BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATL) and the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The exact mechanism(s) through which latency and disease progression are regulated are not fully understood. CCCTC-binding factor (CTCF) is an 11-zinc finger, sequence-specific, DNA-binding protein with thousands of binding sites throughout mammalian genomes. CTCF has been shown to play a role in organization of higher-order chromatin structure, gene expression, genomic imprinting, and serve as a barrier to epigenetic modification. A viral CTCF-binding site (vCTCF-BS) was previously identified within the overlapping p12 (sense) and Hbz (antisense) genes of the HTLV-1 genome. Thus, upon integration, HTLV-1 randomly inserts a vCTCF-BS into the host genome. vCTCF-BS studies to date have focused primarily on HTLV-1 chronically infected or tumor-derived cell lines. In these studies, HTLV-1 was shown to alter the structure and transcription of the surrounding host chromatin through the newly inserted vCTCF-BS. However, the effects of CTCF binding in the early stages of HTLV-1 infection remains unexplored. This study examines the effects of the vCTCF-BS on HTLV-1-induced in vitro immortalization and in vivo viral persistence in infected rabbits.ResultsHTLV-1 and HTLV-1∆CTCF LTR-transactivation, viral particle production, and immortalization capacity were comparable in vitro. The total lymphocyte count, proviral load, and Hbz gene expression were not significantly different between HTLV-1 and HTLV-1∆CTCF-infected rabbits throughout a 12 week study. However, HTLV-1∆CTCF-infected rabbits displayed a significantly decreased HTLV-1-specific antibody response compared to HTLV-1-infected rabbits.ConclusionsMutation of the HTLV-1 vCTCF-BS does not significantly alter T-lymphocyte transformation capacity or early in vivo virus persistence, but results in a decreased HTLV-1-specific antibody response during early infection in rabbits. Ultimately, understanding epigenetic regulation of HTLV-1 gene expression and pathogenesis could provide meaningful insights into mechanisms of immune evasion and novel therapeutic targets.

中文翻译：

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HTLV-1 CTCF 结合位点对于体外永生化和体内持续感染是可有可无的

背景人类 T 细胞白血病病毒 1 型 (HTLV-1) 是成人 T 细胞白血病/淋巴瘤 (ATL) 和神经系统疾病 HTLV-1 相关脊髓病/热带痉挛性下肢轻瘫 (HAM/TSP) 的病原体。调节潜伏期和疾病进展的确切机制尚不完全清楚。CCCTC 结合因子 (CTCF) 是一种 11 锌指、序列特异性 DNA 结合蛋白，在整个哺乳动物基因组中具有数千个结合位点。CTCF 已被证明在高阶染色质结构的组织、基因表达、基因组印记中发挥作用，并作为表观遗传修饰的障碍。先前在 HTLV-1 基因组的重叠 p12（有义）和 Hbz（反义）基因中发现了病毒 CTCF 结合位点 (vCTCF-BS)。因此，在整合时，HTLV-1 在宿主基因组中随机插入一个 vCTCF-BS。迄今为止，vCTCF-BS 研究主要集中在 HTLV-1 慢性感染或肿瘤衍生的细胞系上。在这些研究中，HTLV-1 显示通过新插入的 vCTCF-BS 改变周围宿主染色质的结构和转录。然而，CTCF 结合在 HTLV-1 感染的早期阶段的影响仍有待探索。本研究检查了 vCTCF-BS 对 HTLV-1 诱导的体外永生化和感染兔体内病毒持久性的影响。 结果 HTLV-1 和 HTLV-1∆CTCF LTR 反式激活、病毒颗粒产生和永生化能力相当体外。在 12 周的研究中，感染 HTLV-1 和 HTLV-1∆CTCF 的兔子之间的总淋巴细胞计数、原病毒载量和 Hbz 基因表达没有显着差异。然而，与 HTLV-1 感染的兔子相比，HTLV-1∆CTCF 感染的兔子表现出显着降低的 HTLV-1 特异性抗体反应。结论 HTLV-1 vCTCF-BS 的突变不会显着改变 T 淋巴细胞转化能力或早期体内病毒持续存在，但导致兔早期感染期间 HTLV-1 特异性抗体反应降低。最终，了解 HTLV-1 基因表达和发病机制的表观遗传调控可以提供对免疫逃避机制和新治疗靶点的有意义的见解。结论 HTLV-1 vCTCF-BS 的突变不会显着改变 T 淋巴细胞转化能力或早期体内病毒持久性，但会导致兔早期感染期间 HTLV-1 特异性抗体反应降低。最终，了解 HTLV-1 基因表达和发病机制的表观遗传调控可以提供对免疫逃避机制和新治疗靶点的有意义的见解。结论 HTLV-1 vCTCF-BS 的突变不会显着改变 T 淋巴细胞转化能力或早期体内病毒持久性，但会导致兔早期感染期间 HTLV-1 特异性抗体反应降低。最终，了解 HTLV-1 基因表达和发病机制的表观遗传调控可以提供对免疫逃避机制和新治疗靶点的有意义的见解。