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The survival of viral mediated lymphomas depends upon constitutive nuclear factor kappa B (NF-[kappa]B) activity. AIDS-related human herpesvirus type 8–associated primary effusion lymphoma (PEL) responds poorly to chemotherapy and is almost invariably fatal. We have previously demonstrated that the antiviral combination of interferon alpha (IFN-[alpha]) and azidothymidine (AZT) induces apoptosis in PEL cell lines. We therefore used these agents as therapy for an AIDS patient with PEL. The patient had a dramatic response, with complete resolution of his malignant effusion in 5 days. In PEL cells, the death receptor ligand known as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is markedly up-regulated by IFN-[alpha]; however, signals transduced by death receptors may also activate an antiapoptotic response mediated by NF-[kappa]B. In both the primary tumor cells from our patient and PEL cell lines, AZT selectively blocked nuclear entry of the NF-[kappa]B heterodimer p50 and p65, an effect not seen with other nonthymidine antiviral nucleosides. AZT monophosphate, the principal intracellular metabolite, inhibited phosphorylation and degradation of I[kappa]B by the I[kappa]B kinase complex. AZT- and IFN-[alpha]-mediated apoptosis was blocked by expression and nuclear localization of an I[kappa]B-resistant form of NF-[kappa]B (the p50 subunit linked to the transactivation domain of herpes simplex virus VP16). The proapoptotic effect of AZT and IFN-[alpha] in PEL occurs through the concomitant activation of TRAIL and blockade of NF-[kappa]B and represents a novel antiviral therapy for a virally mediated tumor.