title: Varicella-zoster virus retains major histocompatibility complex class I proteins in the Golgi compartment of infected cells.
abstract: We sought to examine the effects of varicella-zoster virus (VZV) infection on the expression of major histocompatibility complex class I (MHC I) molecules by human fibroblasts and T lymphocytes. By flow cytometry, VZV infection reduced the cell surface expression of MHC I molecules on fibroblasts significantly, yet the expression of transferrin receptor was not affected. Importantly, when human fetal thymus/liver implants in SCID-hu mice were inoculated with VZV, cell surface MHC I expression was downregulated specifically on VZV-infected human CD3+ T lymphocytes, a prominent target that sustains VZV viremia. The stage in the MHC I assembly process that was disrupted by VZV in fibroblasts was examined in pulse-chase and immunoprecipitation experiments in the presence of endoglycosidase H. MHC I complexes continued to be assembled in VZV-infected cells and were not retained in the endoplasmic reticulum. In contrast, immunofluorescence and confocal microscopy showed that VZV infection resulted in an accumulation of MHC I molecules which colocalized to the Golgi compartment. Inhibition of late viral gene expression by treatment of infected fibroblasts with phosphonoacetic acid did not influence the modulation of MHC I expression, nor did transfection of cells with plasmids expressing immediate early viral proteins. However, cells transfected with a plasmid carrying the early gene ORF66 did result in a significant downregulation of MHC I expression, suggesting that this gene encodes a protein with an immunomodulatory function. Thus, VZV downregulates MHC I expression by impairing the transport of MHC I molecules from the Golgi compartment to the cell surface; this effect may enable the virus to evade CD8+ T-cell immune recognition during VZV pathogenesis, including the critical phase of T-lymphocyte-associated viremia.
authors: Centre for Virus Research, Westmead Millennium Institute of Health Research, University of Sydney, Sydney, New South Wales, Australia.
authors: A
authors: A
authors: Abendroth
authors: I
authors: I
authors: Lin
authors: B
authors: B
authors: Slobedman
authors: H
authors: H
authors: Ploegh
authors: A M
authors: AM
authors: Arvin
mesh_terms: D000818:Animals; D002451:Cell Compartmentation; D002460:Cell Line; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D006056:Golgi Apparatus / Q000378:metabolism*; D014645:Herpesvirus 3, Human / Q000276:immunology* / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011233:Precipitin Tests / Q000379:methods; D011506:Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014407:Tumor Cells, Cultured; D014709:Vero Cells; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; D017874:Immediate-Early Proteins; D011506:Proteins; D014764:Viral Proteins