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Journal of Virology, August 2004, p. 8468-8476, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8468-8476.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Development of a DNA Vaccine Targeting Human Papillomavirus Type 16 Oncoprotein E6

Shiwen Peng,1 Hongxiu Ji,1 Cornelia Trimble,2,3 Liangmei He,1 Ya-Chea Tsai,1 Jessica Yeatermeyer,1 David A. K. Boyd,1 Chien-Fu Hung,1,2 and T.-C. Wu1,2,3,4*

Departments of Pathology,1 Oncology,2 Obstetrics and Gynecology,3 Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, Maryland 212874

Received 10 February 2004/ Accepted 7 April 2004

Human papillomavirus (HPV), particularly type 16 (HPV-16), is present in more than 99% of cervical cancers. The HPV oncoproteins E6 and E7 are constantly expressed and therefore represent ideal targets for HPV vaccine development. We previously developed DNA vaccines encoding calreticulin (CRT) linked to HPV-16 E7 and generated potent E7-specific CD8+ T-cell immune responses and antitumor effects against an E7-expressing tumor. Since vaccines targeting E6 also represent an important strategy for controlling HPV-associated lesions, we developed a DNA vaccine encoding CRT linked to E6 (CRT/E6). Our results indicated that the CRT/E6 DNA vaccine, but not a wild-type E6 DNA vaccine, generated significant E6-specific CD8+ T-cell immune responses in vaccinated mice. Mapping of the immunodominant epitope of E6 revealed that an E6 peptide comprising amino acids (aa) 48 to 57 (E6 aa48-57), presented by H-2Kb, is the optimal peptide and that the region of E6 comprising aa 50 to 57 represents the minimal core sequence required for activating E6-specific CD8+ T lymphocytes. We also demonstrated that E6 aa48-57 contains cytotoxic T-lymphocyte epitopes naturally presented by E6-expressing TC-1 cells. Vaccination with a CRT/E6 but not a CRT/mtE6 (lacking aa 50 to 57 of E6) DNA vaccine could protect vaccinated mice from challenge with E6-expressing TC-1 tumors. Thus, our data indicate that E6 aa48-57 contains the immunodominant epitope and that a CRT/E6 DNA vaccine may be useful for control of HPV infection and HPV-associated lesions.

* Corresponding author. Mailing address: Department of Pathology, Johns Hopkins University School of Medicine, Ross 512H, 720 Rutland Ave., Baltimore, MD 21205. Phone: (410) 614-3899. Fax: (443) 287-4295. E-mail: wutc{at}jhmi.edu.

Journal of Virology, August 2004, p. 8468-8476, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8468-8476.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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