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Impact of inhibitors and L2 antibodies upon the infectivity of diverse alpha and beta human papillomavirus types.

Kwak K, Jiang R, Wang JW, Jagu S, Kirnbauer R, Roden RB - PLoS ONE (2014)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, The Johns Hopkins University, Baltimore, Maryland, United States of America.

ABSTRACT
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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Impact of γ-secretase inhibitor on infection by PsV of diverse HPV.PsVs of each indicated HPV type carrying a luciferase reporter gene were transferred to 293TT cells for 72γ-secretase inhibitor XXI (n = 3). After incubation, luciferase activity was measured and percent inhibition of infectivity compared to control calculated. Red and blue bars represent mucosal and cutaneous HPV types, respectively.
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pone-0097232-g004: Impact of γ-secretase inhibitor on infection by PsV of diverse HPV.PsVs of each indicated HPV type carrying a luciferase reporter gene were transferred to 293TT cells for 72γ-secretase inhibitor XXI (n = 3). After incubation, luciferase activity was measured and percent inhibition of infectivity compared to control calculated. Red and blue bars represent mucosal and cutaneous HPV types, respectively.

Mentions: The γ-secretase inhibitor XXI potently blocks HPV16 infection, and homozygous deletion of γ-secretase component subunits nicastrin or presenilin-1 also prevents HPV16 infection [27]. To determine whether the need for γ-secretase function during infection is conserved across diverse HPV types, we examined the impact of 500 nM XXI upon infection of 293TT cells by each PsV types. The γ-secretase inhibitor XXI dramatically reduced the infectivity of the PsV of all 34 HPV types tested (Figure 4), implying that γ-secretase is a key cellular factor that diverse genotypes utilize during infection and its inhibition can broadly inhibit HPV infection [27], [28].


Impact of inhibitors and L2 antibodies upon the infectivity of diverse alpha and beta human papillomavirus types.

Kwak K, Jiang R, Wang JW, Jagu S, Kirnbauer R, Roden RB - PLoS ONE (2014)

Impact of γ-secretase inhibitor on infection by PsV of diverse HPV.PsVs of each indicated HPV type carrying a luciferase reporter gene were transferred to 293TT cells for 72γ-secretase inhibitor XXI (n = 3). After incubation, luciferase activity was measured and percent inhibition of infectivity compared to control calculated. Red and blue bars represent mucosal and cutaneous HPV types, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016295&req=5

pone-0097232-g004: Impact of γ-secretase inhibitor on infection by PsV of diverse HPV.PsVs of each indicated HPV type carrying a luciferase reporter gene were transferred to 293TT cells for 72γ-secretase inhibitor XXI (n = 3). After incubation, luciferase activity was measured and percent inhibition of infectivity compared to control calculated. Red and blue bars represent mucosal and cutaneous HPV types, respectively.
Mentions: The γ-secretase inhibitor XXI potently blocks HPV16 infection, and homozygous deletion of γ-secretase component subunits nicastrin or presenilin-1 also prevents HPV16 infection [27]. To determine whether the need for γ-secretase function during infection is conserved across diverse HPV types, we examined the impact of 500 nM XXI upon infection of 293TT cells by each PsV types. The γ-secretase inhibitor XXI dramatically reduced the infectivity of the PsV of all 34 HPV types tested (Figure 4), implying that γ-secretase is a key cellular factor that diverse genotypes utilize during infection and its inhibition can broadly inhibit HPV infection [27], [28].

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, The Johns Hopkins University, Baltimore, Maryland, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus