SV40 Pathogenesis of Human Infections

SV40 人类感染的发病机制

• 批准号: 7067657
• 负责人: JANET S BUTEL
• 金额: $ 46.64万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-20 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7067657
• 关键词: B lymphocyte; cell transformation; clinical research; communicable disease transmission; genetic library; human subject; longitudinal human study; monocyte; protein structure function; simian virus 40; transplantation; urinalysis; virulence; virus antigen; virus cytopathogenic effect; virus related neoplasm /cancer; virus replication; yeast two hybrid system

DESCRIPTION (provided by applicant): Persuasive evidence now indicates that SV40 is causing infections in the human population today. The Institute of Medicine recently concluded "the biological evidence is of moderate strength that SV40 exposure could lead to cancer in humans under natural conditions" and recommended "further study of the transmissibility of SV40 in humans". Specific human tumor types associated with SV40 include non-Hodgkin's lymphoma. The goals of this proposal are to evaluate the pathogenesis and transmissibility of SV40 in humans and to determine if the variable domain at the carboxy (C) terminus of the viral large T-antigen (T-ag), is functionally important in viral pathogenesis. The specific aims are the following: (1) Determine the prevalence, transmission, and morbidity of SV40 infections in a target human population (organ transplant recipients). We will evaluate prospectively the presence of SV40 in peripheral blood cells and in urine among adult transplant patients. SV40 strains will be characterized and the state and expression of the viral genome in human tissues and malignancies determined. Clinical and pathological correlations will be established between SV40 infections and disease, including the development of systemic lymphomas. (2) Determine the influence of SV40 strain variation on viral replication in human peripheral blood mononuclear cells (PBMCs) and on immortalization of B-cell lymphocytes. Different SV40 strains will be tested for replication potential in subsets of PBMCs and for immortalization ability in B lymphocytes. The state and expression of viral DNA in immortalized B-cells will be determined. Viral regulatory region changes will be monitored in infected PBMCs. (3) Identify C-terminal T-ag interactive cellular proteins. An SV40 T-ag derived from human malignancies will be used to screen a human lymphocyte cDNA library using the yeast two-hybrid system; interactive protein(s) that recognize the C-terminal domain of T-ag will be characterized; interactions with wild-type and mutant T-ags will be compared. This program addresses important gaps in our knowledge concerning the transmission and pathogenesis of SV40 infections in humans. It will reveal if SV40 strains vary in pathogenic effects in humans and the possible role of the C-terminal T-ag domain in those processes. This new information will allow better understanding of the biology of SV40 human infections and may provide insights into the mechanisms of SV40 involvement in human malignancies.

描述（由申请人提供）：现在有说服力的证据表明 SV40 正在当今人群中引起感染。医学研究所最近得出结论，“有中等强度的生物学证据表明，在自然条件下接触 SV40 可能导致人类癌症”，并建议“进一步研究 SV40 在人类中的传播性”。与SV40相关的特定人类肿瘤类型包括非霍奇金淋巴瘤。该提案的目标是评估 SV40 在人类中的发病机制和传播性，并确定病毒大 T 抗原 (T-ag) 羧基 (C) 末端的可变结构域在病毒发病机制中是否具有重要功能。具体目标如下： (1) 确定目标人群（器官移植受者）中 SV40 感染的患病率、传播率和发病率。我们将前瞻性评估成年移植患者外周血细胞和尿液中 SV40 的存在。将鉴定 SV40 毒株的特征，并确定病毒基因组在人体组织和恶性肿瘤中的状态和表达。将建立 SV40 感染与疾病（包括全身性淋巴瘤的发展）之间的临床和病理相关性。 (2)确定SV40毒株变异对人外周血单核细胞(PBMC)中病毒复制和B细胞淋巴细胞永生化的影响。将测试不同 SV40 菌株在 PBMC 子集中的复制潜力和 B 淋巴细胞的永生化能力。永生化 B 细胞中病毒 DNA 的状态和表达将被确定。将在受感染的 PBMC 中监测病毒调控区的变化。 (3) 鉴定C-末端T-ag 相互作用的细胞蛋白。源自人类恶性肿瘤的 SV40 T-ag 将用于利用酵母双杂交系统筛选人类淋巴细胞 cDNA 文库；识别 T-ag C 端结构域的相互作用蛋白将被表征；将比较与野生型和突变型 T-ag 的相互作用。该计划弥补了我们在人类 SV40 感染传播和发病机制方面的知识空白。它将揭示 SV40 菌株对人类的致病作用是否有所不同，以及 C 端 T-ag 结构域在这些过程中的可能作用。这一新信息将有助于更好地了解 SV40 人类感染的生物学，并可能为了解 SV40 参与人类恶性肿瘤的机制提供见解。