Hamster Model for AIDS Lymphomas

描述（由申请人提供）：癌症是HIV感染的重要并发症，系统性非霍奇金淋巴瘤（NHL）是最常见的艾滋病相关恶性肿瘤之一。数据表明，目前抗逆转录病毒治疗的持续疗效可能会使更多的HIV感染者在轻度至中度免疫抑制的情况下生存，从而使他们处于发展为系统性NHL的风险中。传染性因子被预测参与系统性NHL的病因学，因为免疫抑制个体处于病毒相关癌症的风险中。有新的证据表明，多瘤病毒SV 40与HIV感染患者以及HIV阴性个体的系统性NHL显著相关。我们的长期目标是了解病毒介导的淋巴瘤发生的发病机制，并开发抑制这种疾病的方法。目前，还没有小动物模型可以用于此类研究。 这项为期两年的开发计划的目的是建立系统性淋巴瘤的仓鼠模型，使用SV 40作为激发病毒。首先，我们将优化不同SV 40菌株诱导仓鼠淋巴瘤的方法;还将测试接种途径、宿主年龄和接种剂量。工作假设是SV 40菌株的淋巴瘤发生潜力不同。其次，我们将描述仓鼠淋巴瘤的特征。我们将确定肿瘤的组织学类型，肿瘤中病毒阳性细胞的比例，病毒基因组的状态（整合，游离型），T抗原的表达，以及T抗原与p53的复合物形成。我们的假设是，SV 40在病因学上参与了晚期肿瘤的淋巴瘤发生和转移的早期阶段。 该项目是及时和可行的;淋巴瘤仍然是艾滋病患者的一种严重疾病，SV 40存在于许多系统性淋巴瘤中，SV 40在仓鼠中具有淋巴瘤原性，我们对病毒和动物模型具有广泛的研究专长。该项目的潜在影响很大。一旦系统性淋巴瘤的小动物模型建立，各种重要的研究将成为可能。淋巴瘤发展中的病毒和宿主功能的分子基础可以解决。此外，该项目可能会提供新的见解淋巴瘤一般，并可能导致新的诊断和治疗方法的发展，这种恶性肿瘤。

DESCRIPTION (provided by applicant):Cancer is a significant complication of HIV infection, and systemic non-Hodgkin's lymphoma (NHL) is one of the most common AIDS-related malignancies. Data suggest that the continuing efficacy of present antiretroviral therapy may allow more persons with HIV infection to survive with mild to moderate immunosuppression, thereby placing them at risk for the development of systemic NHL. Infectious agents are predicted to be involved in the etiology of systemic NHL, as immunosuppressed individuals are at risk for virus-associated cancers. There is new evidence that polyomavirus SV40 is significantly associated with systemic NHL in HIV-infected patients as well as in HIV-negative individuals. Our long-range goals are to understand the pathogenesis of virus-mediated lymphomagenesis and to develop inhibitory approaches to the disease. Currently, no small animal model exists that can be exploited for such studies. The objective of this two-year developmental proposal is to establish the hamster model for systemic lymphomas, using SV40 as the inciting virus. First, we will optimize the induction of lymphomas in hamsters by different strains of SV40; routes of inoculation, host age, and doses of inoculum will also be tested. The working hypothesis is that strains of SV40 differ in lymphomagenic potential. Second, we will characterize the hamster lymphomas. We will determine the histologic type of tumors, the proportion of virus-positive cells in the tumors, the state of the viral genome (integrated, episomal), expression of T-antigen, and complex formation of T-antigen with p53. Our hypothesis is that SV40 is involved etiologically in early stages of lymphomagenesis and dispensable in advanced tumors. This project is timely and feasible; lymphomas remain a serious disease among AIDS patients, SV40 is present in many systemic lymphomas, SV40 is lymphomagenic in hamsters, and we have extensive research expertise with the virus and with animal models. The potential impact of this project is high. Once the small animal model for systemic lymphomas is established a variety of important studies will be possible. The molecular basis of viral and host functions in lymphoma development can be addressed. In addition, this project may provide new insights into lymphomagenesis in general and may lead to the development of new diagnostic and therapeutic approaches to this malignancy.