Hamster Model of SV40 Infection and Disease

描述(申请人提供)：人类癌症病毒在其宿主中建立持续感染。我们假设，病毒诱发癌症的风险取决于病毒-宿主相互作用的早期事件，这些事件导致病毒载量增加的持续性病毒感染的建立。现在人们认识到多瘤病毒SV40可以引起人类感染，并可以在选定的人类癌症中检测到。在体内感染SV40期间导致癌症发展的早期事件尚未被探索。这个项目将利用仓鼠模型来识别和表征病毒遗传因素和宿主反应，这些因素和宿主反应参与了SV40感染的发病机制和随后的癌症发生。具体目标1将确定影响仓鼠SV40急性和慢性感染模式的病毒遗传因素。野生型SV40和在SV40毒株特异性区域不同的匹配构建物将检查调节区、T抗原可变区和SV40微RNA对体内急性和慢性感染建立以及对病毒载量的影响。具体目标2将确定病毒遗传因素在SV40介导的恶性疾病发展中的作用。不同给药途径暴露于SV40基因变异的仓鼠的肿瘤发病率将与急性和慢性SV40感染的建立和病毒载量有关。早期淋巴瘤将使用无创超声检测，并分析肿瘤进展过程中病毒表达的变化。特异性目标3将确定SV40对淋巴细胞和宿主感染反应的影响。SV40与培养的仓鼠淋巴样细胞的相互作用将从病毒表达和细胞永生化方面进行定义。涉及细胞因子表达和抗体产生的宿主反应将在病毒感染的建立和结果的背景下进行评估。将探索SV40微RNA和细胞因子IL-10在调节宿主对SV40感染的反应中的潜在作用。该项目的创新设计将对SV40感染的生物学和与SV40参与人类恶性肿瘤相关的机制产生重要的新理解。对病毒发病机制早期事件的新见解将适用于人类多瘤病毒感染，并可能为多瘤病毒疗法的发展确定新的靶点。公共卫生相关性：多瘤病毒导致癌症、肾脏疾病和神经系统疾病。这项提议将确定导致慢性病毒感染和随后的疾病发展的病毒遗传因素和宿主反应的相互作用。该项目将提供对多瘤病毒和人类癌症相关机制的新理解，并可能为治疗多瘤病毒感染和预防疾病确定新的靶点。

DESCRIPTION (provided by applicant): Human cancer viruses establish persistent infections in their hosts. We hypothesize that the risk of viral induced cancer is dependent on early events in virus-host interactions that lead to the establishment of persistent viral infections with elevated viral loads. It is now recognized that polyomavirus SV40 can cause human infections and can be detected in selected human cancers. Early events during SV40 infections in vivo that lead to cancer development have not been explored. This project will utilize the hamster model to identify and characterize virus genetic factors and host responses involved in the pathogenesis of SV40 infections and subsequent carcinogenesis. Specific Aim 1 will identify viral genetic factors that influence patterns of SV40 acute and chronic infections in hamsters. Wild-type SV40 and matched constructs that differ in SV40 strain-specific regions will examine the influence of the regulatory region, the T-antigen variable domain, and SV40 microRNA on establishment of acute and chronic infections in vivo and on viral loads. Specific Aim 2 will define the contribution of viral genetic factors to the development of SV40-mediated malignant disease. Tumor incidences in hamsters exposed to SV40 genetic variants by different routes of administration will be related to the establishment and viral loads of acute and chronic SV40 infections. Early-stage lymphomas will be detected using noninvasive ultrasound and changes in viral expression during tumor progression analyzed. Specific Aim 3 will determine SV40 effects on lymphoid cells and on host responses to infection. The interactions of SV40 with cultured hamster lymphoid cells will be defined with respect to viral expression and cell immortalization. Host responses involving cytokine expression and antibody production will be evaluated in the context of establishment and outcome of virus infections. The potential roles of SV40 microRNA and of cytokine IL-10 in modulating host responses to SV40 infections will be explored. The innovative design of this project will yield significant new understandings of the biology of SV40 infections and of mechanisms relevant to SV40 involvement in human malignancies. New insights into early events in viral pathogenesis will be applicable to polyomavirus infections in humans and may identify novel targets for the development of polyomavirus therapeutics. PUBLIC HEALTH RELEVANCE: Polyomaviruses cause cancer, kidney disease, and neurologic disease. This proposal will identify the interactions of virus genetic factors and host responses that lead to chronic viral infections and subsequent disease development. This project will provide new understandings of mechanisms relevant to polyomaviruses and human cancer and may identify novel targets for therapeutics to treat polyomavirus infections and prevent disease.