Human monoclonal antibodies to a novel cluster of conformational epitopes on HCV E2 with resistance to neutralization escape in a genotype 2a isolate.
The majority of broadly neutralizing antibodies to hepatitis C virus (HCV) are against conformational epitopes on the E2 glycoprotein. Many of them recognize overlapping epitopes in a cluster, designated as antigenic domain B, that contains residues G530 and D535. To gain information on other region...
Guardado en:
| Autores principales: | , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2012
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/99cea68e1d0a41cb97e0e5cda0258469 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:99cea68e1d0a41cb97e0e5cda0258469 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:99cea68e1d0a41cb97e0e5cda02584692021-11-18T06:04:31ZHuman monoclonal antibodies to a novel cluster of conformational epitopes on HCV E2 with resistance to neutralization escape in a genotype 2a isolate.1553-73661553-737410.1371/journal.ppat.1002653https://doaj.org/article/99cea68e1d0a41cb97e0e5cda02584692012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22511875/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The majority of broadly neutralizing antibodies to hepatitis C virus (HCV) are against conformational epitopes on the E2 glycoprotein. Many of them recognize overlapping epitopes in a cluster, designated as antigenic domain B, that contains residues G530 and D535. To gain information on other regions that will be relevant for vaccine design, we employed yeast surface display of antibodies that bound to genotype 1a H77C E2 mutant proteins containing a substitution either at Y632A (to avoid selecting non-neutralizing antibodies) or D535A. A panel of nine human monoclonal antibodies (HMAbs) was isolated and designated as HC-84-related antibodies. Each HMAb neutralized cell culture infectious HCV (HCVcc) with genotypes 1-6 envelope proteins with varying profiles, and each inhibited E2 binding to the viral receptor CD81. Five of these antibodies neutralized representative genotypes 1-6 HCVcc. Epitope mapping identified a cluster of overlapping epitopes that included nine contact residues in two E2 regions encompassing aa418-446 and aa611-616. Effect on virus entry was measured using H77C HCV retroviral pseudoparticles, HCVpp, bearing an alanine substitution at each of the contact residues. Seven of ten mutant HCVpp showed over 90% reduction compared to wild-type HCVpp and two others showed approximately 80% reduction. Interestingly, four of these antibodies bound to a linear E2 synthetic peptide encompassing aa434-446. This region on E2 has been proposed to elicit non-neutralizing antibodies in humans that interfere with neutralizing antibodies directed at an adjacent E2 region from aa410-425. The isolation of four HC-84 HMAbs binding to the peptide, aa434-446, proves that some antibodies to this region are to highly conserved epitopes mediating broad virus neutralization. Indeed, when HCVcc were passaged in the presence of each of these antibodies, virus escape was not observed. Thus, the cluster of HC-84 epitopes, designated as antigenic domain D, is relevant for vaccine design for this highly diverse virus.Zhen-yong KeckJinming XiaYong WangWenyan WangThomas KreyJannick PrentoeThomas CarlsenAngela Ying-Jian LiArvind H PatelStanley M LemonJens BukhFelix A ReySteven K H FoungPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 8, Iss 4, p e1002653 (2012) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Zhen-yong Keck Jinming Xia Yong Wang Wenyan Wang Thomas Krey Jannick Prentoe Thomas Carlsen Angela Ying-Jian Li Arvind H Patel Stanley M Lemon Jens Bukh Felix A Rey Steven K H Foung Human monoclonal antibodies to a novel cluster of conformational epitopes on HCV E2 with resistance to neutralization escape in a genotype 2a isolate. |
| description |
The majority of broadly neutralizing antibodies to hepatitis C virus (HCV) are against conformational epitopes on the E2 glycoprotein. Many of them recognize overlapping epitopes in a cluster, designated as antigenic domain B, that contains residues G530 and D535. To gain information on other regions that will be relevant for vaccine design, we employed yeast surface display of antibodies that bound to genotype 1a H77C E2 mutant proteins containing a substitution either at Y632A (to avoid selecting non-neutralizing antibodies) or D535A. A panel of nine human monoclonal antibodies (HMAbs) was isolated and designated as HC-84-related antibodies. Each HMAb neutralized cell culture infectious HCV (HCVcc) with genotypes 1-6 envelope proteins with varying profiles, and each inhibited E2 binding to the