AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
Laboratory of Reference and Research on Viral Hepatitis, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
Biochem Pharmacol. 2021 Oct;192:114666. doi: 10.1016/j.bcp.2021.114666. Epub 2021 Jun 26.
The latent viral reservoir formed by HIV-1, mainly in CD4 + T cells, is responsible for the failure of antiretroviral therapy (ART) to achieve a complete elimination of the virus in infected individuals. We previously determined that CD4 + T cells from individuals with chronic myeloid leukemia (CML) on treatment with dasatinib are resistant to HIV-1 infection ex vivo. The main mechanism for this antiviral effect is the preservation of SAMHD1 activity. In this study, we aimed to evaluate the impact of dasatinib on the viral reservoir of HIV-infected individuals with CML who were on simultaneous treatment with ART and dasatinib. Due to the low estimated incidence of HIV-1 infection and CML (1:65,000), three male individuals were recruited in Spain and Germany. These individuals had been on treatment with standard ART and dasatinib for median 1.3 years (IQR 1.3-5.3 years). Reservoir size and composition in PBMCs from these individuals was analyzed in comparison with HIV-infected individuals on triple ART regimen and undetectable viremia. The frequency of latently infected cells was reduced more than 5-fold in these individuals. The reactivation of proviruses from these cells was reduced more than 4-fold and, upon activation, SAMHD1 phosphorylation was reduced 40-fold. Plasma levels of the homeostatic cytokine IL-7 and CD4 effector subpopulations TEM and TEMRA in peripheral blood were also reduced. Therefore, treatment of HIV-infected individuals with dasatinib as adjuvant of ART could disturb the reservoir reactivation and reseeding, which might have a beneficial impact to reduce its size.
HIV-1 形成的潜伏病毒库主要存在于 CD4+T 细胞中，是导致抗逆转录病毒疗法（ART）无法在感染个体中完全清除病毒的原因。我们之前确定，接受达沙替尼治疗的慢性髓性白血病（CML）个体的 CD4+T 细胞对 HIV-1 感染具有抗性。这种抗病毒作用的主要机制是保持 SAMHD1 活性。在这项研究中，我们旨在评估达沙替尼对同时接受 ART 和达沙替尼治疗的 HIV 感染 CML 个体的病毒库的影响。由于 HIV-1 感染和 CML 的估计发病率较低（1:65,000），在西班牙和德国招募了三名男性个体。这些个体接受标准 ART 和达沙替尼治疗的中位数时间为 1.3 年（IQR 1.3-5.3 年）。与接受三联 ART 方案且病毒载量不可检测的 HIV 感染个体相比，分析了这些个体的 PBMC 中病毒库的大小和组成。这些个体中潜伏感染细胞的频率降低了 5 倍以上。这些细胞中的前病毒的激活减少了 4 倍以上，并且在激活时，SAMHD1 磷酸化减少了 40 倍。外周血中稳态细胞因子 IL-7 和 CD4 效应子亚群 TEM 和 TEMRA 的水平也降低了。因此，用达沙替尼作为 ART 的辅助治疗 HIV 感染个体可能会干扰病毒库的重新激活和再定植，这可能对减少其大小产生有益影响。
