The applicant has found that certain high grade Herpes virus associated lymphomas are sensitive to anti-viral mediated apoptosis in vitro and in vivo. Epstein-Barr Virus positive Burkitt's lymphoma and Human Herpes Virus Type 8 related Primary Effusion Lymphomas undergo apoptosis when cultured in the presence of Azidothymidine (AZT) or AZT and Interferon Alpha (IFN Alpha). He has investigated the mechanisms by which this therapy causes apoptosis in these lymphoma subtypes. He has found that incubation of Burkitt's lymphoma cells with AZT results in upregulation of CD95 and apoptosis. Primary Effusion Lymphoma requires Interferon Alpha to potentiate AZT mediated apoptosis. He has also found that Interferon Alpha induces the death receptor ligands, TRAIL and Fas Ligand in B cell lymphomas. In contrast to Burkitt's lymphoma and Primary Effusion Lymphoma, EBV positive large cell immunoblastic lymphomas and Epstein-Barr virus negative lymphomas were resistant to AZT and Interferon Alpha. These initial findings indicate that some lymphomas might be selectively sensitive to anti-viral therapy. In susceptible lymphomas, AZT and Interferon Alpha mediated apoptosis does not occur solely through Fas/Fas-Ligand interaction and likely involves activation of additional mechanisms of apoptosis. The applicant will investigate the role of viral and cellular pro- and anti-apoptotic proteins in blocking or facilitating AZT and Interferon Alpha induction of apoptosis in primary lymphoma specimens and cell lines developed from these tumors. A mechanism of inducing apoptosis in aggressive lymphomas would benefit patients with these diseases.
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