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Journal of Virology, April 2003, p. 4306-4314, Vol. 77, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.7.4306-4314.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus Cytotoxic T Lymphocytes Recognize and Target Darwinian Positively Selected Autologous K1 Epitopes

Justin Stebbing,1,2 Dimitra Bourboulia,1 Margaret Johnson,3 Stephen Henderson,1 Ian Williams,4 Natalie Wilder,1 Mervyn Tyrer,3 Mike Youle,3 Nesrina Imami,2 Toru Kobu,2 Wolfgang Kuon,5 Joachim Sieper,5 Frances Gotch,2 and Chris Boshoff1*

Cancer Research U.K. Viral Oncology Group, The Wolfson Institute for Biomedical Research,1 Ian Charleson Centre,3 Department of Sexually Transmitted Diseases, The Royal Free and University College Medical Schools, University College London,4 Department of Immunology, Imperial College of Science, Technology and Medicine, London, United Kingdom,2 Medical Department, Klinikum Benjamin Franklin, Freie Universität Berlin, Berlin, Germany5

Received 15 August 2002/ Accepted 3 January 2003

Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of Kaposi's sarcoma (KS) and certain lymphoproliferations particularly in the context of human immunodeficiency virus (HIV) type 1-induced immunosuppression. The introduction of effective therapies to treat HIV has led to a decline in the incidence of KS, suggesting that immune responses may play a role in controlling KSHV infection and pathogenesis. Cytotoxic-T-lymphocyte (CTL) activity against KSHV proteins has been demonstrated; however, the identification of KSHV CTL epitopes remains elusive and problematic. Although the herpesvirus genomic layout is generally conserved, KSHV encodes a unique hypervariable protein, K1, with intense biological selection pressure at specific amino acid sites. To investigate whether this variability is partly driven by cellular immunity, we designed K1 peptides that match only the unique viral sequence for every individual studied here (autologous peptides). We identified functional CTL epitopes within K1's most variable areas, and we show that a given individual responds only to autologous peptides and not to peptides from other individuals. Furthermore, these epitopes are highly conserved sequences within KSHV isolates from a specific strain but are not conserved between different strains. We conclude that CTL recognition contributes to K1, and therefore to KSHV, evolution.

* Corresponding author. Mailing address: The Wolfson Institute for Biomedical Research, University College London, Gower St., London WC1E 6BT, United Kingdom. Phone: 44 20 7679 6850. Fax: 44 20 7679 6851. E-mail: c.boshoff{at}ucl.ac.uk.

Journal of Virology, April 2003, p. 4306-4314, Vol. 77, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.7.4306-4314.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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