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）：有说服力的证据现在表明SV40正在引起当今人口的感染。医学研究所最近得出结论：“生物学证据是中等强度，即在自然条件下SV40暴露会导致癌症的癌症”，并建议“进一步研究人类SV40的可传播性”。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人类中SV40的发病机理和可传播性，并确定病毒大型T抗原（T-AG）的羧基（C）末端的可变结构域在病毒发病机理中在功能上很重要。具体目的是：（1）确定目标人群中SV40感染的患病率，传播和发病率（器官移植受者）。我们将在外周血细胞和成人移植患者中的前瞻性评估SV40的存在。 SV40菌株将被表征，并确定人体组织和恶性肿瘤中病毒基因组的状态和表达。 SV40感染和疾病（包括全身性淋巴瘤的发展）将建立临床和病理相关性。 （2）确定SV40应变变异对人外周血单核细胞（PBMC）和B细胞淋巴细胞的永生化的影响。将测试不同的SV40菌株在PBMC的子集中的复制潜力和B淋巴细胞中的永生化能力。将确定病毒DNA在永生的B细胞中的状态和表达。病毒调节区域的变化将在感染的PBMC中进行监测。 （3）识别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将用于使用酵母双杂交系统筛选人类淋巴细胞cDNA库。识别T-AG的C末端结构域的互动蛋白将被表征；将比较与野生型和突变型T-ags的相互作用。该程序解决了我们知识中有关人类SV40感染的传播和发病机理的重要差距。它将揭示SV40菌株在人类的致病作用以及C末端T-AG结构域在这些过程中的可能作用是否有所不同。这些新信息将使人们更好地了解SV40人类感染的生物学，并可以提供有关SV40参与人类恶性肿瘤机制的见解。