Williams Elizabeth S C P, Szaniawski Matthew A, Martins Laura J, Innis Emily A, Alcamí José, Hanley Timothy M, Spivak Adam M, Coiras Mayte, Planelles Vicente
University of Utah School of Medicine, Department of Pathology, Salt Lake City, UT.
AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
Clin Res HIV AIDS. 2022;8(1). Epub 2022 Nov 30.
Macrophages are one of the main cellular targets of human immunodeficiency virus type 1 (HIV-1). Macrophage infection by HIV-1 is inefficient due to the presence of the viral restriction factor sterile alpha motif and histidine aspartic acid domain containing protein 1 (SAMHD1). human monocyte-derived macrophages (MDMs) express SAMHD1 in an equilibrium between active (unphosphorylated) and inactive (phosphorylated) states. We and others have shown that treatment of MDMs with the FDA-approved tyrosine kinase inhibitor, dasatinib, ablates SAMHD1 phosphorylation, thus skewing the balance towards a cellular state that is refractory to HIV-1 infection. We hypothesized that dasatinib inhibits a putative tyrosine kinase that is upstream of SAMHD1. In search for this tyrosine kinase, we probed several candidates and were unable to identify a single target that, when inhibited, was sufficient to explain the dephosphorylation of SAMHD1 we observe upon treatment with dasatinib. On the other hand, we probed the ability of dasatinib to directly inhibit the serine/threonine cyclin dependent kinases 1, 2, 4 and 6 and confirmed that dasatinib directly inhibits these kinases. Therefore, our results show that inhibition of the proximal CDKs 1, 2, 4 and 6 by dasatinib is clearly detectable, leads to blockade of infection by HIV-1, and may be sufficient to explain the activity of dasatinib against SAMHD1 phosphorylation.
巨噬细胞是1型人类免疫缺陷病毒（HIV-1）的主要细胞靶点之一。由于病毒限制因子无菌α基序和含组氨酸天冬氨酸结构域蛋白1（SAMHD1）的存在，HIV-1对巨噬细胞的感染效率较低。人类单核细胞衍生的巨噬细胞（MDM）在活性（未磷酸化）和非活性（磷酸化）状态之间的平衡中表达SAMHD1。我们和其他人已经表明，用美国食品药品监督管理局（FDA）批准的酪氨酸激酶抑制剂达沙替尼处理MDM，可以消除SAMHD1的磷酸化，从而使平衡向对HIV-1感染具有抗性的细胞状态倾斜。我们假设达沙替尼抑制了SAMHD1上游的一种假定的酪氨酸激酶。为了寻找这种酪氨酸激酶，我们对几个候选物进行了探究，但未能确定单一靶点，当该靶点被抑制时，足以解释我们在用达沙替尼处理后观察到的SAMHD1的去磷酸化现象。另一方面，我们探究了达沙替尼直接抑制丝氨酸/苏氨酸细胞周期蛋白依赖性激酶1、2、4和6的能力，并证实达沙替尼直接抑制这些激酶。因此，我们的结果表明，达沙替尼对近端细胞周期蛋白依赖性激酶1、2、4和6的抑制作用是明显可检测到的，导致HIV-1感染受阻，并且可能足以解释达沙替尼对SAMHD1磷酸化的作用。
