Viruses and their mammalian hosts have co-evolved for millions of years, resulting in intricate host–pathogen interactions. As a result viruses have evolved several mechanisms to 'hide' from the host immune system.
Virus-infected cells are detected by host cytotoxic T cells when the infected cell displays on the surface a virus-derived peptide bound to an MHC class I molecule. This pathway, termed antigen presentation, is a target for viral immune evasion proteins.
Antigen presentation involves proteasome-dependent peptide generation in the cytoplasm, TAP-dependent peptide transport into the lumen of the endoplasmic reticulum (ER), where binding to MHC class I molecules occurs, and transit of stable peptide-loaded MHC class I molecules through the secretory pathway to the plasma membrane for T cell recognition.
To evade T cell recognition, viruses have evolved elaborate mechanisms to block antigen presentation. The viral immune evasion mechanisms include: inhibition of proteasome function, TAP-mediated peptide transport, chaperone-facilitated peptide loading and transit of MHC class I molecules from the ER.
Viruses also co-opt ubiquitin-dependent pathways to remove nascent MHC class I molecules from the ER for proteasome-mediated degradation or induce rapid endocytosis of surface MHC class I molecules for lysosome-mediated degradation. Interestingly, the existence of host proteins with similar structures and functions suggest that the viruses have acquired ancestral homologues from the host, which have evolved for use as immune evasion proteins.
The finding that viral immune evasion proteins are potent and highly specific for host protein interactions makes these natural inhibitors effective probes for dissecting physiological pathways.
The cell surface display of peptides by MHC class I molecules to lymphocytes provides the host with an important surveillance mechanism to protect against invading pathogens. However, in turn, viruses have evolved elegant strategies to inhibit various stages of the MHC class I antigen presentation pathway and prevent the display of viral peptides. This Review highlights how the elucidation of mechanisms of viral immune evasion is important for advancing our understanding of virus–host interactions and can further our knowledge of the MHC class I presentation pathway as well as other cellular pathways.
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We are grateful for the scientific critiquing of Dr X. Wang. Funding from National Institutes of Health (NIH) grants AI019687 (T.H.H.) and AI045070 (M.B.) is acknowledged.
A giant multicatalytic protease that resides in the cytoplasm and the nucleus. The 20S core, which contains three distinct catalytic subunits, can be appended at either end by a 19S cap or an 11S cap. The binding of two 19S caps to the 20S core forms the 26S proteasome, which degrades polyubiquitylated proteins. In addition to having a crucial role in protein turnover, the proteasome is involved in the first catalytic step in the processing of most, if not all, antigens for MHC class I presentation.
A non-classical MHC class II molecule that has a crucial role in mediating the catalytic exchange of peptides bound to MHC class II molecules in endosomal and lysosomal compartments of cells.
A non-classical MHC class Ib molecule that is involved in the establishment of immune tolerance at the maternal–fetal interface, the major soluble isoforms of which are HLA-G1 and HLA-G5.
- Cargo receptor
A protein that is implicated in the trafficking of endoplasmic reticulum (ER)-synthesized proteins between the ER and Golgi.
- Signal peptide peptidase
An enzyme that removes signal peptides. Co-translational translocation of most secreted and membrane-bound proteins is initiated by a hydrophobic signal peptide that is recognized by the translocation apparatus. This is then cleaved from the mature protein by signal peptide peptidases after translocation.
- E3 ubiquitin ligase
An enzyme that is required to attach the molecular tag ubiquitin to proteins. Depending on the position and number of ubiquitin molecules that are attached, the ubiquitin tag can target proteins for degradation in the proteasomal complex, sort them to specific subcellular compartments or modify their biological activity.
A complex of proteins associated with the translocation of nascent proteins across the endoplasmic reticulum (ER) membrane from the cytoplasm to the ER lumen.
- MICA and MICB
Ligands for the human natural killer cell activating receptor NKG2D (natural killer group 2, member D). They are closely related stress-inducible molecules that are encoded by genes located in the human MHC region. These molecules are expressed by tumours of epithelial origin and by certain melanomas.
- Multivesicular body
An endocytic intermediate organelle in the lysosomal degradative pathway, which contains small vesicles and is surrounded by a limiting membrane.
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Hansen, T., Bouvier, M. MHC class I antigen presentation: learning from viral evasion strategies. Nat Rev Immunol 9, 503–513 (2009). https://doi.org/10.1038/nri2575
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