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Journal of Virology, October 2006, p. 9772-9778, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.00564-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Persistent High Frequencies of Varicella-Zoster Virus ORF4 Protein-Specific CD4+ T Cells after Primary Infection

Louise Jones,1 Antony P. Black,1 Gathsaurie N. Malavige,1,3 and Graham S. Ogg1,2*

MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom,1 Department of Dermatology, Churchill Hospital, Oxford OX3 7LJ, United Kingdom,2 Department of Microbiology, Faculty of Medical Sciences, University of Sri Jayawardanapura, Nugegoda, Sri Lanka3

Received 17 March 2006/ Accepted 12 July 2006

Open reading frame 4 (ORF4) of varicella-zoster virus (VZV) encodes an immediate-early protein that is believed to be important for viral infectivity and establishing latency. Evidence suggests that VZV-specific T cells are crucial in the control of viral replication, but there are no data addressing the existence of potential ORF4 protein-specific CD4+ T cells. We tested the hypothesis that VZV ORF4 protein-specific CD4+ T cells could be identified and characterized within the peripheral blood of healthy immune donors following primary infection. Gamma interferon (IFN-{gamma}) immunosorbent assays were used to screen peripheral blood mononuclear cells obtained from healthy seropositive donors for responses to overlapping ORF4 peptides, viral lysate, and live vaccine. High frequencies of ORF4 protein-specific T cells were detected ex vivo in individuals up to 52 years after primary infection. Several immunogenic regions of the ORF4 protein were identified, including a commonly recognized epitope which was restricted through HLA-DRB1*07. Total ORF4 protein-specific responses comprised 19.7% and 20.7% of the total lysate and vaccine responses, respectively, and were dominated by CD4+ T cells. Indeed, CD4+ T cells were found to dominate the overall virus-specific IFN-{gamma} cellular immune response both ex vivo and after expansion in vitro. In summary, we have identified an ORF4 protein as a novel target antigen for persistent VZV-specific CD4+ T cells, with implications for disease pathogenesis and future vaccine development.

* Corresponding author. Mailing address: Cutaneous Immunology, Weatherall Institute of Molecular Medicine, Oxford OX3 9DS, United Kingdom. Phone: 44 1865 222334. Fax: 44 1865 222502. E-mail: graham.ogg{at}clinical-medicine.oxford.ac.uk.

Journal of Virology, October 2006, p. 9772-9778, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.00564-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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