title: Herpes simplex virus type 1 renders infected cells resistant to cytotoxic T-lymphocyte-induced apoptosis.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle 98195, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Jerome
authors.forename: J F
authors.initials: JF
authors.lastname: Tait
authors.forename: D M
authors.initials: DM
authors.lastname: Koelle
authors.forename: L
authors.initials: L
authors.lastname: Corey
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D002462:Cell Membrane / Q000378:metabolism; D002999:Clone Cells; D053938:DNA Fragmentation; D018922:HL-60 Cells; D006561:Herpes Simplex / Q000276:immunology / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D066298:In Vitro Techniques; D010718:Phosphatidylserines / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D010718:Phosphatidylserines