Human cytomegalovirus protein pp65 mediates accumulation of HLA-DR in lysosomes and destruction of the HLA-DR α-chain

• Published in: Blood 2003-06, Vol.101 (12), p.4870-4877
• Main Authors: Odeberg, Jenny, Plachter, Bodo, Brandén, Lars, Söderberg-Nauclér, Cecilia
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Biological Transport; Cytomegalovirus - chemistry; Cytomegalovirus - genetics; Cytomegalovirus - immunology; Dendritic Cells - immunology; Fibroblasts - ultrastructure; Fibroblasts - virology; Flow Cytometry; Gene Deletion; Gene Expression; HLA-D Antigens - metabolism; HLA-DR Antigens - genetics; HLA-DR Antigens - metabolism; Human viral diseases; Humans; Infectious diseases; Interferon-gamma - pharmacology; Interferon-Stimulated Gene Factor 3; Janus Kinase 1; Janus Kinase 2; Leukocytes, Mononuclear - immunology; Lysosomes - metabolism; Medical sciences; Medicin och hälsovetenskap; Microscopy, Confocal; Phosphoproteins - genetics; Phosphoproteins - physiology; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transcription Factors - metabolism; Transfection; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Viral Matrix Proteins - genetics; Viral Matrix Proteins - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-05-1504

Human cytomegalovirus (HCMV) has developed multiple strategies to escape immune recognition. Here, we demonstrate that HCMV down-regulates HLA-DR expression in infected interferon γ (IFN-γ)–stimulated fibroblasts at 1 day after infection. Decreased HLA-DR expression was not observed on cells infected with an HCMV strain lacking the pp65 gene (RVAD65), but was observed on cells transfected with the pp65 gene. HLA-DR expression accumulated in vacuoles near the nucleus in HCMV-infected, but not in uninfected or RVAD65-infected cells. In addition, the HLA-DR α-chain, but not the β-chain or HLA-DM, was degraded in HCMV-infected but not in RVAD65-infected cells. Thus, the HCMV protein pp65 mediates decreased expression of HLA-DR, by mediating an accumulation of HLA class II molecules in lysosomes that results in degradation of the HLA-DR α-chain.