Pathogenesis of ovine betaretroviruses

逆转录病毒诱导肿瘤的动物模型为我们目前对肿瘤发生的理解提供了许多基础。本文重点研究了两种具有重要经济意义的绵羊逆转录病毒：羊jaagsiekte绵羊逆转录病毒（JSRV），它是绵羊肺腺癌的病原，以及与地方性鼻腺癌相关的鼻肿瘤病毒（ENTV）。JSRV和ENTV在致癌性逆转录病毒中是独特的，因为它们是已知的唯一感染呼吸道的逆转录病毒，并且与大多数复制能力逆转录病毒不同，它们通过插入激活细胞原癌基因或通过获取细胞原癌基因而致癌，JSRV和ENTV的包膜（Env）蛋白是致癌性的，因此代表了一种独特的转化机制。几种信号通路与env介导的转化有关，细胞质尾部（CT），特别是该区域的YxxØ基序，对转化至关重要。大多数逆转录病毒Env蛋白在其CT中含有YxxØ基序，作为内吞作用，细胞内靶向或病毒粒子合并信号。YxxØ基序如何促进JSRV和Env的转化尚不清楚。虽然JSRV和ENTV是高度相关的逆转录病毒，它们利用相同的细胞表面受体进入细胞，但它们具有不同的肿瘤诱导能力，其原因尚不清楚。鉴于这两种病毒之间共享的高核苷酸同一性，这为研究疾病趋向性的决定因素提供了一个独特的系统，特别是因为我们的研究工作表明，LTR和Env都不是单独决定趋向性的。基于这些原因，我们提出实验来研究疾病趋向性的决定因素，并确定Env CT中Env结合伴侣和基序在细胞转化、病毒进入和病毒组装中的作用。预计该研究项目将有助于我们对病毒诱导的癌症的理解，揭示逆转录病毒组装的潜在新机制，并阐明呼吸上皮肿瘤转化的机制。

Animal models of retrovirus-induced tumors have provided us with much of the foundation for our current understanding of oncogenesis. This proposal focuses on two economically important oncogenic ovine retroviruses, jaagsiekte sheep retrovirus (JSRV), which is the etiologic agents of ovine pulmonary adenocarcinoma, and enzootic nasal tumor virus (ENTV), which is associated with enzootic nasal adenocarcinoma. JSRV and ENTV are unique among oncogenic retroviruses as they are the only retroviruses known to infect the respiratory tract and, unlike most replication-competent retroviruses, which cause cancer by insertional activation of cellular proto-oncogenes or through acquisition of cellular proto-oncogenes, the envelope (Env) protein of JSRV and ENTV is oncogenic and thus represents a unique mechanism of transformation. Several signalling pathways have been implicated in Env-mediated transformation and the cytoplasmic tail (CT), in particular YxxØ motifs in this region, are essential for transformation. Most retroviral Env proteins harbor YxxØ motifs in their CT that act as endocytosis, intracellular targeting, or virion incorporation signals. How YxxØ motifs contribute to transformation by JSRV and ENTV Env is not known. While JSRV and ENTV are highly related retroviruses that utilize the same cell surface receptor for virus entry, they have distinct tumor-inducing capabilities and the reason for this is not known. Given the high nucleotide identity shared between these two viruses, this provides an unique system for studying determinants of disease tropism especially because our research efforts suggest that neither the LTR nor the Env alone dictate tropism. For these reasons we propose experiments to investigate the determinants of disease tropism, and to ascertain the role of Env binding partners and motifs within the CT of Env in cellular transformation, virus entry, and virus assembly. It is anticipated that this research program will contribute to our understanding of virally-induced cancers, uncover a potentially novel mechanism for retrovirus assembly, and shed light on mechanisms governing neoplastic transformation of respiratory epithelium.