Therapy for lymphoproliferative disease in immunocompromised patients is problematic. These patients often have a poor response to cytotoxic agents that also worsens their underlying immunosuppression. Nonetheless, there are distinct pathophysiologic features of these tumors that may be exploited as therapeutic targets. These lymphomas are often associated with gamma herpesviruses and dependent upon constitutive expression of NF-kappaB. We have identified a novel, pro-apoptotic therapy for Humanherpes Virus Type 8 (HHV-8), Primary Effusion Lymphoma (PEL) and Epstein Barr Virus (EBV) lymphomas. Azidothymidine (AZT) and Interferon alpha induce death receptor ligand mediated apoptosis in PEL. This occurs through a potent activation of the ligand TRAIL mediated by interferon alpha coupled with suppression of NF-kappaB by AZT. We hypothesize that death receptor signaling is potentiated upon suppression of NF-kappaB dependent anti-apoptotic factors. NF-kappaB blockade is effected by the monophosphate form of AZT which is preferentially generated in HHV-8 and EBV associated lymphomas. We have demonstrated the effectiveness of antiviral therapy for gamma herpesvirus associated lymphomas in both animal models and patients. We propose to investigate the cellular and viral factors that mediate this apoptosis by 1) defining the signal transduction pathways induced by antivirals in herpesvirus lymphomas; 2) determining the role of cellular and viral proteins (such as vFlip) in NF-kappaB mediated blockade of death receptor mediated apoptosis; 3) investigating the role of viral thymidine kinase in the phosphorylation of antiviral thymidine analogues and the initiation of apoptosis and; 4) studying the anti-lymphoma effects of antivirals in a recently developed SCID mouse model. Development of a therapeutic strategy based on antiviral therapy would represent a targeted, biological approach to lymphomas in resource poor settings. ? ?
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