Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV.
Eliciting broadly neutralizing antibodies (bnAbs) targeting envelope (Env) is a major goal of HIV vaccine development, but cross-clade breadth from immunization has only sporadically been observed. Recently, Xu et al (2018) elicited cross-reactive neutralizing antibody responses in a variety of anim...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2018-07-01
|
| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC6049957?pdf=render |
| _version_ | 1818175937348370432 |
|---|---|
| author | Adam S Dingens Priyamvada Acharya Hugh K Haddox Reda Rawi Kai Xu Gwo-Yu Chuang Hui Wei Baoshan Zhang John R Mascola Bridget Carragher Clinton S Potter Julie Overbaugh Peter D Kwong Jesse D Bloom |
| author_facet | Adam S Dingens Priyamvada Acharya Hugh K Haddox Reda Rawi Kai Xu Gwo-Yu Chuang Hui Wei Baoshan Zhang John R Mascola Bridget Carragher Clinton S Potter Julie Overbaugh Peter D Kwong Jesse D Bloom |
| author_sort | Adam S Dingens |
| collection | DOAJ |
| description | Eliciting broadly neutralizing antibodies (bnAbs) targeting envelope (Env) is a major goal of HIV vaccine development, but cross-clade breadth from immunization has only sporadically been observed. Recently, Xu et al (2018) elicited cross-reactive neutralizing antibody responses in a variety of animal models using immunogens based on the epitope of bnAb VRC34.01. The VRC34.01 antibody, which was elicited by natural human infection, targets the N terminus of the Env fusion peptide, a critical component of the virus entry machinery. Here we precisely characterize the functional epitopes of VRC34.01 and two vaccine-elicited murine antibodies by mapping all single amino-acid mutations to the BG505 Env that affect viral neutralization. While escape from VRC34.01 occurred via mutations in both fusion peptide and distal interacting sites of the Env trimer, escape from the vaccine-elicited antibodies was mediated predominantly by mutations in the fusion peptide. Cryo-electron microscopy of four vaccine-elicited antibodies in complex with Env trimer revealed focused recognition of the fusion peptide and provided a structural basis for development of neutralization breadth. Together, these functional and structural data suggest that the breadth of vaccine-elicited antibodies targeting the fusion peptide can be enhanced by specific interactions with additional portions of Env. Thus, our complete maps of viral escape both delineate pathways of resistance to these fusion peptide-directed antibodies and provide a strategy to improve the breadth or potency of future vaccine-induced antibodies against Env's fusion peptide. |
| first_indexed | 2024-12-11T20:08:14Z |
| format | Article |
| id | doaj.art-7396244872b54dd7b3e97ee5bf534f38 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-11T20:08:14Z |
| publishDate | 2018-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-7396244872b54dd7b3e97ee5bf534f382022-12-22T00:52:21ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742018-07-01147e100715910.1371/journal.ppat.1007159Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV.Adam S DingensPriyamvada AcharyaHugh K HaddoxReda RawiKai XuGwo-Yu ChuangHui WeiBaoshan ZhangJohn R MascolaBridget CarragherClinton S PotterJulie OverbaughPeter D KwongJesse D BloomEliciting broadly neutralizing antibodies (bnAbs) targeting envelope (Env) is a major goal of HIV vaccine development, but cross-clade breadth from immunization has only sporadically been observed. Recently, Xu et al (2018) elicited cross-reactive neutralizing antibody responses in a variety of animal models using immunogens based on the epitope of bnAb VRC34.01. The VRC34.01 antibody, which was elicited by natural human infection, targets the N terminus of the Env fusion peptide, a critical component of the virus entry machinery. Here we precisely characterize the functional epitopes of VRC34.01 and two vaccine-elicited murine antibodies by mapping all single amino-acid mutations to the BG505 Env that affect viral neutralization. While escape from VRC34.01 occurred via mutations in both fusion peptide and distal interacting sites of the Env trimer, escape from the vaccine-elicited antibodies was mediated predominantly by mutations in the fusion peptide. Cryo-electron microscopy of four vaccine-elicited antibodies in complex with Env trimer revealed focused recognition of the fusion peptide and provided a structural basis for development of neutralization breadth. Together, these functional and structural data suggest that the breadth of vaccine-elicited antibodies targeting the fusion peptide can be enhanced by specific interactions with additional portions of Env. Thus, our complete maps of viral escape both delineate pathways of resistance to these fusion peptide-directed antibodies and provide a strategy to improve the breadth or potency of future vaccine-induced antibodies against Env's fusion peptide.http://europepmc.org/articles/PMC6049957?pdf=render |
| spellingShingle | Adam S Dingens Priyamvada Acharya Hugh K Haddox Reda Rawi Kai Xu Gwo-Yu Chuang Hui Wei Baoshan Zhang John R Mascola Bridget Carragher Clinton S Potter Julie Overbaugh Peter D Kwong Jesse D Bloom Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV. PLoS Pathogens |
| title | Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV. |
| title_full | Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV. |
| title_fullStr | Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV. |
| title_full_unstemmed | Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV. |
| title_short | Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV. |
| title_sort | complete functional mapping of infection and vaccine elicited antibodies against the fusion peptide of hiv |
| url | http://europepmc.org/articles/PMC6049957?pdf=render |
| work_keys_str_mv | AT adamsdingens completefunctionalmappingofinfectionandvaccineelicitedantibodiesagainstthefusionpeptideofhiv AT priyamvadaacharya completefunctionalmappingofinfectionandvaccineelicitedantibodiesagainstthefusionpeptideofhiv AT hughkhaddox completefunctionalmappingofinfectionandvaccineelicitedantibodiesagainstthefusionpeptideofhiv AT redarawi completefunctionalmappingofinfectionandvaccineelicitedantibodiesagainstthefusionpeptideofhiv AT kaixu completefunctionalmappingofinfectionandvaccineelicitedantibodiesagainstthefusionpeptideofhiv AT gwoyuchuang completefunctionalmappingofinfectionandvaccineelicitedantibodiesagainstthefusionpeptideofhiv AT huiwei completefunctionalmappingofinfectionandvaccineelicitedantibodiesagainstthefusionpeptideofhiv AT baoshanzhang completefunctionalmappingofinfectionandvaccineelicitedantibodiesagainstthefusionpeptideofhiv AT johnrmascola completefunctionalmappingofinfectionandvaccineelicitedantibodiesagainstthefusionpeptideofhiv AT bridgetcarragher completefunctionalmappingofinfectionandvaccineelicitedantibodiesagainstthefusionpeptideofhiv AT clintonspotter completefunctionalmappingofinfectionandvaccineelicitedantibodiesagainstthefusionpeptideofhiv AT julieoverbaugh completefunctionalmappingofinfectionandvaccineelicitedantibodiesagainstthefusionpeptideofhiv AT peterdkwong completefunctionalmappingofinfectionandvaccineelicitedantibodiesagainstthefusionpeptideofhiv AT jessedbloom completefunctionalmappingofinfectionandvaccineelicitedantibodiesagainstthefusionpeptideofhiv |