CHIMERIC PAPILLOMAVIRUS VIRUS-LIKE PARTICLES ELICIT ANTITUMOR IMMUNITY AGAINST THE E7 ONCOPROTEIN IN AN HPV16 TUMOR-MODEL

Papillomavirus-like particles (VLPs) are a promising prophylactic vacc ine candidate to prevent human papillomavirus (HPV) infections and ass ociated epithelial neoplasia, However, they are unlikely to have thera peutic effects because the virion capsid proteins are not detected in the proliferating cells of the infected epithelia or in cervical carci nomas, To increase the number of viral antigen targets for cell-mediat ed immune responses in VLP-based vaccine,,ve have generated stable chi meric VLPs consisting of the L1 major capsid protein plus the entire E 7 (11 kDa) or E2 (43 kDa) nonstructural papillomavirus protein fused t o the L2 minor capsid protein. The chimeric VLPs are indistinguishable from the parental VLPs in their morphology and in their ability to ag glutinate erythrocytes and elicit high titers of neutralizing antibodi es, Protection from tumor challenge was tested in C57BL/6 mice by usin g the tumor cell line TC-1, which expresses HPV16 E7, but not the viri on structural proteins, Injection of HPV16 L1/L2-HPV16 E7 chimeric VLP s, but not HPV16 L1/L2 VLPs, protected the mice from tumor challenge, even in the absence of adjuvant. The chimeric VLPs also induced protec tion against tumor challenge in major histocompatibility class II-defi cient mice, but not in beta(2)-microglobulin or perforin knockout mice implying that protection was mediated by class I-restricted cytotoxic lymphocytes, These findings raise the possibility that VLPs may gener ally be efficient vehicles for generating cell-mediated immune respons es and that, specifically, chimeric VLPs containing papillomavirus non structural proteins may increase the therapeutic potential of VLP-base d prophylactic vaccines in humans.