Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8.
Antibody 10E8 targets the membrane-proximal external region (MPER) of HIV-1 gp41, neutralizes >97% of HIV-1 isolates, and lacks the auto-reactivity often associated with MPER-directed antibodies. The developmental pathway of 10E8 might therefore serve as a promising template for vaccine design, b...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4907498?pdf=render |
| _version_ | 1818272104721678336 |
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| author | Cinque Soto Gilad Ofek M Gordon Joyce Baoshan Zhang Krisha McKee Nancy S Longo Yongping Yang Jinghe Huang Robert Parks Joshua Eudailey Krissey E Lloyd S Munir Alam Barton F Haynes NISC Comparative Sequencing Program James C Mullikin Mark Connors John R Mascola Lawrence Shapiro Peter D Kwong |
| author_facet | Cinque Soto Gilad Ofek M Gordon Joyce Baoshan Zhang Krisha McKee Nancy S Longo Yongping Yang Jinghe Huang Robert Parks Joshua Eudailey Krissey E Lloyd S Munir Alam Barton F Haynes NISC Comparative Sequencing Program James C Mullikin Mark Connors John R Mascola Lawrence Shapiro Peter D Kwong |
| author_sort | Cinque Soto |
| collection | DOAJ |
| description | Antibody 10E8 targets the membrane-proximal external region (MPER) of HIV-1 gp41, neutralizes >97% of HIV-1 isolates, and lacks the auto-reactivity often associated with MPER-directed antibodies. The developmental pathway of 10E8 might therefore serve as a promising template for vaccine design, but samples from time-of-infection-often used to infer the B cell record-are unavailable. In this study, we used crystallography, next-generation sequencing (NGS), and functional assessments to infer the 10E8 developmental pathway from a single time point. Mutational analysis indicated somatic hypermutation of the 2nd-heavy chain-complementarity determining region (CDR H2) to be critical for neutralization, and structures of 10E8 variants with V-gene regions reverted to genomic origin for heavy-and-light chains or heavy chain-only showed structural differences >2 Å relative to mature 10E8 in the CDR H2 and H3. To understand these developmental changes, we used bioinformatic sieving, maximum likelihood, and parsimony analyses of immunoglobulin transcripts to identify 10E8-lineage members, to infer the 10E8-unmutated common ancestor (UCA), and to calculate 10E8-developmental intermediates. We were assisted in this analysis by the preservation of a critical D-gene segment, which was unmutated in most 10E8-lineage sequences. UCA and early intermediates weakly bound a 26-residue-MPER peptide, whereas HIV-1 neutralization and epitope recognition in liposomes were only observed with late intermediates. Antibody 10E8 thus develops from a UCA with weak MPER affinity and substantial differences in CDR H2 and H3 from the mature 10E8; only after extensive somatic hypermutation do 10E8-lineage members gain recognition in the context of membrane and HIV-1 neutralization. |
| first_indexed | 2024-12-12T21:36:46Z |
| format | Article |
| id | doaj.art-60b7bd1713514882bff820a0623ed3bb |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T21:36:46Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-60b7bd1713514882bff820a0623ed3bb2022-12-22T00:11:09ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01116e015740910.1371/journal.pone.0157409Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8.Cinque SotoGilad OfekM Gordon JoyceBaoshan ZhangKrisha McKeeNancy S LongoYongping YangJinghe HuangRobert ParksJoshua EudaileyKrissey E LloydS Munir AlamBarton F HaynesNISC Comparative Sequencing ProgramJames C MullikinMark ConnorsJohn R MascolaLawrence ShapiroPeter D KwongAntibody 10E8 targets the membrane-proximal external region (MPER) of HIV-1 gp41, neutralizes >97% of HIV-1 isolates, and lacks the auto-reactivity often associated with MPER-directed antibodies. The developmental pathway of 10E8 might therefore serve as a promising template for vaccine design, but samples from time-of-infection-often used to infer the B cell record-are unavailable. In this study, we used crystallography, next-generation sequencing (NGS), and functional assessments to infer the 10E8 developmental pathway from a single time point. Mutational analysis indicated somatic hypermutation of the 2nd-heavy chain-complementarity determining region (CDR H2) to be critical for neutralization, and structures of 10E8 variants with V-gene regions reverted to genomic origin for heavy-and-light chains or heavy chain-only showed structural differences >2 Å relative to mature 10E8 in the CDR H2 and H3. To understand these developmental changes, we used bioinformatic sieving, maximum likelihood, and parsimony analyses of immunoglobulin transcripts to identify 10E8-lineage members, to infer the 10E8-unmutated common ancestor (UCA), and to calculate 10E8-developmental intermediates. We were assisted in this analysis by the preservation of a critical D-gene segment, which was unmutated in most 10E8-lineage sequences. UCA and early intermediates weakly bound a 26-residue-MPER peptide, whereas HIV-1 neutralization and epitope recognition in liposomes were only observed with late intermediates. Antibody 10E8 thus develops from a UCA with weak MPER affinity and substantial differences in CDR H2 and H3 from the mature 10E8; only after extensive somatic hypermutation do 10E8-lineage members gain recognition in the context of membrane and HIV-1 neutralization.http://europepmc.org/articles/PMC4907498?pdf=render |
| spellingShingle | Cinque Soto Gilad Ofek M Gordon Joyce Baoshan Zhang Krisha McKee Nancy S Longo Yongping Yang Jinghe Huang Robert Parks Joshua Eudailey Krissey E Lloyd S Munir Alam Barton F Haynes NISC Comparative Sequencing Program James C Mullikin Mark Connors John R Mascola Lawrence Shapiro Peter D Kwong Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8. PLoS ONE |
| title | Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8. |
| title_full | Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8. |
| title_fullStr | Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8. |
| title_full_unstemmed | Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8. |
| title_short | Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8. |
| title_sort | developmental pathway of the mper directed hiv 1 neutralizing antibody 10e8 |
| url | http://europepmc.org/articles/PMC4907498?pdf=render |
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