viral receptor CD81. Five of these antibodies neutralized representative genotypes 1-6 HCVcc. Epitope mapping identified a cluster of overlapping epitopes that included nine contact residues in two E2 regions encompassing aa418-446 and aa611-616. Effect on virus entry was measured using H77C HCV retroviral pseudoparticles, HCVpp, bearing an alanine substitution at each of the contact residues. Seven of ten mutant HCVpp showed over 90% reduction compared to wild-type HCVpp and two others showed approximately 80% reduction. Interestingly, four of these antibodies bound to a linear E2 synthetic peptide encompassing aa434-446. This region on E2 has been proposed to elicit non-neutralizing antibodies in humans that interfere with neutralizing antibodies directed at an adjacent E2 region from aa410-425. The isolation of four HC-84 HMAbs binding to the peptide, aa434-446, proves that some antibodies to this region are to highly conserved epitopes mediating broad virus neutralization. Indeed, when HCVcc were passaged in the presence of each of these antibodies, virus escape was not observed. Thus, the cluster of HC-84 epitopes, designated as antigenic domain D, is relevant for vaccine design for this highly diverse virus. |
| format |
article |
| author |
Zhen-yong Keck Jinming Xia Yong Wang Wenyan Wang Thomas Krey Jannick Prentoe Thomas Carlsen Angela Ying-Jian Li Arvind H Patel Stanley M Lemon Jens Bukh Felix A Rey Steven K H Foung |
| author_facet |
Zhen-yong Keck Jinming Xia Yong Wang Wenyan Wang Thomas Krey Jannick Prentoe Thomas Carlsen Angela Ying-Jian Li Arvind H Patel Stanley M Lemon Jens Bukh Felix A Rey Steven K H Foung |
| author_sort |
Zhen-yong Keck |
| title |
Human monoclonal antibodies to a novel cluster of conformational epitopes on HCV E2 with resistance to neutralization escape in a genotype 2a isolate. |
| title_short |
Human monoclonal antibodies to a novel cluster of conformational epitopes on HCV E2 with resistance to neutralization escape in a genotype 2a isolate. |
| title_full |
Human monoclonal antibodies to a novel cluster of conformational epitopes on HCV E2 with resistance to neutralization escape in a genotype 2a isolate. |
| title_fullStr |
Human monoclonal antibodies to a novel cluster of conformational epitopes on HCV E2 with resistance to neutralization escape in a genotype 2a isolate. |
| title_full_unstemmed |
Human monoclonal antibodies to a novel cluster of conformational epitopes on HCV E2 with resistance to neutralization escape in a genotype 2a isolate. |
| title_sort |
human monoclonal antibodies to a novel cluster of conformational epitopes on hcv e2 with resistance to neutralization escape in a genotype 2a isolate. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/99cea68e1d0a41cb97e0e5cda0258469 |
| work_keys_str_mv |
AT zhenyongkeck humanmonoclonalantibodiestoanovelclusterofconformationalepitopesonhcve2withresistancetoneutralizationescapeinagenotype2aisolate AT jinmingxia humanmonoclonalantibodiestoanovelclusterofconformationalepitopesonhcve2withresistancetoneutralizationescapeinagenotype2aisolate AT yongwang humanmonoclonalantibodiestoanovelclusterofconformationalepitopesonhcve2withresistancetoneutralizationescapeinagenotype2aisolate AT wenyanwang humanmonoclonalantibodiestoanovelclusterofconformationalepitopesonhcve2withresistancetoneutralizationescapeinagenotype2aisolate AT thomaskrey humanmonoclonalantibodiestoanovelclusterofconformationalepitopesonhcve2withresistancetoneutralizationescapeinagenotype2aisolate AT jannickprentoe humanmonoclonalantibodiestoanovelclusterofconformationalepitopesonhcve2withresistancetoneutralizationescapeinagenotype2aisolate AT thomascarlsen humanmonoclonalantibodiestoanovelclusterofconformationalepitopesonhcve2withresistancetoneutralizationescapeinagenotype2aisolate AT angelayingjianli humanmonoclonalantibodiestoanovelclusterofconformationalepitopesonhcve2withresistancetoneutralizationescapeinagenotype2aisolate AT arvindhpatel humanmonoclonalantibodiestoanovelclusterofconformationalepitopesonhcve2withresistancetoneutralizationescapeinagenotype2aisolate AT stanleymlemon humanmonoclonalantibodiestoanovelclusterofconformationalepitopesonhcve2withresistancetoneutralizationescapeinagenotype2aisolate AT jensbukh humanmonoclonalantibodiestoanovelclusterofconformationalepitopesonhcve2withresistancetoneutralizationescapeinagenotype2aisolate AT felixarey humanmonoclonalantibodiestoanovelclusterofconformationalepitopesonhcve2withresistancetoneutralizationescapeinagenotype2aisolate AT stevenkhfoung humanmonoclonalantibodiestoanovelclusterofconformationalepitopesonhcve2withresistancetoneutralizationescapeinagenotype2aisolate |
| _version_ |
1718424620117262336 |