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Journal of Virology, April 2003, p. 4635-4645, Vol. 77, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.8.4635-4645.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Human Papillomavirus Type 16 L1 Capsomeres Induce L1-Specific Cytotoxic T Lymphocytes and Tumor Regression in C57BL/6 Mice{dagger}

Peter Öhlschläger,1 Wolfram Osen,1 Kerstin Dell,1 Stefan Faath,1,{ddagger} Robert L. Garcea,2 Ingrid Jochmus,1,{ddagger} Martin Müller,1 Michael Pawlita,1 Klaus Schäfer,1,§ Peter Sehr,1 Caroline Staib,3 Gerd Sutter,3 and Lutz Gissmann1*

Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, D-69120 Heidelberg,1 GSF-Institut für Molekulare Virologie, D-81675 Munich, Germany,3 Section of Pediatric Hematology/Oncology, University of Colorado School of Medicine, Denver, Colorado 802622

Received 4 November 2002/ Accepted 22 January 2003

We analyzed capsomeres of human papillomavirus type 16 (HPV16) consisting of the L1 major structural protein for their ability to trigger a cytotoxic T-cell (CTL) response. To this end, we immunized C57BL/6 mice and used the L1165-173 peptide for ex vivo restimulation of splenocytes prior to analysis (51Cr release assay and enzyme-linked immunospot assay [ELISPOT]). This peptide was identified in this study as a Db-restricted naturally processed CTL epitope by HPV16 L1 sequence analysis, major histocompatibility complex class I binding, and 51Cr release assays following immunization of C57BL/6 mice with HPV16 L1 virus-like particles (VLPs). HPV16 L1 capsomeres were obtained by purification of HPV16 L1 lacking 10 N-terminal amino acids after expression in Escherichia coli as a glutathione S-transferase fusion protein (GST-HPV16 L1{Delta}N10). Sedimentation analysis revealed that the majority of the purified protein consisted of pentameric capsomeres, and assembled particles were not observed in minor contaminating higher-molecular-weight material. Subcutaneous (s.c.) as well as intranasal immunization of C57BL/6 mice with HPV16 L1 capsomeres triggered an L1-specific CTL response in a dose-dependent manner as measured by ELISPOT and 51Cr release assay. Significant reduction of contaminating bacterial endotoxin (lipopolysaccharide) from the capsomere preparation did not diminish the immunogenicity. Antibody responses (serum and vaginal) were less robust under the experimental conditions employed. In addition, s.c. vaccination with HPV16 L1 capsomeres induced regression of established tumors expressing L1 determinants (C3 tumor cells). Our data demonstrate that capsomeres are potent inducers of CTL responses similar to completely assembled T=7 VLPs. This result is of potential relevance for the development of (combined prophylactic and therapeutic) HPV-specific vaccines, since capsomeres can be produced easily and also can be modified to incorporate heterologous sequences such as early HPV proteins.

* Corresponding author. Mailing address: Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, D-69120 Heidelberg, Germany. Phone: 49-6221-424603. Fax: 49-6221-42524603. E-mail: l.gissmann{at}dkfz.de.

{dagger} This work is dedicated to Harold zur Hausen in gratitude for his constant support of our research.

{ddagger} Present address: MediGene AG, D-82152 Martinsried, Germany.

{ddagger} Present address: MediGene AG, D-82152 Martinsried, Germany.

§ Present address: MediGene AG, D-82152 Martinsried, Germany.

Journal of Virology, April 2003, p. 4635-4645, Vol. 77, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.8.4635-4645.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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