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.
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