HIV-1 感染可通过抗逆转录病毒治疗 (ART) 有效控制，但病毒在 CD4 T 细胞和巨噬细胞形成的长寿命储存库中的持续存在会阻碍病毒根除，并产生慢性炎症环境。达沙替尼是一种酪氨酸激酶抑制剂，临床上用于治疗慢性粒细胞白血病 (CML)，也显示出抗炎潜力。我们之前报道过，达沙替尼通过保留 SAMHD1 的抗病毒活性，非常有效地干扰 CD4 T 细胞的 HIV-1 感染，SAMHD1 是一种先天免疫因子，可阻止 T 细胞活化和增殖，并通过 T592 (pSAMHD1) 磷酸化而失活。 。我们观察到，用达沙替尼进行短期体外治疗可显着降低从 HIV 感染者 (PWH) 和健康捐赠者中分离出的单核细胞衍生巨噬细胞 (MDM) 中的 pSAMHD1，从而干扰 HIV-1 感染。这种抑制是基于低水平的 2-LTR 环和前病毒整合，而病毒逆转录不受影响。从长期接受达沙替尼治疗的 CML 患者中分离出的 MDM 也显示出低水平的 pSAMHD1，并且对 HIV-1 感染具有抵抗力。此外，达沙替尼通过减少 M1 相关细胞因子（如 TNFα、IL-1β、IL-6、CXCL8 和 CXCL9）的释放来降低 MDM 的炎症潜力，但通过正常水平的 IL-12 和 IFNγ 保留抗病毒活性。由于 M2 相关抗炎细胞因子（如 IL-1RA 和 IL-10）的产生也受到损害，达沙替尼似乎会干扰 MDM 的分化。达沙替尼与 ART 结合使用可对抗 CD4 和巨噬细胞中的 HIV-1 储存库，并减轻 PWH 的慢性炎症特征。版权所有 © 2024。由 Elsevier Inc. 出版。

HIV-1 infection is efficiently controlled by the antiretroviral treatment (ART) but viral persistence in long-lived reservoirs formed by CD4 + T cells and macrophages impedes viral eradication and creates a chronic inflammatory environment. Dasatinib is a tyrosine kinase inhibitor clinically used against chronic myeloid leukemia (CML) that has also showed an anti-inflammatory potential. We previously reported that dasatinib is very efficient at interfering with HIV-1 infection of CD4 + T cells by preserving the antiviral activity of SAMHD1, an innate immune factor that blocks T-cell activation and proliferation and that is inactivated by phosphorylation at T592 (pSAMHD1). We observed that short-term treatment in vitro with dasatinib significantly reduced pSAMHD1 in monocyte-derived macrophages (MDMs) isolated from people with HIV (PWH) and healthy donors, interfering with HIV-1 infection. This inhibition was based on low levels of 2-LTR circles and proviral integration, while viral reverse transcription was not affected. MDMs isolated from people with CML on long-term treatment with dasatinib also showed low levels of pSAMHD1 and were resistant to HIV-1 infection. In addition, dasatinib decreased the inflammatory potential of MDMs by reducing the release of M1-related cytokines like TNFα, IL-1β, IL-6, CXCL8, and CXCL9, but preserving the antiviral activity through normal levels of IL-12 and IFNγ. Due to the production of M2-related anti-inflammatory cytokines like IL-1RA and IL-10 was also impaired, dasatinib appeared to interfere with MDMs differentiation. The use of dasatinib along with ART could be used against HIV-1 reservoir in CD4 and macrophages and to alleviate the chronic inflammation characteristic of PWH.Copyright © 2024. Published by Elsevier Inc.