Azidothymidine and interferon-alpha induce apoptosis in herpesvirus-associated lymphomas

Lymphoproliferative diseases that occur in immunocompromised patients are f requently associated with herpesviruses, These patients often fare poorly a fter treatment with conventional chemotherapy, We reported previously that patients with AIDS-related Burkitt's lymphoma (BL) responded to parenteral azidothymidine (AZT) and IFN-alpha. We found that EBV-positive lymphoma cel ls derived from these patients cultured with AZT express CD95 and undergo a poptosis, AZT-mediated apoptosis was caspase dependent and occurred despite Pas receptor blockade. In contrast, EBV-negative lymphomas were resistant to AZT-induced apoptosis, as were EBV-positive lymphomas that expressed hig h levels of bcl-2, Primary effusion lymphoma (PEL) cell lines infected with human herpesvirus type 8 required IFN-alpha to potentiate AZT-induced apop tosis, IFN-alpha did not up-regulate CD95 in RT, or PEL but did induce expr ession of the death receptor ligand, CD95 ligand, AZT-sensitive lymphomas a lso accumulated significantly higher intracellular AZT monophosphate than d id resistant lymphomas, Our data demonstrated distinct apoptotic responses to AZT and IFN-alpha in herpesvirus-associated lymphomas, EBV-positive BL c ells that expressed low BCL-2 levels were sensitive to AZT alone; PEL cells required the addition of IFN-alpha to enhance apoptosis, and EBV-negative lymphomas were insensitive to both agents. AZT-sensitive BL cells transfect ed with BCL-2 became resistant, Susceptibility to antivirus-mediated apopto sis may be exploited to improve the therapy of certain herpesvirus-associat ed lymphomas.