Analyzing the mechanisms of interferon-induced apoptosis using CrmA and hepatitis C virus NS5A

The dsRNA-dependent protein kinase, PKR, is a key component of interferon ( IFN)-mediated anti-viral action and is frequently inhibited by many viruses following infection of the cell. Recently, we have demonstrated that IFN a nd PKR can sensitize cells to apoptosis predominantly through the FADD/casp ase-8 pathway (s. Balachandran, P. C. Roberts, T. Kipperman, K. N. Bhalla, R. W. Compans, D. R. Archer, and G. N. Barber. (2000b) J. Virol. 74, 1513-1 523). Given these findings, it is thus plausible that rather than specifica lly target IFN-inducible genes such as PKR, viruses could also subvert the mechanisms of IFN action, in part, at locations that could block the apopto tic cascade. To explore this possibility, we analyzed whether the poxvirus caspase-8 inhibitor, CrmA, was able to inhibit IFN or PKR/dsRNA-mediated ap optosis. Our findings indicated that CrmA could indeed inhibit apoptosis in duced by both viral infection and dsRNA without blocking PKR activity or in hibiting IFN signaling. In contrast HCV-encoded NS5A, a putative inhibitor of PKR, did not appear to inhibit cell death mediated by a number of apopto tic stimuli, including IFN, TRAIL, and etoposide. Our data imply that viral -encoded inhibitors of apoptosis, such as CrmA, can block the innate arms o f the immune response, including IFN-mediated apoptosis, and therefore pote ntially constitute an alternative family of inhibitors of IFN action in the cell. (C) 2001 Academic Press.