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Human cytomegalovirus inhibits peptide translocation into the endoplasmic reticulum for MHC class I assembly

Human cytomegalovirus inhibits peptide translocation into the endoplasmic reticulum for MHC class I assembly. antigen by CD4+ T JNJ-31020028 cells by a novel mechanism. US3 JNJ-31020028 bound to class II / complexes in the endoplasmic reticulum (ER), reducing their association with Ii. Class II molecules moved normally from the ER to the Golgi apparatus in US3-expressing cells but were not sorted efficiently to the class II loading compartment. As a consequence, formation of peptide-loaded class II complexes was reduced. We concluded that US3 and US2 can collaborate to inhibit class II-mediated presentation of endogenous HCMV antigens to CD4+ T cells, allowing virus-infected cells to resist recognition by CD4+ T cells. Human cytomegalovirus (HCMV) is ubiquitous and normally causes relatively benign clinical manifestations (6). HCMV infections are lifelong and are characterized by low-level persistence, latency, and bouts of reactivation. However, HCMV JNJ-31020028 causes serious disease in immunosuppressed or immunocompromised individuals, e.g., patients undergoing transplant-related therapy or patients with AIDS (54). HCMV infection can cause neurologic sequelae, including hearing loss and mental retardation, and organ failure in young children (54, 56). HCMV infects many cell types, including epithelial cells, fibroblasts, endothelial cells, glial cells, and monocytes/macrophages. Infection of epithelial cells of the upper respiratory tract, salivary gland, and kidney allows excretion and spread to other hosts (54), while infection of monocytes/macrophages provides a site for virus latency (53) and a means for dissemination throughout the body. HCMV replicates slowly, often at low levels, without causing rapid cell destruction. The virus escapes vigorous host defenses by establishing a latent state in which gene expression is highly restricted. However, following reactivation from latency, the virus replicates in the face of fully primed cell-mediated immunity. Nevertheless, the virus often persists in the body for long periods of time, with an astonishing ability to withstand the strong anti-HCMV immune response. Apparently, HCMV uses a variety of immune evasion tactics to allow virus replication in certain cell types and at defined times in the virus life cycle (reviewed in references 15, 28, 30, and 60). Among these are a panel of inhibitors that apparently reduce recognition by T lymphocytes and NK cells. HCMV expresses four glycoproteins, all encoded by homologous genes in the US2-to-US11 gene region of the viral genome, that can independently inhibit various steps in the major histocompatibility complex class I (MHC-I) antigen presentation pathway. US2 and US11 cause retrotranslocation of class I proteins from the endoplasmic reticulum (ER) and proteasome-mediated degradation (33, 62, 63). US3 causes retention of class I proteins in the ER, although US3 itself apparently dissociates from MHC-I and moves through the Golgi apparatus in time (2, 19, 20, 32). US6 binds the transporter associated with antigen presentation (TAP) in the ER (3, 25, 37) and allosterically affects the cytosolic ATPase activity of TAP (26, 34) so that peptides are not available to assemble class I molecules. The HCMV tegument protein pp65 reduces presentation of viral protein pp72 to CD8+ T cells (18). Additionally, HCMV encodes two membrane glycoproteins, UL16 and UL18, that mediate resistance to NK cells (10, 47). We recently described a novel form of immune JNJ-31020028 evasion: inhibition of the MHC-II antigen presentation pathway by HCMV Rabbit Polyclonal to SLC6A15 US2 (58). Cells expressing US2 are less able to present antigens via the class II pathway to CD4+ T lymphocytes. CD4+ T cells normally recognize antigens presented by professional antigen-presenting cells (APCs), macrophages, dendritic cells, and B cells, that take up extracellular viral proteins by phagocytosis or endocytosis and process the proteins to antigenic peptides in endosomal compartments. MHC-II / heterodimers assemble with invariant chain (Ii) in the ER (reviewed in reference 42). Nonameric complexes of class II //Ii are targeted to the MHC-II loading compartment (MIIC) by signals present in the N terminus of Ii (35, 39). During this transport to the MIIC, Ii is partially degraded, and, in the MIIC, a fragment of Ii is exchanged for.