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Broadly Immunogenic HLA Class I Supertype-Restricted Elite CTL Epitopes Recognized in a Diverse Population Infected with Different HIV-1 Subtypes¹

Carina L. Pérez^*, Mette V. Larsen, Rasmus Gustafsson^*, Melissa M. Norström^*, Ann Atlas, Douglas F. Nixon, Morten Nielsen, Ole Lund and Annika C. Karlsson^2,*

^* Department of Microbiology, Cell Biology, and Tumor Biology, Karolinska Institutet, and The Swedish Institute of Infectious Disease Control, Stockholm, Sweden; Center for Biological Sequence Analysis, BioCentrum, Technical University of Denmark, Lyngby, Denmark; Department of Medicine Solna, Infectious Diseases Unit, Karolinska University Hospital, Stockholm, Sweden; and Department of Medicine, University of California, San Francisco, CA 94110

The genetic variations of the HIV-1 virus and its human host constitute major obstacles for obtaining potent HIV-1-specific CTL responses in individuals of diverse ethnic backgrounds infected with different HIV-1 variants. In this study, we developed and used a novel algorithm to select 184 predicted epitopes representing seven different HLA class I supertypes that together constitute a broad coverage of the different HIV-1 strains as well as the human HLA alleles. Of the tested 184 HLA class I-restricted epitopes, 114 were recognized by at least one study subject, and 45 were novel epitopes, not previously described in the HIV-1 immunology database. In addition, we identified 21 "elite" epitopes that induced CTL responses in at least 4 of the 31 patients. A majority (27 of 31) of the study population recognized one or more of these highly immunogenic epitopes. We also found a limited set of 9 epitopes that together induced HIV-1-specific CTL responses in all HIV-1-responsive patients in this study. Our results have important implications for the validation of potent CTL responses and show that the goal for a vaccine candidate in inducing broadly reactive CTL immune responses is attainable.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the Swedish Agency for International Development Cooperation (2005-001756), the Swedish Research Council (K2007-56X-20345-01-3), the Swedish Physicians against AIDS Research Foundation, and National Institutes of Health Grants R01 AI60379 and P01 AI71713 and contract HHSN266200400083C.

² Address correspondence and reprint requests to Dr. Annika C. Karlsson, Department of Virology, The Swedish Institute of Infectious Disease Control, SE-171 82 Solna, Sweden. E-mail address: annika.karlsson{at}smi.ki.se

³ Abbreviations used in this paper: CRF, circulating recombinant form; CEF, CMV, EBV, and flu; SEB, staphylococcal enterotoxin B; SFU, spot forming unit; IQR, interquartile range.

⁴ The online version of this article contains supplemental material.

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