Impact of Naturally Occurring Variation in the Human Papillomavirus 58 Capsid Proteins on Recognition by Type-Specific Neutralizing Antibodies

Background. Naturally occurring variants of human papillomavirus (HPV) 58 have been defined as lineages and sublineages but little is known about the impact of this diversity on protein function. We investigated the impact of variation within the major (L1) and minor (L2) capsid proteins of HPV58 on susceptibility to neutralizing antibodies. Methods. Pseudovirus (PsV) representing A1, A2, A3, B1, B2, C, D1, and D2 variants were evaluated for their susceptibility to antibodies elicited during natural infection, preclinical antisera generated against virus-like particles, and monoclonal antibodies (MAbs). Results. Lineage C PsV demonstrated a decreased sensitivity to antibodies raised against lineage A antigens. Exchange of the DE, FG, and/or HI loops between sublineage A1 and lineage C demonstrated that residues within all 3 loops were essential for the differential sensitivity to natural infection antibodies, with slightly different requirements for the animal antisera and MAbs. Comparison between the HPV58 A1 L1 pentamer crystal structure and an HPV58 C homology model indicated that these differences in neutralization sensitivity were likely due to subtle epitope sequence changes rather that major structural alterations. Conclusions. These data improve our understanding of the impact of natural variation on HPV58 capsid antigenicity and raise the possibility of lineage-specific serotypes.