraissy, J. F.;Goujard, C.;Taoufik, Y.
通讯作者：
Taoufik, Y.