Induction of a TRAIL mediated suicide program by interferon alpha in primary effusion lymphoma

Gammaherpes viruses are often detected in lymphomas arising in immunocompro mised patients. We have found that Azidothymidine (AZT) alone induces apopt osis in Epstein Barr Virus (EBV) positive Burkitt's lymphoma (BL) cells but requires interferon alpha (IFN-alpha) to induce apoptosis in Human Herpes Virus Type 8 (HHV-8) positive Primary Effusion Lymphomas (PEL). Our analysi s of a series of AIDS lymphomas revealed that IFN-alpha selectively induced very high levels of the Death Receptor (DR) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in HHV-8 positive PEL lines and primary t umor cells whereas little or no induction was observed in primary EBV+ AIDS lymphomas and ERV-Burkitt's lines. AZT and IFN-alpha mediated apoptosis in PEL was blocked by stable overexpression of dominant negative Fas Associat ed Death Domain (FADD), decoy receptor 2 (DcR2), soluble TRAIL receptor fus ion proteins (DR-4 and DR-5) and thymidine. Trimeric TRAIL (in place of IFN -alpha) similarly synergized with AZT to induce apoptosis in HHV-8 positive PEL cells. This is the first demonstration that IFN-alpha induces function al TRAIL in a malignancy that can be exploited to effect a suicide program. This novel antiviral approach to Primary Effusion lymphomas is targeted an d may represent a highly effective and relatively non-toxic therapy.