Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope
Abstract HIV-1 vaccine design aims to develop an immunogen that elicits broadly neutralizing antibodies against a desired epitope, while eliminating responses to off-target regions of HIV-1 Env. We report characterization of Ab1245, an off-target antibody against the Env gp120-gp41 interface, from V...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-10-01
|
| Series: | npj Vaccines |
| Online Access: | https://doi.org/10.1038/s41541-021-00387-4 |
| _version_ | 1797642262357737472 |
|---|---|
| author | Morgan E. Abernathy Harry B. Gristick Jost Vielmetter Jennifer R. Keeffe Priyanthi N. P. Gnanapragasam Yu E. Lee Amelia Escolano Rajeev Gautam Michael S. Seaman Malcolm A. Martin Michel C. Nussenzweig Pamela J. Bjorkman |
| author_facet | Morgan E. Abernathy Harry B. Gristick Jost Vielmetter Jennifer R. Keeffe Priyanthi N. P. Gnanapragasam Yu E. Lee Amelia Escolano Rajeev Gautam Michael S. Seaman Malcolm A. Martin Michel C. Nussenzweig Pamela J. Bjorkman |
| author_sort | Morgan E. Abernathy |
| collection | DOAJ |
| description | Abstract HIV-1 vaccine design aims to develop an immunogen that elicits broadly neutralizing antibodies against a desired epitope, while eliminating responses to off-target regions of HIV-1 Env. We report characterization of Ab1245, an off-target antibody against the Env gp120-gp41 interface, from V3-glycan patch immunogen-primed and boosted macaques. A 3.7 Å cryo-EM structure of an Ab1245-Env complex reveals one Ab1245 Fab binding asymmetrically to Env trimer at the gp120-gp41 interface using its long CDRH3 to mimic regions of gp41. The mimicry includes positioning of a CDRH3 methionine into the gp41 tryptophan clasp, resulting in displacement of the fusion peptide and fusion peptide-proximal region. Despite fusion peptide displacement, Ab1245 is non-neutralizing even at high concentrations, raising the possibility that only two fusion peptides per trimer are required for viral–host membrane fusion. These structural analyses facilitate immunogen design to prevent elicitation of Ab1245-like antibodies that block neutralizing antibodies against the fusion peptide. |
| first_indexed | 2024-03-11T13:57:36Z |
| format | Article |
| id | doaj.art-dc207aad5e0148e593ea440eea90a943 |
| institution | Directory Open Access Journal |
| issn | 2059-0105 |
| language | English |
| last_indexed | 2024-03-11T13:57:36Z |
| publishDate | 2021-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Vaccines |
| spelling | doaj.art-dc207aad5e0148e593ea440eea90a9432023-11-02T06:20:22ZengNature Portfolionpj Vaccines2059-01052021-10-01611910.1038/s41541-021-00387-4Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitopeMorgan E. Abernathy0Harry B. Gristick1Jost Vielmetter2Jennifer R. Keeffe3Priyanthi N. P. Gnanapragasam4Yu E. Lee5Amelia Escolano6Rajeev Gautam7Michael S. Seaman8Malcolm A. Martin9Michel C. Nussenzweig10Pamela J. Bjorkman11Division of Biology and Biological Engineering, California Institute of TechnologyDivision of Biology and Biological Engineering, California Institute of TechnologyDivision of Biology and Biological Engineering, California Institute of TechnologyDivision of Biology and Biological Engineering, California Institute of TechnologyDivision of Biology and Biological Engineering, California Institute of TechnologyDivision of Biology and Biological Engineering, California Institute of TechnologyLaboratory of Molecular ImmunologyLaboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of HealthCenter for Virology and Vaccine Research, Beth Israel Deaconess Medical CenterLaboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Molecular ImmunologyDivision of Biology and Biological Engineering, California Institute of TechnologyAbstract HIV-1 vaccine design aims to develop an immunogen that elicits broadly neutralizing antibodies against a desired epitope, while eliminating responses to off-target regions of HIV-1 Env. We report characterization of Ab1245, an off-target antibody against the Env gp120-gp41 interface, from V3-glycan patch immunogen-primed and boosted macaques. A 3.7 Å cryo-EM structure of an Ab1245-Env complex reveals one Ab1245 Fab binding asymmetrically to Env trimer at the gp120-gp41 interface using its long CDRH3 to mimic regions of gp41. The mimicry includes positioning of a CDRH3 methionine into the gp41 tryptophan clasp, resulting in displacement of the fusion peptide and fusion peptide-proximal region. Despite fusion peptide displacement, Ab1245 is non-neutralizing even at high concentrations, raising the possibility that only two fusion peptides per trimer are required for viral–host membrane fusion. These structural analyses facilitate immunogen design to prevent elicitation of Ab1245-like antibodies that block neutralizing antibodies against the fusion peptide.https://doi.org/10.1038/s41541-021-00387-4 |
| spellingShingle | Morgan E. Abernathy Harry B. Gristick Jost Vielmetter Jennifer R. Keeffe Priyanthi N. P. Gnanapragasam Yu E. Lee Amelia Escolano Rajeev Gautam Michael S. Seaman Malcolm A. Martin Michel C. Nussenzweig Pamela J. Bjorkman Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope npj Vaccines |
| title | Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope |
| title_full | Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope |
| title_fullStr | Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope |
| title_full_unstemmed | Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope |
| title_short | Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope |
| title_sort | antibody elicited by hiv 1 immunogen vaccination in macaques displaces env fusion peptide and destroys a neutralizing epitope |
| url | https://doi.org/10.1038/s41541-021-00387-4 |
| work_keys_str_mv | AT morganeabernathy antibodyelicitedbyhiv1immunogenvaccinationinmacaquesdisplacesenvfusionpeptideanddestroysaneutralizingepitope AT harrybgristick antibodyelicitedbyhiv1immunogenvaccinationinmacaquesdisplacesenvfusionpeptideanddestroysaneutralizingepitope AT jostvielmetter antibodyelicitedbyhiv1immunogenvaccinationinmacaquesdisplacesenvfusionpeptideanddestroysaneutralizingepitope AT jenniferrkeeffe antibodyelicitedbyhiv1immunogenvaccinationinmacaquesdisplacesenvfusionpeptideanddestroysaneutralizingepitope AT priyanthinpgnanapragasam antibodyelicitedbyhiv1immunogenvaccinationinmacaquesdisplacesenvfusionpeptideanddestroysaneutralizingepitope AT yuelee antibodyelicitedbyhiv1immunogenvaccinationinmacaquesdisplacesenvfusionpeptideanddestroysaneutralizingepitope AT ameliaescolano antibodyelicitedbyhiv1immunogenvaccinationinmacaquesdisplacesenvfusionpeptideanddestroysaneutralizingepitope AT rajeevgautam antibodyelicitedbyhiv1immunogenvaccinationinmacaquesdisplacesenvfusionpeptideanddestroysaneutralizingepitope AT michaelsseaman antibodyelicitedbyhiv1immunogenvaccinationinmacaquesdisplacesenvfusionpeptideanddestroysaneutralizingepitope AT malcolmamartin antibodyelicitedbyhiv1immunogenvaccinationinmacaquesdisplacesenvfusionpeptideanddestroysaneutralizingepitope AT michelcnussenzweig antibodyelicitedbyhiv1immunogenvaccinationinmacaquesdisplacesenvfusionpeptideanddestroysaneutralizingepitope AT pamelajbjorkman antibodyelicitedbyhiv1immunogenvaccinationinmacaquesdisplacesenvfusionpeptideanddestroysaneutralizingepitope |