Division of Neuroimmunology, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima City, Kagoshima, JAPAN.
Medical Corporation Sanshukai Ohkatsu Hospital, Kagoshima City, Kagoshima, JAPAN.
PLoS Negl Trop Dis. 2020 Jul 15;14(7):e0008361. doi: 10.1371/journal.pntd.0008361. eCollection 2020 Jul.
Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles of cellular genes in HTLV-1-infected CD4+ T cells await discovery. We performed microarray analysis of CD4+ T cells from HAM/TSP patients and found that the ABL1 is an important gene in HAM/TSP. ABL1 is a known survival factor for T- and B-lymphocytes and is part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML). ABL1 tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are used clinically for treating CML. To evaluate whether ABL1 is indeed important for HAM/TSP, we investigated the effect of TKIs on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKIs. Treating the PBMCs with nilotinib or dasatinib induced significant reductions in PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, ABL1 siRNA transfection reduced cell viability in HTLV-1-infected cell lines, but not in uninfected cell lines. A retrospective survey based on our clinical records found a rare case of HAM/TSP who also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhibiting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is an important gene for the survival of HTLV-1-infected cells and that TKIs may be potential therapeutic agents for HAM/TSP.
人类 T 细胞白血病病毒 1 型（HTLV-1）可引起无法治愈的成人 T 细胞白血病和 HTLV-1 相关性脊髓病/热带痉挛性截瘫（HAM/TSP）。与无症状 HTLV-1 携带者相比，HAM/TSP 患者体内 HTLV-1 感染细胞的水平升高。然而，细胞基因在 HTLV-1 感染的 CD4+T 细胞中的作用仍有待发现。我们对 HAM/TSP 患者的 CD4+T 细胞进行了微阵列分析，发现 ABL1 是 HAM/TSP 中的一个重要基因。ABL1 是 T 细胞和 B 细胞的已知存活因子，也是导致慢性髓性白血病（CML）的融合基因（BCR-ABL）的一部分。ABL1 酪氨酸激酶抑制剂（TKI），包括伊马替尼、尼罗替尼和达沙替尼，临床上用于治疗 CML。为了评估 ABL1 是否对 HAM/TSP 确实重要，我们研究了 TKI 对 HTLV-1 感染细胞的影响。我们开发了一种碘化丙啶单偶氮 HTLV-1 存活定量 PCR 检测方法，该方法可区分活细胞和死细胞的 DNA。使用该方法，当用 TKI 处理 HAM/TSP 病例的外周血单核细胞（PBMC）时，我们能够单独测量活细胞中的 HTLV-1 前病毒载量（PVL）。尼罗替尼或达沙替尼处理 PBMC 可使活细胞中的 PVL 分别显著降低 21.0%和 17.5%。此外，ABL1 siRNA 转染可降低 HTLV-1 感染细胞系中的细胞活力，但不降低未感染细胞系中的细胞活力。基于我们的临床记录的回顾性调查发现了一例罕见的 HAM/TSP 合并 CML 的病例。该患者在用伊马替尼治疗 CML 后，PVL 降低了 84.2%。我们得出结论，抑制 ABL1 酪氨酸激酶可特异性降低 HAM/TSP 患者 PBMC 中的 PVL，表明 ABL1 是 HTLV-1 感染细胞存活的重要基因，TKI 可能是 HAM/TSP 的潜在治疗药物。
