NATURAL-KILLER-CELL LYSIS OF CYTOMEGALOVIRUS (CMV)-INFECTED CELLS CORRELATES WITH VIRALLY INDUCED CHANGES IN CELL-SURFACE LYMPHOCYTE FUNCTION-ASSOCIATED ANTIGEN-3 (LFA-3) EXPRESSION AND NOT WITH THE CMV-INDUCED DOWN-REGULATION OF CELL-SURFACE CLASS-I HLA

CMV and other viruses down-regulate the cell surface expression of cla ss I HLA, and while this allows them to evade CTL, it may make infecte d cells more susceptible to lysis by NK cells, due to the failure to e ngage class I inhibitory receptors on the NK cell. We studied CMV infe ction and found that fibroblasts infected with virus strains Towne, To ledo, Davis, and C1FE were refractory to NK lysis, while those infecte d with strains AD169, C1F, or R7 were susceptible, All viral strains d own-regulated class I HLA to a similar extent, and we concluded that t here was no evidence for any correlation between the latter and suscep tibility to Ng lysis, In contrast, there was a strong correlation betw een NK killing of CMV-infected cells and cell surface levels of lympho cyte function-associated antigen-3 (LFA-3). Fibroblasts infected with the Towne, Toledo, Davis, and C1FE strains of CMV downregulated LFA-3 expression and were refractory to lysis, while strains AD169, C1F, and R7 up-regulated LFA-3 and were susceptible to NK killing. U373 MG (ma lignant glioma) cells expressed constitutively high levels of LFA-3 an d were sensitive to NK lysis when infected with any of the above-liste d CMV strains. We estimated that a minimum of between 29,000 and 71,00 0 LFA-3 molecules per target cell were needed for NK susceptibility. T he effects on LFA-3 expression were due to immediate early/early viral gene products. We also demonstrated that fibroblasts infected with th e strains Towne, Toledo, Davis, and C1FE expressed a ganciclovir-sensi tive late CMV gene product, which delivered an inhibitory signal to NK cells.