Immunopathology and Viral Reservoir Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; Biomedical Research Center Network in Infectious Diseases (CIBERINFEC), Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
Immunopathology and Viral Reservoir Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; PhD Program in Biomedical Sciences and Public Health, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain; Hematology and Hemotherapy Service, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid, Spain.
Biochem Pharmacol. 2024 Nov;229:116512. doi: 10.1016/j.bcp.2024.116512. Epub 2024 Sep 1.
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.
HIV-1 感染可以通过抗逆转录病毒治疗（ART）有效控制，但 CD4+T 细胞和巨噬细胞形成的长期储存库中的病毒持续存在阻碍了病毒的清除，并造成慢性炎症环境。达沙替尼是一种酪氨酸激酶抑制剂，临床上用于治疗慢性髓性白血病（CML），也具有抗炎潜力。我们之前报道过，达沙替尼通过保存 SAMHD1 的抗病毒活性，非常有效地干扰 CD4+T 细胞中的 HIV-1 感染，SAMHD1 是一种先天免疫因子，可阻止 T 细胞激活和增殖，并在 T592 磷酸化时失活（pSAMHD1）。我们观察到，体外短期用达沙替尼处理，可显著降低从 HIV 感染者（PWH）和健康供体分离的单核细胞衍生巨噬细胞（MDM）中的 pSAMHD1，干扰 HIV-1 感染。这种抑制基于 2-LTR 环和前病毒整合的低水平，而病毒逆转录不受影响。长期用达沙替尼治疗的 CML 患者的 MDM 也显示出低水平的 pSAMHD1，并且对 HIV-1 感染具有抗性。此外，达沙替尼通过降低 TNFα、IL-1β、IL-6、CXCL8 和 CXCL9 等 M1 相关细胞因子的释放，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，达沙替尼似乎干扰了 MDM 的分化。达沙替尼与 ART 一起使用，可用于对抗 CD4 和巨噬细胞中的 HIV-1 储存库，并缓解 PWH 的慢性炎症特征。
