Type I consensus IFN (IFN-con1) gene transfer into KSHV/HHV-8-infected BCBL-1 cells causes inhibition of viral lytic cycle activation via induction of apoptosis and abrogates tumorigenicity in SCID mice

In this study, we investigated the effects of human type I consensus interf eron (IFN-con1) (Amgen) gene transfer into body cavity-based lymphomas (BCB L)-1 cells, which are latently infected with Kaposi's sarcoma-associated he rpesvirus (KSHV) human herpesvirus-8 (HHV-8), Both the basal and 12-O-tetra decanoyl phorbol-13-acetate (TPA)-stimulated production of KSHV/HHV-8 matur e virions was strongly inhibited in genetically modified IFN-producing BCBL -1 cells as compared with parental or control transduced counterparts. A si milar inhibition was obtained on treatment of parental BCBL-1 cells with ex ogenous IFN-con1, The reduction in KSHV/HHV-8 production was associated wit h a decrease in the basal and TPA-stimulated intracellular amount of the li near form of the viral genome. Interestingly, 25%-40% of the IFN-producing BCBL-1 cell population underwent spontaneous apoptosis in vitro. TPA treatm ent, which did not significantly affect the viability of the parental and c ontrol BCBL-1 cells, resulted in the apoptotic death of up to 70% of the IF N-producing cell population. Addition of exogenous IFN-con1 to parental BCB L-1 cells produced similar effects, although less intense. Injection of eit her parental or control-transduced BCBL-1 cells into SCID mice resulted in progressively growing tumors characterized by an unusually high level of tu mor angiogenesis, In contrast, complete tumor regression was observed in al l the mice injected either subcutaneously (s.c.) or intraperitoneally (i.p. ) with the IFN-producing BCBL-1 cells. These results represent the first ev idence that type I IFN can counteract the activation of a productive herpes virus infection in latently infected tumor cells by the induction of apopto sis, providing an interesting link between the antiviral and antitumor acti vities of this cytokine, These data suggest the possible advantages of stra tegies of type I IFN gene transfer (with respect to the use of the exogenou s cytokine) for the treatment of patients with some HHV-8-induced malignanc ies.