HSV and glycoprotein J inhibit caspase activation and apoptosis induced bygranzyme B or Fas

HSV-1 inhibits apoptosis of infected cells, presumably to ensure that the i nfected cell survives long enough to allow completion of viral replication. Because cytotoxic lymphocytes kill their targets via the induction of apop tosis, protection from apoptosis could constitute a mechanism of immune eva sion for HSV. Several HSV genes are involved in the inhibition of apoptosis , including Us5, which encodes glycoprotein J (gJ). Viruses deleted for Us5 showed defects in inhibition of caspase activation after Fas ligation or U V irradiation. Transfected cells expressing the Us5 gene product gJ were pr otected from Fas- or UV-induced apoptosis, as measured by morphology, caspa se activation, membrane permeability changes, or mitochondrial transmembran e potential. In contrast, caspase 3 activation in mitochondria-free cell ly sates by granzyme (gr)B was inhibited equivalently by Us5 deletion and resc ue viruses, suggesting that gJ is not required for HSV to inhibition this p rocess. However, mitochondria-free lysates from transfected cells expressin g Us5/gJ were protected from grB-induced caspase activation, suggesting tha t Us5/gJ is sufficient to inhibit this process. Transfected cells expressin g Us5/gJ were also protected from death induced by incubation with purified grB and perforin. These findings suggest that HSV has a comprehensive set of immune evasion functions that antagonize both Fas ligand- and grB-mediat ed pathways of CTL-induced apoptosis. The understanding of HSV effects on k illing by CTL effector mechanisms may shed light on the incomplete control of HSV infections by the immune system and may allow more rational approach es to the development of immune modulatory treatments for HSV infection.