TY - JOUR
T1 - Impact of inhibitors and L2 antibodies upon the infectivity of diverse alpha and beta human papillomavirus types
AU - Kwak, Kihyuck
AU - Jiang, Rosie
AU - Wang, Joshua W.
AU - Jagu, Subhashini
AU - Kirnbauer, Reinhard
AU - Roden, Richard B.S.
N1 - Funding Information:
This study was partly funded by Sanofi Pasteur. Subhashini Jagu and Richard Roden are co-inventors on L2 patents (20090047301 Papillomavirus L2 N-Terminal Peptides for the Induction of Broadly Cross-Neutralizing Antibodies and 20100297144 MULTITYPE HPV PEPTIDE COMPOSITIONS AND METHODS FOR TREATMENT OR PREVENTION OF HUMAN PAPILLOMAVIRUS INFECTION), licensed to Shantha Biotechnics Ltd., GlaxoSmithKline, PaxVax, Inc., and Acambis, Inc., and have received research funding from Shantha Biotechnics Ltd., Sanofi Pasteur and GlaxoSmithKline. Richard Roden is a founder of Papivax LLC. The terms of these arrangements are managed by Johns Hopkins University in accordance with its conflict of interest policies. Reinhard Kirnbauer is a co-inventor on patent (7,361,356 Self-assembling recombinant papillomavirus capsid proteins), licensed to GlaxoSmithKline (GSK) and Merck (MSD). This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
PY - 2014/5/9
Y1 - 2014/5/9
N2 - The licensed human papillomavirus (HPV) vaccines elicit type-restricted immunity but do not target cutaneous HPV types of the beta genus that are associated with non-melanoma skin cancer in immune-compromised patients, and it is unclear if these diverse types share a common mechanism of infection. Residues 11-88 of minor capsid protein L2 contain cross-protective epitopes, and vaccination with concatamers of this region derived from as many as eight alpha HPV (L2 α11-88x8) is being developed as an alternative prophylactic vaccine with potentially broader efficacy. There is also interest in developing broadly protective topical microbicides, such as carrageenan or heparin that block HPV receptor interactions, or small molecule inhibitors of infection. Here we have examined several inhibitors of HPV infection and antisera to L2 α11-88x8 for their breadth of activity against infection by 34 HPV types from within both the alpha and beta families using pseudovirions (PsV) carrying a luciferase reporter as surrogates for native virus. We observed that both heparin and carrageenan prevented infection by mucosatropic HPV types, but surprisingly PsV of several epidermotropic alpha4 and beta HPV types exhibited increased infectivity especially at low inhibitor concentrations. Furin and γ-secretase inhibitors and L2 α11-88x8 antiserum blocked infection by all HPV PsV types tested. These findings suggest that the distinct tropism of mucosal and cutaneous HPV may reflect distinct cell surface receptor interactions, but a common uptake mechanism dependent upon furin and γ-secretase proteolytic activities. Carrageenan, which is being tested as a vaginal microbicide, broadly inhibited infection by the high-risk mucosatropic HPV PsV, but not most skin tropic alpha and beta HPV. Vaccination with an L2 multimer derived exclusively from alpha papillomavirus sequences induced antibodies that broadly neutralized PsV of all 34 HPVs from within both the alpha and beta families, suggesting each displays conserved L2 neutralizing epitopes.
AB - The licensed human papillomavirus (HPV) vaccines elicit type-restricted immunity but do not target cutaneous HPV types of the beta genus that are associated with non-melanoma skin cancer in immune-compromised patients, and it is unclear if these diverse types share a common mechanism of infection. Residues 11-88 of minor capsid protein L2 contain cross-protective epitopes, and vaccination with concatamers of this region derived from as many as eight alpha HPV (L2 α11-88x8) is being developed as an alternative prophylactic vaccine with potentially broader efficacy. There is also interest in developing broadly protective topical microbicides, such as carrageenan or heparin that block HPV receptor interactions, or small molecule inhibitors of infection. Here we have examined several inhibitors of HPV infection and antisera to L2 α11-88x8 for their breadth of activity against infection by 34 HPV types from within both the alpha and beta families using pseudovirions (PsV) carrying a luciferase reporter as surrogates for native virus. We observed that both heparin and carrageenan prevented infection by mucosatropic HPV types, but surprisingly PsV of several epidermotropic alpha4 and beta HPV types exhibited increased infectivity especially at low inhibitor concentrations. Furin and γ-secretase inhibitors and L2 α11-88x8 antiserum blocked infection by all HPV PsV types tested. These findings suggest that the distinct tropism of mucosal and cutaneous HPV may reflect distinct cell surface receptor interactions, but a common uptake mechanism dependent upon furin and γ-secretase proteolytic activities. Carrageenan, which is being tested as a vaginal microbicide, broadly inhibited infection by the high-risk mucosatropic HPV PsV, but not most skin tropic alpha and beta HPV. Vaccination with an L2 multimer derived exclusively from alpha papillomavirus sequences induced antibodies that broadly neutralized PsV of all 34 HPVs from within both the alpha and beta families, suggesting each displays conserved L2 neutralizing epitopes.
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U2 - 10.1371/journal.pone.0097232
DO - 10.1371/journal.pone.0097232
M3 - Article
C2 - 24816794
AN - SCOPUS:84901196608
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 5
M1 - e97232
ER -