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Journal of Virology, January 2004, p. 768-778, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.768-778.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Dual Stimulation of Epstein-Barr Virus (EBV)-Specific CD4+- and CD8+-T-Cell Responses by a Chimeric Antigen Construct: Potential Therapeutic Vaccine for EBV-Positive Nasopharyngeal Carcinoma

G. S. Taylor, T. A. Haigh,{dagger} N. H. Gudgeon, R. J. Phelps, S. P. Lee, N. M. Steven, and A. B. Rickinson*

CRUK Institute for Cancer Studies and MRC Centre for Immune Regulation, University of Birmingham, Birmingham B15 2TT, United Kingdom

Received 4 August 2003/ Accepted 30 September 2003

Virus-associated malignancies are potential targets for immunotherapeutic vaccines aiming to stimulate T-cell responses against viral antigens expressed in tumor cells. Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma, a high-incidence tumor in southern China, expresses a limited set of EBV proteins, including the nuclear antigen EBNA1, an abundant source of HLA class II-restricted CD4+ T-cell epitopes, and the latent membrane protein LMP2, a source of subdominant CD8+ T-cell epitopes presented by HLA class I alleles common in the Chinese population. We used appropriately modified gene sequences from a Chinese EBV strain to generate a modified vaccinia virus Ankara recombinant, MVA-EL, expressing the CD4 epitope-rich C-terminal domain of EBNA1 fused to full-length LMP2. The endogenously expressed fusion protein EL is efficiently processed via the HLA class I pathway, and MVA-EL-infected dendritic cells selectively reactivate LMP2-specific CD8+ memory T-cell responses from immune donors in vitro. Surprisingly, endogenously expressed EL also directly accesses the HLA class II presentation pathway and, unlike endogenously expressed EBNA1 itself, efficiently reactivates CD4+ memory T-cell responses in vitro. This unscheduled access to the HLA class II pathway is coincident with EL-mediated redirection of the EBNA1 domain from its native nuclear location to dense cytoplasmic patches. Given its immunogenicity to both CD4+ and CD8+ T cells, MVA-EL has potential as a therapeutic vaccine in the context of nasopharyngeal carcinoma.

* Corresponding author. Mailing address: CRUK Institute for Cancer Studies, The University of Birmingham, Vincent Dr., Edgbaston, Birmingham B15 2TT, United Kingdom. Phone: 44 121 414 4492. Fax: 44 121 414 4486. E-mail: A.B.Rickinson{at}bham.ac.uk.

{dagger} T.A.H. and N.H.G. contributed equally to this work.

Journal of Virology, January 2004, p. 768-778, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.768-778.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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