VIRAL FLICE-INHIBITORY PROTEINS (FLIPS) PREVENT APOPTOSIS INDUCED BY DEATH RECEPTORS

Viruses have evolved many distinct strategies to avoid the host's apop totic response(1,2). Here we describe a new family of viral inhibitors (v-FLIPs) which interfere with apoptosis signalled through death rece ptors(3) and which are present in several gamma-herpesviruses (includi ng Kaposi's-sarcoma-associated human herpesvirus-8), as well as in the tumorigenic human molluscipoxvirus(4). v-FLIPs contain two death-effe ctor domains which interact with the adaptor protein FADD(5,6) and thi s inhibits the recruitment and activation of the protease FLICE(7,8) b y the CD95 death receptor(3). Cells expressing v-FLIPs are protected a gainst apoptosis induced by CD95 or by the related death receptors TRA MP(9-12) and TRAIL-R. The herpesvirus saimiri FLIP is detected late du ring the lytic viral replication cycle, at a time when host cells are partially protected from CD95-ligand-mediated apoptosis, protection of virus-infected cells against death-receptor-induced apoptosis may lea d to higher virus production and contribute to the persistence and onc ogenicity(13) of several FLIP-encoding viruses.