Herpes simplex virus type 1 renders infected cells resistant to cytotoxic T-lymphocyte-induced apoptosis

Many viruses interfere with apoptosis of infected cells, presumably preventing cellular apoptosis as a direct response to viral infection, Since cytotoxic T lymphocytes (CTL) induce apoptosis of infected cells as part of the ''lethal hit,'' inhibition of apoptosis could represent an effective immune evasion strategy, We report here herpes simplex virus type 1 (HSV-1) interference with CTL-induced apoptosis of infected cells and show that HSV-1 inhibits the nuclear manifestations of apoptosis but not the membrane changes, The HL-60 cell line (human promyelocytic leukemia) undergoes apoptosis in response to many stimuli, including incubation with ethanol, After HSV-1 infection (strains E115 and 17+), ethanol-treated cells did not produce oligonucleosomal DNA fragments characteristic of apoptosis, as assayed by gel electrophoresis and enzyme-linked immunosorbent assay, Inhibition was detected 2 h after infection and increased over time, Importantly, HSV-1-infected cells were resistant to apoptosis induced by antigen-specific CD4(+) CTL, despite the fact that CTL recognition and degranulation in response to infected targets remained intact, Unlike HSV-1, HSV-2 (strains 333 and HG52) did not inhibit DNA fragmentation, In contrast to the inhibition of DNA fragmentation by HSV-1, none of the HSV-1 or -2 strains interfered with the ethanol-induced exposure of surface phosphatidylserine characteristic of apoptosis, as determined by annexin V binding, These results demonstrate that genes of HSV-1 inhibit the nuclear manifestations of apoptosis but not the membrane manifestations, suggesting that these may be mediated via separate pathways, They also suggest that HSV-1 inhibition of CTL-induced apoptosis may be an important mechanism of immune evasion.