This Article Full Text Full Text (PDF) Other Versions of this Article: JVI.02251-07v1 82/9/4585    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Google Scholar Articles by McSharry, B. P. Articles by Wilkinson, G. W. G. PubMed PubMed Citation Articles by McSharry, B. P. Articles by Wilkinson, G. W. G.

Adenovirus E3/19K Promotes Evasion of NK Cell Recognition by Intracellular Sequestration of the NKG2D Ligands Major Histocompatibility Complex Class I Chain-Related Proteins A and B

Brian P. McSharry,^1, Hans-Gerhard Burgert,^2, Douglas P. Owen,² Richard J. Stanton,¹ Virginie Prod'homme,¹ Martina Sester,^2, Katja Koebernick,^2, Veronika Groh,³ Thomas Spies,³ Steven Cox,⁴ Ann-Margaret Little,⁴ Eddie C. Y. Wang,⁵ Peter Tomasec,¹ and Gavin W. G. Wilkinson^1*

Departments of Medical Microbiology,¹ Medical Biochemistry and Immunology, Cardiff University, Tenovus Building, Heath Park, Cardiff CF14 4XX, United Kingdom,⁵ Department of Biological Sciences, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, United Kingdom,² Fred Hutchinson Cancer Research Center, Clinical Research Division, 1100 Fairview Avenue North, Seattle, WA 98109,³ The Anthony Nolan Trust, Royal Free Hospital, Pond Street, London NW3 2QG, United Kingdom⁴

Received 17 October 2007/ Accepted 7 February 2008

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 recognized as a paradigm for viral immune evasion. However, HLA-I downregulation 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 while infection with wild-type Ad enhances synthesis of the NKG2D ligands, major histocompatibility complex class I chain-related proteins A and B (MICA and 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 analyzing a range of cell lines and viruses carrying 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 Ad-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.

Published ahead of print on 20 February 2008.

These authors contributed equally to the work.

Present address: Department of Internal Medicine IV, University of the Saarland, 66421 Homburg, Germany.

Present address: Institute for Biochemistry, Department of Developmental Biochemistry, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.