In addition to their role in the acute innate response to viral infection, a major function of NK cells is the recognition and cytolysis of cells that have downregulated MHC class I molecules as a foil to pathogen attempts to evade detection by CTLs. Accordingly, viruses that target the MHC class I pathway have also evolved mechanisms to repress the cytolytic activity of NK cells. Strategies here include, but are not limited to, expression of viral homologs of MHC class I that engage killer inhibitory receptors (KIRs) and leukocyte inhibitory receptors (LIRs). For example, human CMV produces a homolog of HLA class I called
Fig. 13.24 Immunoevasins produced by viruses interfere with the processing of antigens that bind to MHC class I molecules.
UL18, which binds LIR1 on NK cells and provides an inhibitory signal that blocks NKcell cytolysis. Viral products have been defined that also antagonize activating receptors on NK cells, as well as inhibit NKcell effector pathways.
DNA viruses have evolved mechanisms to subvert additional functions of the immune system. The mechanisms used include the expression of viral homologs of cytokines or chemokines and their receptors, or viral proteins
Fig. 13.25 The peptide-loading complex in the endoplasmic reticulum is targeted by viral immunoevasins. the left panel shows blockade of peptide entry to the endoplasmic reticulum (eR). the cytosolic iCP47 protein from herpes simplex virus (HSV)-1 prevents peptides from binding to taP in the cytosol, whereas the uS6 protein from human CMV interferes with the atP-dependent transfer of peptides through taP. the middle panel shows the retention of MHC class i molecules in the eR by the adenovirus e19 protein. this binds certain MHC molecules and retains them in the eR through an eR-retention motif, at the same time competing with tapasin to prevent association with taP and peptide loading. the right panel shows how the murine herpes virus mK3 protein, an e3ubiquitin ligase, targets newly synthesized MHC class i molecules. mK3 associates with tapasin:taP complexes and directs the addition of ubiquitin subunits with K48 linkages (see Section 7-5) to the cytoplasmic tail of the MHC class i molecule. the polyubiquitination of the cytoplasmic tail of MHC initiates the process of degradation of the MHC molecule by the proteasomal pathway.
that bind cytokines or their receptors to inhibit their actions. As type I and II interferons are major effector cytokines in antiviral defense, diverse viral strategies are centered on the inhibition of this family of cytokines, whether by production of decoy receptors or inhibitory binding proteins, inhibition of JAK/STAT signaling by IFN receptors, inhibition of cytokine transcription, or interference with transcription factors induced by IFNs. Some DNA viruses also produce antagonists of the proinflammatory cytokines IL1, IL18, and TNFα, among others. Viral homologs of immunosuppressive cytokines are also produced. CMV impairs antiviral responses by producing a homolog of the cytokine IL10, called cmvIL10, which downregulates the production of several proinflammatory cytokines by immune cells, including IFNγ, IL12, IL1, and TNFα, to promote tolerogenic rather than immunogenic adaptive responses to viral antigens.