How the virus outsmarts the host: function and structure of cytomegalovirus MHC-I-like molecules in the evasion of natural killer cell surveillance

Abstract

Natural killer (NK) cells provide an initial host immune response to infection by many viral pathogens. Consequently, the viruses have evolved mechanisms to attenuate the host response, leading to improved viral fitness. One mechanism employed by members of the β-herpesvirus family, which includes the cytomegaloviruses, is to modulate the expression of cell surface ligands recognized by NK cell activation molecules. A novel set of cytomegalovirus (CMV) genes, exemplified by the mouse m145 family, encode molecules that have structural and functional features similar to those of host major histocompatibility-encoded (MHC) class I molecules, some of which are known to contribute to immune evasion. In this review, we explore the function, structure, and evolution of MHC-I-like molecules of the CMVs and speculate on the dynamic development of novel immunoevasive functions based on the MHC-I protein fold.

Figure 1

MCMV-encoded proteins disrupt NK-cell recognition of infected cells. During MCMV infection, the surface expression of the stress-induced molecules, ligands for NKG2D, is downregulated: m152 downregulates all isoforms of RAE-1, m145 and m155 interfere with H60 and MULT-1, respectively, and m138 downregulates H60, MULT-1, and RAE-1ε (a). m157 binds both inhibitory NK receptor, Ly49I, and activating NK receptor, Ly49H (b).

Figure 2

Amino acid sequence alignments of the extracellular domains of classical MHC-I molecules from mouse (H-2D^d) and human (HLA-A2) with MHC-I-like viral immunoevasins were generated using ClustalW module of MacVector 10.6.6. H-2D^d and HLA-A2 share significant similarity at 81.7% (a). UL18 and m144 show detectable sequence similarity (21–40%) with HLA-A2 and H-2D^d. Conserved cysteine residues are in yellow (b). The alignment of m145 family members and other MHC-I-like immunoevasins shows 6–40% sequence similarity to the canonical MHC-I molecules (c).

Figure 3

X-ray structures of m157 (2NYK) [64], m153 (205N) [74, 84], m144 (IU58), HCMV UL18 (3D2U) [75], Tanapox 2L protein (3IT8) [85], and H-2D^d (3ECB) [86] reveal both shared and unique features. The disulfide bonds are in yellow. The α1, α2 and H2b helices and α3 domain are labeled. Ribbon diagrams of the structures in (a), rotated 90° to the right in (b), reveal differences in β2m and peptide binding (a, b). The view from the top shows differences in the peptide binding pocket (c). Illustrations were prepared from the superposed structures of the molecules using PyMOL http://www.pymol.org/.