Classical and non-classical MHC I molecule manipulation by human cytomegalovirus: so many targets—but how many arrows in the quiver?

Abstract

Major mechanisms for the recognition of pathogens by immune cells have evolved to employ classical and non-classical major histocompatibility complex class I (MHC I) molecules. Classical MHC I molecules present antigenic peptide ligands on infected cells to CD8+ T cells, whereas a key function for non-classical MHC I molecules is to mediate inhibitory or activating stimuli in natural killer (NK) cells. The structural diversity of MHC I puts immense pressure on persisting viruses, including cytomegaloviruses. The very large coding capacity of the human cytomegalovirus allows it to express a whole arsenal of immunoevasive factors assigned to individual MHC class I targets. This review summarizes achievements from more than two decades of intense research on how human cytomegalovirus manipulates MHC I molecules and escapes elimination by the immune system.

A TB40/E-Derived Human Cytomegalovirus Genome with an Intact US-Gene Region and a Self-Excisable BAC Cassette for Immunological Research

“…Hence, in agreement with the sequencing data showing correct insertion, the functionality of the repaired US2US6 gene region was also demonstrated. The fact that the parental RV-TB40-BAC KL7 also down-regulated MHC-I surface molecules to some extent is explained by the presence of the known MHC-I down modulator US11 as well as other potential immune modulators not yet fully characterized, such as US8 and US10 (29). …”

Aminobisphosphonates Synergize with Human Cytomegalovirus To Activate the Antiviral Activity of Vγ9Vδ2 Cells

“…Additionally, several viral microRNAs and proteins downmodulate the expression of stress molecules on the surface of HCMV-infected cells. This is the case for UL16-binding proteins and MHC class I chain-related Ags, which stimulate activating receptors on NK cells and gd cells (22,23).…”

NK cell interplay with cytomegaloviruses

“…CMVs encode several proteins that regulate the surface amount of MHC I: MCMV encodes m06 and m152 that target MHC I to degradation or retention inside the cell, respectively (reviewed in [2]). HCMV encodes MHC I regulators with well-defined roles (US2 and US11 as MHC I degraders, US3 -an MHC I retainer and TAP inhibitor US6), and several others still under investigation (reviewed in [3]). …”

“…HLA-A and B molecules are better antigen presenters to CD8T cells but only a smaller portion of HLA-A and B molecules are recognized by KIR or CD94/NKG2 receptors, whereas the opposite is true of HLA-C. HCMV not only spares HLA-E from some of its MHC I modulators, it also stabilizes it on the cell surface by encoding a signal peptide within UL40 that mimics signal peptides of other HLA molecules that are normally presented by HLA-E (Figure 1i). Moreover, loading of this peptide into HLA-E molecules is TAP-independent thus avoiding control by US6 (reviewed in detail in [3]). The reason for preserving HLA-E is that it binds the inhibitory receptor NKG2A (Figure 1i).…”