Center for Retrovirus Research, Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States.
Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio, United States.
PLoS Pathog. 2023 Jun 16;19(6):e1011459. doi: 10.1371/journal.ppat.1011459. eCollection 2023 Jun.
Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic cause of adult T-cell leukemia/lymphoma (ATL) and encodes a viral oncoprotein (Hbz) that is consistently expressed in asymptomatic carriers and ATL patients, suggesting its importance in the development and maintenance of HTLV-1 leukemic cells. Our previous work found Hbz protein is dispensable for virus-mediated T-cell immortalization but enhances viral persistence. We and others have also shown that hbz mRNA promotes T-cell proliferation. In our current studies, we evaluated the role of hbz mRNA on HTLV-1-mediated immortalization in vitro as well as in vivo persistence and disease development. We generated mutant proviral clones to examine the individual contributions of hbz mRNA, hbz mRNA secondary structure (stem-loop), and Hbz protein. Wild-type (WT) and all mutant viruses produced virions and immortalized T-cells in vitro. Viral persistence and disease development were also evaluated in vivo by infection of a rabbit model and humanized immune system (HIS) mice, respectively. Proviral load and sense and antisense viral gene expression were significantly lower in rabbits infected with mutant viruses lacking Hbz protein compared to WT or virus with an altered hbz mRNA stem-loop (M3 mutant). HIS mice infected with Hbz protein-deficient viruses showed significantly increased survival times compared to animals infected with WT or M3 mutant virus. Altered hbz mRNA secondary structure, or loss of hbz mRNA or protein, has no significant effect on T-cell immortalization induced by HTLV-1 in vitro; however, the Hbz protein plays a critical role in establishing viral persistence and leukemogenesis in vivo.
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）的病因，它编码一种病毒癌蛋白（Hbz），在无症状携带者和 ATL 患者中始终表达，这表明其在 HTLV-1 白血病细胞的发展和维持中具有重要作用。我们之前的工作发现 Hbz 蛋白对于病毒介导的 T 细胞永生化不是必需的，但增强了病毒的持久性。我们和其他人还表明，hbz mRNA 促进 T 细胞增殖。在我们目前的研究中，我们评估了 hbz mRNA 在体外 HTLV-1 介导的永生化以及体内持久性和疾病发展中的作用。我们生成了突变前病毒克隆，以检查 hbz mRNA、hbz mRNA 二级结构（茎环）和 Hbz 蛋白的单独作用。野生型（WT）和所有突变病毒均在体外产生病毒粒子和永生化 T 细胞。通过感染兔模型和人源化免疫系统（HIS）小鼠，还评估了病毒的持久性和疾病发展。与 WT 或 hbz mRNA 茎环改变的病毒（M3 突变体）相比，缺失 Hbz 蛋白的突变病毒感染的兔子中的前病毒载量以及 sense 和 antisense 病毒基因表达显著降低。与感染 WT 或 M3 突变病毒的动物相比，感染缺乏 Hbz 蛋白的病毒的 HIS 小鼠的存活时间明显延长。改变 hbz mRNA 二级结构或缺失 hbz mRNA 或蛋白，对 HTLV-1 在体外诱导的 T 细胞永生化没有显著影响；然而，Hbz 蛋白在体内建立病毒持久性和白血病发生中起着关键作用。
