IMMUNOBIOLOGY OF SIV ASSOCIATED LYMPHOMAS

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Non-Hodgkin's lymphoma (NHL) is a major AIDS-related clinical problem. AIDS-associated NHL (AIDS-NHL) is heterogeneous in histology and anatomic distribution, but is characterized by a consistent set of immunobiologic features including B-cell origin, monoclonality, frequent association with EBV, deregulation of cytokine networks, and characteristic genetic lesions in proto-oncogenes and tumor suppressor genes. Many questions regarding the basic mechanisms of lymphomagenesis in this system remain unanswered, as do questions regarding novel approaches to clinical intervention, in part because of the lack of a suitable animal model. Infection of the rhesus macaque with simian immunodeficiency virus (SIV) appears to represent an excellent model for AIDS-NHL. Lymphoma occurs in the SIV-infected rhesus macaque with incidence and kinetics comparable to that in the HIV-infected population. The incidence, anatomical distribution, heterogeneity, and presence of an EBV-like herpesvirus (RhEBV) in SIV-associated lymphomas appears to model the clinical situation observed in HIV-infected AIDS patients quite accurately. Although lymphoma has been associated with SIV infection in the rhesus macaque for the past decade, little is known about the mechanisms of pathogenesis operative in that system. The objective of the present proposal is to examine critical aspects of SIV-associated lymphomagenesis in order to evaluate their contribution to the disease process. First, simian lymphomas will be classified morphologically, and evaluated for cell type of origin, clonality, and characteristic genetic lesions. Second, the significance of RhEBV infection in lymphomagenesis will be assessed based on 4 criteria incidence of infection in lymphomas as compared to control animals, occurrence of RhEBV within tumor cells, clonality of tumors with respect to viral infection, and patterns of expression of latency-associated and other RhEBV genes in lymphomas. Third, the hypothesis will be evaluated that cytokine deregulation acts in SIV-associated lymphomagenesis by stimulating tumor cell proliferation, and/or by altering the anti-tumor immune response. These possibilities will be evaluated by defining the patterns of cytokine and cytokine receptor expression in lymphomas. Cytokines in sera collected from the time of SIV-infection to the development of lymphoma will also be defined and quantified. The proposed study will contribute an understanding of the pathogenic mechanisms operative in SIV-associated lymphomagenesis that is essential to the development of new approaches to its early diagnosis, treatment or prevention.