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Journal of Virology, May 2003, p. 5226-5240, Vol. 77, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.9.5226-5240.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Ex Vivo Profiling of CD8+-T-Cell Responses to Human Cytomegalovirus Reveals Broad and Multispecific Reactivities in Healthy Virus Carriers

Rebecca Elkington, Susan Walker, Tania Crough, Moira Menzies, Judy Tellam, Mandvi Bharadwaj, and Rajiv Khanna*

Tumour Immunology Laboratory and Co-Operative Centre for Vaccine Technology, Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, and Joint Oncology Program, Department of Molecular and Cellular Pathology, University of Queensland, Brisbane, Queensland 4029, Australia

Received 19 September 2002/ Accepted 5 February 2003

Human cytomegalovirus (HCMV) can establish both nonproductive (latent) and productive (lytic) infections. Many of the proteins expressed during these phases of infection could be expected to be targets of the immune response; however, much of our understanding of the CD8+-T-cell response to HCMV is mainly based on the pp65 antigen. Very little is known about T-cell control over other antigens expressed during the different stages of virus infection; this imbalance in our understanding undermines the importance of these antigens in several aspects of HCMV disease pathogenesis. In the present study, an efficient and rapid strategy based on predictive bioinformatics and ex vivo functional T-cell assays was adopted to profile CD8+-T-cell responses to a large panel of HCMV antigens expressed during different phases of replication. These studies revealed that CD8+-T-cell responses to HCMV often contained multiple antigen-specific reactivities, which were not just constrained to the previously identified pp65 or IE-1 antigens. Unexpectedly, a number of viral proteins including structural, early/late antigens and HCMV-encoded immunomodulators (pp28, pp50, gH, gB, US2, US3, US6, and UL18) were also identified as potential targets for HCMV-specific CD8+-T-cell immunity. Based on this extensive analysis, numerous novel HCMV peptide epitopes and their HLA-restricting determinants recognized by these T cells have been defined. These observations contrast with previous findings that viral interference with the antigen-processing pathway during lytic infection would render immediate-early and early/late proteins less immunogenic. This work strongly suggests that successful HCMV-specific immune control in healthy virus carriers is dependent on a strong T-cell response towards a broad repertoire of antigens.

* Corresponding author. Mailing address: Tumor Immunology Laboratory, Division of Infectious Diseases, Queensland Institute Medical Research, 300 Herston Rd., Herston (Qld) 4006, Australia. Phone: 61-7-3362 0385. Fax: 61-7-3845 3510. E-mail: rajivK{at}qimr.edu.au.

Journal of Virology, May 2003, p. 5226-5240, Vol. 77, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.9.5226-5240.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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