The multiple immune-evasion genes of murine cytomegalovirus are not redundant: m4 and m152 inhibit antigen presentation in a complementary and cooperative fashion

Both human cytomegaloviruses (HCMVs) and murine cytomegaloviruses (MCMVs) e ncode multiple genes that interfere with antigen presentation by major hist ocompatibility complex (MHC) class I, and thus protect infected targets fro m lysis by virus-specific cytotoxic T lymphocytes (CTLs). HCMV has been sho wn to encode four such genes and MCMV to encode two. MCMV m152 blocks the e xport of class I from a pre-Golgi compartment, and MCMV m6 directs class I to the lysosome for degradation. A third MCMV gene, m4, encodes a glycoprot ein which is expressed at the cell surface in association with class I. Her e we here show that m4 is a CTL-evasion gene which, unlike previously descr ibed immune-evasion genes, inhibited CTLs without blocking class I surface expression. m152 was necessary to block antigen presentation to both K-b- a nd D-b-restricted CTL clones, while m4 was necessary to block presentation only to K-b-restricted clones. m152 caused complete retention of D-b, but o nly partial retention of K-b, in a pre-Golgi compartment. Thus, while m152 effectively inhibited D-b-restricted CTLs, m4 was required to completely in hibit K-b-restricted CTLs. We propose that cytomegaloviruses encode multipl e immune-evasion genes in order to cope with the diversity of class I molec ules in outbred host populations.