Low-dose human cytomegalovirus infection of human fibroblast cultures induces lymphokine-activated killer cell resistance: interferon-beta-mediated target cell protection does not correlate with up-regulation of HLA class I surface molecules.

We have investigated the susceptibility of human foreskin fibroblast (HFF) monolayers infected at low level with human cytomegalovirus (HCMV) strain AD 169, or a clinical HCMV isolate, to lysis mediated by interleukin-2(IL-2)-activated killer cells (LAK). HFF cultures inoculated with a multiplicity of infection (MOI) dose of 0.001-0.01 had significantly decreased susceptibility to lysis by IL-2-activated non-adherent blood cells (PNAC) or purified CD56+ cells in comparison to mock-infected cultures. By 12h post incubation HFF cultures showed diminished susceptibility to LAK cell cytotoxicity when HFF cultures were incubated with HCMV (MOI 0.01) or interferon-beta (IFN-beta; 100 U/ml). Cytofluorometric analysis of HCMV-infected HFF cultures showed a modulation of HLA class I expression on single cells 3 days post-infection, namely, segregation of the cells in low- and high-density HLA class I-expressing cells depended on the dose of HCMV inoculum. However, up-regulation of HLA class I surface molecules was not significantly enhanced 12 h post-incubation with HCMV inoculum or IFN-beta. Anti-IFN-beta antibodies prevented both the development of the resistance and the increase of HLA class I expression in infected HFF cultures. In summary, the comparison of HLA class I expression and the LAK susceptibility of HCMV-infected HFF cultures may lead to the following conclusions: IFN-beta mediates the protection of neighbouring uninfected fibroblasts, but the modulation of HLA class I expression on uninfected cells does not correlate with the diminished susceptibility.