Cytotoxic T-lymphocytes (CTLs), by virtue of their ability to recognize and induce apoptotic death of virus-infected cells, comprise a major antiviral defense mechanism. The induction of apoptosis by CTLs can be completely accounted for by two mechanisms: (i) a Ca-dependent component that involves the exocytotic release of serine proteases known as granzymes from CTL granules and their subsequent insertion into the target cell to induce apoptosis and (ii) a Ca-independent component that involves the activation of Fas, a receptor on the target cell membrane that triggers apoptosis. Although viruses have evolved several indirect mechanisms for evading the CTL response, direct inhibition of the apoptotic cascade has never been described. We now show for the first time that the cowpox virus protein CrmA, a protease inhibitor of the serpin family, is capable of inhibiting CTL-mediated cytolysis. The inhibitory effect is largely the result of blockade of the Ca-independent (i.e. Fas-mediated) component of CTL killing. CrmA thus represents the first example of a viral gene product capable of directly blocking CTL-mediated cell death.

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