Inhibition of the MHC class II antigen presentation pathway by human cytomegalovirus

Human cytomegalovirus (HCMV) causes serious disease in immunocompromised individuals. Normally, anti-HCMV immune response controls virus replication following reactivation from latency. However, HCMV, like other large herpesviruses, encodes immune evasion proteins that allow the virus to replicate, for a time or in specific tissues, and produce viral progeny in the face of robust host immunity. HCMV glycoproteins US2, US3, US6 and US11 all inhibit different stages of the MHC class I antigen presentation pathway and can reduce recognition by CD8+ T lymphocytes. Here, we discuss two novel inhibitors of the MHC class II antigen presentation pathway, HCMV glycoproteins US2 and US3. Both US2 and US3 can inhibit presentation of exogenous protein antigens to CD4+ T lymphocytes in in vitro assays. US2 causes degradation of MHC class II molecules: HLA-DR-alpha and HLA-DM-alpha, as well as class I heavy chain (HC), but does not affect DR-beta or DM-beta chains. Mutant forms of US2 have been constructed that can bind to DR-alpha and class I HC but do not cause their degradation, separating the binding step from other processes that precede degradation. We also found evidence that US2-induced degradation of class I and II proteins involves a cellular component, other than Sec61, that is limiting in quantity. Unlike US2, US3 binds newly synthesized class II alpha/beta complexes, reducing the association with the invariant chain (Ii) and causing mislocalization of class II complexes in cells. US3 expression reduces accumulation of class II complexes in peptide-loading compartments and loading of peptides. Since US2 and US3 are expressed solely within HCMV-infected cells, it appears that these viral proteins have evolved to inhibit presentation of endogenous, intracellular viral antigens to anti-HCMV CD4+ T cells. This is different from how the MHC class II pathway is normally viewed, as a pathway for presentation of exogenous, extracellular proteins. The existence of these proteins indicates the importance of class II-mediated presentation of endogenous antigens in signalling virus infection to CD4+ T cells.