Down-regulation of the class I HLA heterodimer and beta2-microglobulin on the surface of cells infected with cytomegalovirus

Abstract

Cytotoxic T cell recognition of virus-infected cells requires the presentation of viral peptides by class I HLA molecules on the cell surface. We report here that cytomegalovirus (CMV) infection of human fibroblasts results in a progressive decrease in the cell surface expression of class I HLA and fl2-microglobulin (fl2m) such that in the late stages of infection the majority of infected cells have no detectable surface class I HLA. Coincident with decreased surface expression of class I HLA was an increase in his cytoplasmic expression. Confocal scanning laser microscopic analysis demonstrated that class I HLA and fl2m accumulate in a perinuclear compartment inside the CMV-infected cell. Our data thus support the concept that CMV infection induces altered transport of class I HLA to the cell surface. We suggest that the virus has evolved this mechanism as a strategy to avoid T cell recognition of infected cells.

Human Cytomegalovirus Inhibits Peptide Translocation into the Endoplasmic Reticulum for MHC Class I Assembly

“…This mutant lacks a 15 kb spanning genomic region within the unique short region (Us) corresponding to the genes U,,ql-USI5 (Kollert-J6ns et al, 1991;Mockenhaupt et al, 1994;Yamanishi & Rapp, 1979). As reported by several laboratories (Barnes & Grundy, 1992;Beersma et al, 1993;Hengel et al, 1995 ;Warren et al, 1994;Yamashita et al, 1993), fibroblasts infected with AD169 for 72 h express drastically reduced steady state levels of MHC class I complexes as…”

“…While infection of the immunocompetent host is usually asymptomatic, the virus causes protean disease manifestations in immunologically immature or immunodeficient individuals such as organ transplant recipients or AIDS patients (Ho, 1982 CMVs have evolved functions to avoid the cellular immune response. Both human CMV (HCMV) and mouse CMV (MCMV) interfere with surface expression of class I MHC and antigen presentation to CD8 + T lymphocytes (Barnes & Grundy, 1992, Del Valet al, 1989. In MCMV-infected cells, correctly assembled peptide-charged MHC class I complexes are retained in the ER/cis-Golgi compartment by an early gene function leading to abrogation of cytotoxic T lymphocyte recognition (Del Valet al, 1992).…”

Cytokines restore MHC class I complex formation and control antigen presentation in human cytomegalovirus-infected cells

“…Previous studies have demonstrated that MHC class I molecules are downregulated by HCMV without reducing the mRNA levels of MHC class I gene products (Barnes & Grundy, 1992;Browne et al, 1990;Warren et al, 1994). This viral effect is associated with both a reduced stability of MHC class I heavy chains and decreased steady state levels of assembled ternary MHC class I complexes.…”

“…This ability of MCMV to inhibit antigen presentation and to evade CD8 + T cell-mediated immune control is overcome by the action of interferon-(IFN-~) in vitro as well as in vivo . Like MCMV, HCMV is able to decrease MHC class I expression (Barnes & Grundy, 1992). Beersma et al (1993) reported that nascent MHC class I molecules are unstable in infected cells.…”

Down-regulation of surface major histocompatibility complex class I by guinea pig cytomegalovirus

“…Down-regulation of class I during lytic replication has now been reported for all eight human herpesviruses and several animal herpesviruses (Ambagala et al, 2000;Barnes & Grundy, 1992;Campbell & Slater, 1994;Cohen, 1998;Hariharan et al, 1993;Hirata et al, 2001;Hudson et al, 2001;Hunt et al, 2001;Ishido et al, 2000;Jones et al, 1995;Nataraj et al, 1997;Stevenson et al, 2000;Tomazin et al, 1998;Yamashita et al, 1993;York et al, 1994;Zeidler et al, 1997). Thus, class I downregulation is clearly an important, perhaps essential, component in the herpesviral arsenal of immune evasion mechanisms.…”