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) encode multiple genes that interfere with antigen presentation by major histocompatibility complex (MHC) class I, and thus protect infected targets from lysis by virus-specific cytotoxic T lymphocytes (CTLs). HCMV has been shown to encode four such genes and MCMV to encode two. MCMV m152 blocks the export 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 glycoprotein which is expressed at the cell surface in association with class I. Here we here show that m4 is a CTL-evasion gene which, unlike previously described immune-evasion genes, inhibited CTLs without blocking class I surface expression. m152 was necessary to block antigen presentation to both K^b- and 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 only partial retention of K^b, in a pre-Golgi compartment. Thus, while m152 effectively inhibited D^b-restricted CTLs, m4 was required to completely inhibit K^b-restricted CTLs. We propose that cytomegaloviruses encode multiple immune-evasion genes in order to cope with the diversity of class I molecules in outbred host populations.