A) Viral interference with NKG2D receptor. NKG2D ligands are not expressed on healthy cells, only on those that are stressed, transformed or undergoing infection. Binding of NKG2D to its ligands can cause NK cell activation even in the presence of inhibitory signals. MCMV encodes 4 regulators of NKG2D ligands: m145 downmodulates MULT-1, m152 downmodulates RAE-1 family of molecules, while H60 is targeted by m155. Additionally, m138 targets H60, MULT-1 and RAE-1ε. EBV, KSHV and HCMV target MICB by microRNAs. ZPXV produce soluble NKG2D ligands and thus saturate NKG2D receptors on NK cells. B) Herpesviral regulation of MICB via miRNAs. EBV, KSHV and HCMV encode microRNA, small RNAs that, after processing and loading into RISC complex, bind to 3′-UTR of MICB messenger RNA and prevent efficient translation of MICB mRNA. C) MCMV interactions with Ly49 receptors. MCMV encodes MHC I homologue m157 which, in some MCMV sensitive mice serves as a ligand for inhibitory Ly49I receptor. However, some mouse strains, during the course of the evolution with MCMV, have developed activating Ly49H receptor capable of recognizing m157. In MA/My mice resistance is conferred through the recognition of m04/MHC I complexes on the cell surface. As there is no evolutionary advantage for the virus to develop and keep protein displayed on the infected cell surface which is recognized by an activating receptor, it is quite possible that inhibitory Ly49 receptor specific for the m04/MHC I complexes is waiting to be found.

Normal, healthy cells display MHC I molecules on their cell surface presenting cellular peptides which are not recognized by CD8⁺ T cell receptor. MHC I molecules are ligands for inhibitory NK cell receptors and their expression on the cell surface ensures tolerance through prevalence of inhibitory signals. In order to avoid detection by CD8⁺ T cells viruses may be tempted to downregulate all MHC I molecules from the cell surface. However this would render them sensitive to NK cells through “missing-self” recognition. Dengue virus causes upregulation of MHC I molecules thus enforcing inhibition of NK cells but risking detection by CD8⁺ T cells. HCMV selectively downregulates MHC I molecules capable of presenting peptides to CD8⁺ T cells while leaving HLA-E molecules capable of engaging inhibitory NK cell receptors. As HLA-E display peptides derived from leader sequences of other MHC I molecules, HCMV encodes gpUL40 whose leader sequence is similar to leader sequences of other MHC I molecules for loading into HLA-E. In addition HCMV also encodes MHC surrogate gpUL18 which is a ligand for inhibitory LIR-1 receptor.