Abstract
BackgroundVirus-like particles (VLPs) formed by the human papillomavirus (HPV) L1 capsid protein are currently being tested in clinical trials as prophylactic vaccines against genital warts and cervical cancer. The efficacy of these vaccines is critically dependent upon L1 type-specific conformational epitopes. To investigate the molecular determinants of the HPV16 L1 conformational epitope recognized by monoclonal antibody 16A, we utilized a domain-swapping approach to generate a series of L1 proteins composed of a canine oral papillomavirus (COPV) L1 backbone containing different regions of HPV16 L1.ResultsGross domain swaps, which did not alter the ability of L1 to assemble into VLPs, demonstrated that the L1 N-terminus encodes at least a component of the 16A antigenic determinant. Finer epitope mapping, using GST-L1 fusion proteins, mapped the 16A epitope to the L1 variable regions I and possibly II within the N-terminus.ConclusionsThese results suggest that non-contiguous loop regions of L1 display critical components of a type-specific, conformational epitope.
Highlights
Virus-like particles (VLPs) formed by the human papillomavirus (HPV) L1 capsid protein are currently being tested in clinical trials as prophylactic vaccines against genital warts and cervical cancer
The monoclonal antibody 16A is strongly immunoreactive with intact HPV16 L1 VLPs, but is non-reactive with either denatured HPV16 L1 protein or with intact canine oral papillomavirus (COPV) L1 VLPs, demonstrating that 16A recognizes a conformationdependent epitope presented on the surface of intact HPV16 VLPs. 16A does not react with HPV18, HPV11 or HPV6 VLPs
To evaluate the role of various L1 domains in conformational epitope formation, chimeric L1 proteins expressed in Sf9 cells were tested by immunofluoresence microscopy using the HPV16 L1-specific, conformation-dependent monoclonal antibody 16A (Figure 2d)
Summary
Virus-like particles (VLPs) formed by the human papillomavirus (HPV) L1 capsid protein are currently being tested in clinical trials as prophylactic vaccines against genital warts and cervical cancer. The efficacy of these vaccines is critically dependent upon L1 type-specific conformational epitopes. Serological studies of papillomavirus virus like particles (VLPs) demonstrate that antibodies cross-reactive with multiple HPV VLP types recognize type-common epitopes and generally are not neutralizing This has been shown with both monoclonal antibodies and with polyclonal sera [14,15,16,17,18,19,20]. This suggests that different papillomavirus genotypes may represent different serotypes and that (page number not for citation purposes)
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