Host shutoff during productive Epstein–Barr virus infection is mediated by BGLF5 and may contribute to immune evasion

doi:10.1073/pnas.0611128104

Host shutoff during productive Epstein–Barr virus infection is mediated by BGLF5 and may contribute to immune evasion

*Division of Cancer Studies, University of Birmingham Medical School, Vincent Drive, Edgbaston, Birmingham B15 2TT, United Kingdom;
^†Howard Hughes Medical Institute, Departments of Microbiology and Medicine, University of California, San Francisco, CA 94143;
^§Department of Medical Microbiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; and
^¶Department of Pathology, Free University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands

Communicated by Johannes van Rood, Europdonor Foundation, Leiden, The Netherlands, December 19, 2006 (received for review July 17, 2006)

Abstract

Relatively little is known about immune evasion during the productive phase of infection by the γ₁-herpesvirus Epstein–Barr virus (EBV). The use of a unique system to isolate cells in lytic cycle allowed us to identify a host shutoff function operating in productively EBV-infected B cells. This impairment of protein synthesis results from mRNA degradation induced upon expression of the early lytic-cycle gene product BGLF5. Recently, a γ₂-herpesvirus, Kaposi sarcoma herpesvirus, has also been shown to encode a host shutoff function, indicating that host shutoff appears to be a general feature of γ-herpesviruses. One of the consequences of host shutoff is a block in the synthesis of HLA class I and II molecules, reflected by reduced levels of these antigen-presenting complexes at the surface of cells in EBV lytic cycle. This effect could lead to escape from T cell recognition and elimination of EBV-producing cells, thereby allowing generation of viral progeny in the face of memory T cell responses.

Footnotes

^‖To whom correspondence should be addressed. E-mail: wiertz{at}lumc.nl
Author contributions: M.R., B.G., and D.v.L. contributed equally to this work; M.R., B.G., D.G., E.J.H.J.W., and M.E.R. designed research; M.R., B.G., D.v.L., J.Z., D.S., and M.E.R. performed research; J.M. contributed new reagents/analytic tools; M.R., B.G., D.v.L., J.Z., D.G., E.J.H.J.W., and M.E.R. analyzed data; and M.R., B.G., E.J.H.J.W., and M.E.R. wrote the paper.
↵ ^‡Present address: Department of Plant and Microbial Biology, 111 Koshland Hall, University of California, Berkeley, CA 94720.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0611128104/DC1.
Abbreviations:

KSHV,

Kaposi sarcoma-associated herpesvirus;

PAA,

phosphonoacetic acid;

vhs,

virion host shutoff;

Ct,

cycle threshold;

AE,

alkaline exonuclease;

HSV-1,

herpes simplex virus 1;

CTL,

cytotoxic T lymphocyte;

TAP,

transporter associated with antigen processing.