Human herpesvirus 8 viral FLICE-inhibitory protein inhibits Fas-mediated apoptosis through binding and prevention of procaspase-8 maturation

Viral FLICE-inhibitory proteins (v-FLIPs) encoded by several herpesviruses and poxviruses share the ability to inhibit apoptosis after engagement of d eath receptors. In the current article, we provide insights into the mechan isms by which the v-FLIP of human herpesvirus 8 (HHV-8) (also referred to a s Kaposi's sarcoma-associated virus) protects cells from apoptosis after Fa s-induced signaling. Using v-FLIP expression vectors, our results clearly s how that HHV8 v-FLIP reduces the cleavage of procaspase-8 into its active p 18 and p10 protease subunits upon Fas-induced cell death. These results wer e confirmed by lower caspase-8 and caspase-3 protease activities in extract s of HeLa cells expressing HHV-8 v-FLIP. Coimmunoprecipitation studies furt her indicate that HHV-8 v-FLIP physically interacts with procaspase-8, but not with Fas-associated protein with death domain in the cellular cytoplasm . These results suggest that binding of HHV-8 v-FLIP to procaspase-8 affect s the recruitment and the activation of the latter at the death-induced sig naling complex, resulting in diminished apoptotic cascade initiation. Becau se cellular FLIP was recently reported to modulate promoter containing NF k appaB motifs and that both HHV-8 and human immunodeficiency virus type 1 (H IV-1) can infect monocytes, we studied the effects of v-FLIP on HIV-1 gene expression. Cotransfection experiments indicated that v-FLIP expression is associated with activation of HIV long terminal repeats: events that were s trictly dependent on the presence of NF-KB consensus elements. In conclusio n, HHV-8 v-FLIP can possibly contribute to the pathogenesis of both HHV-8 a nd HIV-1 through impaired Fas-dependent killing of infected cells by cytoto xic T cells and through activation of HIV gene expression.