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Journal of Virology, March 2008, p. 2385-2393, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.01946-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The DNase of Gammaherpesviruses Impairs Recognition by Virus-Specific CD8+ T Cells through an Additional Host Shutoff Function{triangledown}

Jianmin Zuo,1 Wendy Thomas,1 Daphne van Leeuwen,2 Jaap M. Middeldorp,3 Emmanuel J. H. J. Wiertz,2 Maaike E. Ressing,2 and Martin Rowe1*

Division of Cancer Studies, University of Birmingham Medical School, Edgbaston, Birmingham B15 2TT, United Kingdom,1 Department of Medical Microbiology, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands,2 Department of Pathology, Free University Medical Center, DeBoelelaan 1117, 1081 Amsterdam, The Netherlands3

Received 5 September 2007/ Accepted 14 December 2007

The DNase/alkaline exonuclease (AE) genes are well conserved in all herpesvirus families, but recent studies have shown that the AE proteins of gammaherpesviruses such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) exhibit an additional function which shuts down host protein synthesis. One correlate of this additional shutoff function is that levels of cell surface HLA molecules are downregulated, raising the possibility that shutoff/AE genes of gammaherpesviruses might contribute to viral immune evasion. In this study, we show that both BGLF5 (EBV) and SOX (KSHV) shutoff/AE proteins do indeed impair the ability of virus-specific CD8+ T-cell clones to recognize endogenous antigen via HLA class I. Random mutagenesis of the BGLF5 gene enabled us to genetically separate the shutoff and AE functions and to demonstrate that the shutoff function was the critical factor determining whether BGLF5 mutants can impair T-cell recognition. These data provide further evidence that EBV has multiple mechanisms to modulate HLA class I-restricted T-cell responses, thus enabling the virus to replicate and persist in the immune-competent host.

* Corresponding author. Mailing address: Division of Cancer Studies, University of Birmingham Medical School, Edgbaston, Birmingham B15 2TT, United Kingdom. Phone: 44 121 4147144. Fax: 44 121 4144486. E-mail: m.rowe{at}bham.ac.uk

{triangledown} Published ahead of print on 19 December 2007.

Journal of Virology, March 2008, p. 2385-2393, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.01946-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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