Hamster Model for AIDS Lymphomas

描述(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，目前的抗逆转录病毒疗法的持续疗效可能会使更多的艾滋病毒感染者在轻度到中度免疫抑制的情况下存活下来，从而使他们面临发展为系统性非霍奇金淋巴瘤的风险。感染因素被预测参与了系统性非霍奇金淋巴瘤的病因学，因为免疫抑制的人有患病毒相关癌症的风险。有新的证据表明，多瘤病毒SV40与HIV感染患者和HIV阴性患者的系统性非霍奇金淋巴瘤显著相关。我们的长期目标是了解病毒介导的淋巴肿大的发病机制，并开发抑制这种疾病的方法。目前，尚不存在可用于此类研究的小型动物模型。这项为期两年的发展计划的目标是建立系统淋巴瘤的仓鼠模型，使用SV40作为激发病毒。首先，我们将优化不同SV40毒株对金黄地鼠淋巴瘤的诱导；还将测试接种途径、宿主年龄和接种剂量。工作假设是，SV40的菌株在产生淋巴癌的潜力上有所不同。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类型，肿瘤中病毒阳性细胞的比例，病毒基因组的状态(整合的，异体的)，T抗原的表达，以及T抗原与P53的复合体形成。我们的假设是，SV40在淋巴肿大的早期病因学上参与其中，而在晚期肿瘤中是必不可少的。这个项目是及时和可行的；淋巴瘤仍然是艾滋病患者中的一种严重疾病，SV40存在于许多系统性淋巴瘤中，SV40在仓鼠中产生淋巴癌，我们在病毒和动物模型方面拥有广泛的研究专业知识。这个项目的潜在影响很大。一旦建立了系统性淋巴瘤的小动物模型，就有可能进行各种重要的研究。病毒和宿主功能在淋巴瘤发展中的分子基础是可以解决的。此外，该项目可能为淋巴增生症提供新的见解，并可能导致对这种恶性肿瘤的新诊断和治疗方法的发展。

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.