HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies.
Broadly neutralizing antibody (bnAb) induction is a high priority for effective HIV-1 vaccination. VRC01-class bnAbs that target the CD4 binding site (CD4bs) of trimeric HIV-1 envelope (Env) glycoprotein spikes are particularly attractive to elicit because of their extraordinary breadth and potency...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-11-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC6237427?pdf=render |
| _version_ | 1818511892924071936 |
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| author | Celia C LaBranche Andrew T McGuire Matthew D Gray Shay Behrens Peter D Kwong Xuejun Chen Tongqing Zhou Quentin J Sattentau James Peacock Amanda Eaton Kelli Greene Hongmei Gao Haili Tang Lautaro G Perez Xuejun Chen Kevin O Saunders Peter D Kwong John R Mascola Barton F Haynes Leonidas Stamatatos David C Montefiori |
| author_facet | Celia C LaBranche Andrew T McGuire Matthew D Gray Shay Behrens Peter D Kwong Xuejun Chen Tongqing Zhou Quentin J Sattentau James Peacock Amanda Eaton Kelli Greene Hongmei Gao Haili Tang Lautaro G Perez Xuejun Chen Kevin O Saunders Peter D Kwong John R Mascola Barton F Haynes Leonidas Stamatatos David C Montefiori |
| author_sort | Celia C LaBranche |
| collection | DOAJ |
| description | Broadly neutralizing antibody (bnAb) induction is a high priority for effective HIV-1 vaccination. VRC01-class bnAbs that target the CD4 binding site (CD4bs) of trimeric HIV-1 envelope (Env) glycoprotein spikes are particularly attractive to elicit because of their extraordinary breadth and potency of neutralization in vitro and their ability to protect against infection in animal models. Glycans bordering the CD4bs impede the binding of germline-reverted forms of VRC01-class bnAbs and therefore constitute a barrier to early events in initiating the correct antibody lineages. Deleting a subset of these glycans permits Env antigen binding but not virus neutralization, suggesting that additional barriers impede germline-reverted VRC01-class antibody binding to functional Env trimers. We investigated the requirements for functional Env trimer engagement of VRC01-class naïve B cell receptors by using virus neutralization and germline-reverted antibodies as surrogates for the interaction. Targeted deletion of a subset of N-glycans bordering the CD4bs, combined with Man5 enrichment of remaining N-linked glycans that are otherwise processed into larger complex-type glycans, rendered HIV-1 426c Env-pseudotyped virus (subtype C, transmitted/founder) highly susceptible to neutralization by near germline forms of VRC01-class bnAbs. Neither glycan modification alone rendered the virus susceptible to neutralization. The potency of neutralization in some cases rivaled the potency of mature VRC01 against wildtype viruses. Neutralization by the germline-reverted antibodies was abrogated by the known VRC01 resistance mutation, D279K. These findings improve our understanding of the restrictions imposed by glycans in eliciting VRC01-class bnAbs and enable a neutralization-based strategy to monitor vaccine-elicited early precursors of this class of bnAbs. |
| first_indexed | 2024-12-10T23:39:13Z |
| format | Article |
| id | doaj.art-68f457ac76f9484896850bcdbd585d15 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-10T23:39:13Z |
| publishDate | 2018-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-68f457ac76f9484896850bcdbd585d152022-12-22T01:29:06ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742018-11-011411e100743110.1371/journal.ppat.1007431HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies.Celia C LaBrancheAndrew T McGuireMatthew D GrayShay BehrensPeter D KwongXuejun ChenTongqing ZhouQuentin J SattentauJames PeacockAmanda EatonKelli GreeneHongmei GaoHaili TangLautaro G PerezXuejun ChenKevin O SaundersPeter D KwongJohn R MascolaBarton F HaynesLeonidas StamatatosDavid C MontefioriBroadly neutralizing antibody (bnAb) induction is a high priority for effective HIV-1 vaccination. VRC01-class bnAbs that target the CD4 binding site (CD4bs) of trimeric HIV-1 envelope (Env) glycoprotein spikes are particularly attractive to elicit because of their extraordinary breadth and potency of neutralization in vitro and their ability to protect against infection in animal models. Glycans bordering the CD4bs impede the binding of germline-reverted forms of VRC01-class bnAbs and therefore constitute a barrier to early events in initiating the correct antibody lineages. Deleting a subset of these glycans permits Env antigen binding but not virus neutralization, suggesting that additional barriers impede germline-reverted VRC01-class antibody binding to functional Env trimers. We investigated the requirements for functional Env trimer engagement of VRC01-class naïve B cell receptors by using virus neutralization and germline-reverted antibodies as surrogates for the interaction. Targeted deletion of a subset of N-glycans bordering the CD4bs, combined with Man5 enrichment of remaining N-linked glycans that are otherwise processed into larger complex-type glycans, rendered HIV-1 426c Env-pseudotyped virus (subtype C, transmitted/founder) highly susceptible to neutralization by near germline forms of VRC01-class bnAbs. Neither glycan modification alone rendered the virus susceptible to neutralization. The potency of neutralization in some cases rivaled the potency of mature VRC01 against wildtype viruses. Neutralization by the germline-reverted antibodies was abrogated by the known VRC01 resistance mutation, D279K. These findings improve our understanding of the restrictions imposed by glycans in eliciting VRC01-class bnAbs and enable a neutralization-based strategy to monitor vaccine-elicited early precursors of this class of bnAbs.http://europepmc.org/articles/PMC6237427?pdf=render |
| spellingShingle | Celia C LaBranche Andrew T McGuire Matthew D Gray Shay Behrens Peter D Kwong Xuejun Chen Tongqing Zhou Quentin J Sattentau James Peacock Amanda Eaton Kelli Greene Hongmei Gao Haili Tang Lautaro G Perez Xuejun Chen Kevin O Saunders Peter D Kwong John R Mascola Barton F Haynes Leonidas Stamatatos David C Montefiori HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies. PLoS Pathogens |
| title | HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies. |
| title_full | HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies. |
| title_fullStr | HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies. |
| title_full_unstemmed | HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies. |
| title_short | HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies. |
| title_sort | hiv 1 envelope glycan modifications that permit neutralization by germline reverted vrc01 class broadly neutralizing antibodies |
| url | http://europepmc.org/articles/PMC6237427?pdf=render |
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