The MHC class I antigen presentation pathway: strategies for viral immune evasion

Abstract

Presumably because of the selective pressure exerted by the immune system, many viruses have evolved proteins that interfere with antigen presentation by major histocompatibility complex (MHC) class I molecules. These viruses utilize a whole variety of ingenious strategies to inhibit the MHC class I pathway. Viral proteins have been characterized that exploit bottlenecks in the MHC class I pathway, such as peptide translocation by the transporter associated with antigen processing. Alternatively, viral proteins can cause the degradation or mislocalization of MHC class I molecules. This is often achieved by the subversion of the host cell's own protein degradation and trafficking pathways. As a consequence elucidation of how these viral proteins act to subvert host cell function will continue to give important insights not only into virus-host interactions but also the function and mechanism of cellular pathways.

Figure 1

The MHC class I antigen presentation pathway. (1) Proteins are proteolytically processed in the cytosol by the proteasome. (2) Peptides generated by the proteasome are translocated into the ER lumen by TAP. (3) MHC class I molecules (heavy chain and associated β₂M) fold and assemble in the ER lumen with the aid of the ER chaperones calnexin, calreticulum and ERP57. (4) The MHC class I molecule in a complex with calreticulum and ERP57 associates with TAP and tapasin facilitates peptide binding. (5) Peptide loaded MHC class I molecules dissociate from TAP and are transported through the secretory pathway to the plasma membrane.

Figure 2

Viral inhibition of the MHC class I antigen presentation pathway. Viruses have evolved proteins that inhibit the MHC class I pathway at virtually every step. US2 and US11 dislocate the MHC class I heavy chain into the cytosol where it is degraded by the proteasome. ICP47 and US6 inhibit peptide translocation by TAP. E19 inhibits MHC class I association with TAP, E19 also inhibits MHC class I trafficking by retrieving MHC class I molecules from the cis-Golgi. Similarly US3 and US10 inhibit the ER export of class I molecules. U21 diverts MHC class I molecules to the lysosome. Nef down-regulates MHC class I molecules from the plasma membrane sequestering them in the TGN. Finally K3 and K5 down-regulate MHC class I molecules and sort them into the late endocytic pathway where they are degraded.