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J. Virol. doi:10.1128/JVI.02251-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Adenovirus E3/19K Promotes Evasion of NK Cell Recognition by Intracellular Sequestration of the NKG2D Ligands MICA and MICB

Department of Medical Microbiology and Medical Biochemistry & Immunology, Cardiff University, Tenovus Building, Heath Park, Cardiff, CF14 4XX, UK; Department of Biological Sciences, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK; Fred Hutchinson Cancer Research Center, Clinical Research Division, 1100 Fairview Avenue North, Seattle, WA98109, USA; The Anthony Nolan Trust, Royal Free Hospital, Pond Street, London, NW3 2QG, UK

^* To whom correspondence should be addressed. Email: WilkinsonGW1{at}cf.ac.uk.

	Abstract

The adenovirus (Ad) early transcription unit 3 (E3) encodes multiple immunosubversive functions that are presumed to facilitate the establishment and persistence of infection. Indeed, the capacity of E3/19K to inhibit transport of HLA-class I (HLA-I) to the cell surface, thereby preventing peptide presentation to CD8 T cells, has long been recognised as a paradigm for viral immune evasion. However, HLA-I down-regulation has the potential to render Ad infected cells vulnerable to Natural Killer (NK) cell recognition. Furthermore, expression of the immediate early Ad gene E1A is associated with efficient induction of ligands for the key NK cell activating receptor NKG2D. Here we show that whilst infection with wild-type Ad enhances synthesis of the NKG2D ligands, MHC class I chain-like proteins A and B (MICA & MICB), their expression on the cell surface is actively suppressed. Both MICA and MICB are retained within the endoplasmic reticulum as immature endoglycosidase H-sensitive forms. By analysing a range of cell lines and viruses encoding mutated versions of the E3 gene region, E3/19K was identified as the gene responsible for this activity. The structural requirements within E3/19K necessary to sequester MICA/B and HLA-I are similar. In functional assays, deletion of E3/19K rendered adenoviral infected cells more sensitive to NK cell recognition. We report the first NK evasion function in the Adenoviridae and describe a novel function for E3/19K. Thus, E3/19K has a dual function: Inhibition of T cell recognition and NK cell activation.

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