BackgroundAmong human T cell leukemia virus type 1 (HTLV-1)-infected individuals, there is an association between HTLV-1 tax subgroups (subgroup-A or subgroup-B) and the risk of HAM/TSP in the Japanese population. To investigate the role of HTLV-1 subgroups in viral pathogenesis, we studied the functional difference in the subgroup-specific viral transcriptional regulators Tax and HBZ using microarray analysis, reporter gene assays, and evaluation of viral-host protein–protein interaction.Results(1) Transcriptional changes in Jurkat Tet-On human T-cells that express each subgroup of Tax or HBZ protein under the control of an inducible promoter revealed different target gene profiles; (2) the number of differentially regulated genes induced by HBZ was 2–3 times higher than that induced by Tax; (3) Tax and HBZ induced the expression of different classes of non-coding RNAs (ncRNAs); (4) the chemokine CXCL10, which has been proposed as a prognostic biomarker for HAM/TSP, was more efficiently induced by subgroup-A Tax (Tax-A) than subgroup-B Tax (Tax-B), in vitro as well as in unmanipulated (ex vivo) PBMCs obtained from HAM/TSP patients; (5) reporter gene assays indicated that although transient Tax expression in an HTLV-1-negative human T-cell line activated the CXCL10 gene promoter through the NF-κB pathway, there was no difference in the ability of each subgroup of Tax to activate the CXCL10 promoter; however, (6) chromatin immunoprecipitation assays showed that the ternary complex containing Tax-A is more efficiently recruited onto the promoter region of CXCL10, which contains two NF-κB binding sites, than that containing Tax-B.ConclusionsOur results indicate that different HTLV-1 subgroups are characterized by different patterns of host gene expression. Differential expression of pathogenesis-related genes by subgroup-specific Tax or HBZ may be associated with the onset of HAM/TSP.

中文翻译：

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不同 HTLV-1 亚组的病毒反式激活因子诱导的不同基因表达特征赋予不同的 HAM/TSP 风险

背景在人类 T 细胞白血病病毒 1 型 (HTLV-1) 感染的个体中，HTLV-1 税收亚组（亚组 A 或亚组 B）与日本人群中 HAM/TSP 的风险之间存在关联。为了研究 HTLV-1 亚群在病毒发病机制中的作用，我们使用微阵列分析、报告基因分析和病毒-宿主蛋白-蛋白质相互作用评估研究了亚群特异性病毒转录调节因子 Tax 和 HBZ 的功能差异。 1) Jurkat Tet-On 人类 T 细胞在诱导型启动子控制下表达每个亚组 Tax 或 HBZ 蛋白的转录变化揭示了不同的靶基因谱；(2) HBZ诱导的差异调节基因数量比Tax诱导的高2-3倍；(3) Tax和HBZ诱导了不同类别的非编码RNAs(ncRNAs)的表达；(4) 趋化因子 CXCL10 已被提议作为 HAM/TSP 的预后生物标志物，在体外和亚组 B 税 (Tax-B) 中，A 亚组 Tax (Tax-A) 更有效地诱导在从 HAM/TSP 患者获得的未经处理的（离体）PBMC 中；(5) 报告基因检测表明，虽然 HTLV-1 阴性人类 T 细胞系中的瞬时 Tax 表达通过 NF-κB 途径激活了 CXCL10 基因启动子，但每个亚组的 Tax 激活能力没有差异CXCL10 启动子；然而，（6）染色质免疫沉淀分析表明，与含有 Tax-B 的三元复合物相比，含有 Tax-A 的三元复合物更有效地募集到 CXCL10 的启动子区域，该区域包含两个 NF-κB 结合位点。结论我们的结果表明，不同的 HTLV-1 亚组具有不同的宿主基因表达模式。亚组特异性 Tax 或 HBZ 对发病相关基因的差异表达可能与 HAM/TSP 的发生有关。