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...
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| Veröffentlicht in: | PLoS pathogens 2018-11, Vol.14 (11), p.e1007431-e1007431 |
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| creator | LaBranche, Celia C McGuire, Andrew T Gray, Matthew D Behrens, Shay Kwong, Peter D Chen, Xuejun Zhou, Tongqing Sattentau, Quentin J Peacock, James Eaton, Amanda Greene, Kelli Gao, Hongmei Tang, Haili Perez, Lautaro G Chen, Xuejun Saunders, Kevin O Kwong, Peter D Mascola, John R Haynes, Barton F Stamatatos, Leonidas Montefiori, David C |
| 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. |
| doi_str_mv | 10.1371/journal.ppat.1007431 |
| format | Article |
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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.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1007431</identifier><identifier>PMID: 30395637</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animal models ; Antibodies ; Antibodies, Monoclonal - immunology ; Antibodies, Neutralizing - immunology ; Antigens ; B-Lymphocytes - immunology ; Binding Sites ; Biology and Life Sciences ; Broadly Neutralizing Antibodies ; Cancer ; CD4 antigen ; CD4 Antigens - immunology ; Clonal deletion ; env Gene Products, Human Immunodeficiency Virus - immunology ; Epitopes - immunology ; Gene deletion ; Gene mutations ; Genetic aspects ; Glycan ; Glycoproteins ; Glycosylation ; HIV ; HIV (Viruses) ; HIV Antibodies - immunology ; HIV Envelope Protein gp120 - immunology ; HIV Infections - immunology ; HIV Seropositivity ; HIV-1 - immunology ; Human immunodeficiency virus ; Humans ; Immunoglobulins ; Immunology ; Infectious diseases ; Lymphocytes B ; Medical research ; Medicine ; Medicine and Health Sciences ; Mutation ; N-glycans ; Neutralization ; Neutralizing ; Polysaccharides ; Polysaccharides - immunology ; Polysaccharides - metabolism ; Receptors ; Research and analysis methods ; Supervision ; Surgery ; Trimers ; Vaccination ; Vaccines ; Viral antibodies ; Virology ; Viruses</subject><ispartof>PLoS pathogens, 2018-11, Vol.14 (11), p.e1007431-e1007431</ispartof><rights>COPYRIGHT 2018 Public Library of Science</rights><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. 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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.</description><subject>Animal models</subject><subject>Antibodies</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Neutralizing - immunology</subject><subject>Antigens</subject><subject>B-Lymphocytes - immunology</subject><subject>Binding Sites</subject><subject>Biology and Life Sciences</subject><subject>Broadly Neutralizing Antibodies</subject><subject>Cancer</subject><subject>CD4 antigen</subject><subject>CD4 Antigens - immunology</subject><subject>Clonal deletion</subject><subject>env Gene Products, Human Immunodeficiency Virus - immunology</subject><subject>Epitopes - immunology</subject><subject>Gene deletion</subject><subject>Gene mutations</subject><subject>Genetic aspects</subject><subject>Glycan</subject><subject>Glycoproteins</subject><subject>Glycosylation</subject><subject>HIV</subject><subject>HIV (Viruses)</subject><subject>HIV Antibodies - immunology</subject><subject>HIV Envelope Protein gp120 - immunology</subject><subject>HIV Infections - immunology</subject><subject>HIV Seropositivity</subject><subject>HIV-1 - immunology</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Immunoglobulins</subject><subject>Immunology</subject><subject>Infectious diseases</subject><subject>Lymphocytes B</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Mutation</subject><subject>N-glycans</subject><subject>Neutralization</subject><subject>Neutralizing</subject><subject>Polysaccharides</subject><subject>Polysaccharides - immunology</subject><subject>Polysaccharides - metabolism</subject><subject>Receptors</subject><subject>Research and 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envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies</title><author>LaBranche, Celia C ; McGuire, Andrew T ; Gray, Matthew D ; Behrens, Shay ; Kwong, Peter D ; Chen, Xuejun ; Zhou, Tongqing ; Sattentau, Quentin J ; Peacock, James ; Eaton, Amanda ; Greene, Kelli ; Gao, Hongmei ; Tang, Haili ; Perez, Lautaro G ; Chen, Xuejun ; Saunders, Kevin O ; Kwong, Peter D ; Mascola, John R ; Haynes, Barton F ; Stamatatos, Leonidas ; Montefiori, David C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5371-b67572c785b4748c04e3068acb017c9c03c5e488849a1b46f976befc99277fe23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animal models</topic><topic>Antibodies</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Antibodies, Neutralizing - immunology</topic><topic>Antigens</topic><topic>B-Lymphocytes - 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Kelli</au><au>Gao, Hongmei</au><au>Tang, Haili</au><au>Perez, Lautaro G</au><au>Chen, Xuejun</au><au>Saunders, Kevin O</au><au>Kwong, Peter D</au><au>Mascola, John R</au><au>Haynes, Barton F</au><au>Stamatatos, Leonidas</au><au>Montefiori, David C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2018-11-01</date><risdate>2018</risdate><volume>14</volume><issue>11</issue><spage>e1007431</spage><epage>e1007431</epage><pages>e1007431-e1007431</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>30395637</pmid><doi>10.1371/journal.ppat.1007431</doi><orcidid>https://orcid.org/0000-0001-7170-1937</orcidid><orcidid>https://orcid.org/0000-0002-4260-9784</orcidid><orcidid>https://orcid.org/0000-0002-1106-7097</orcidid><orcidid>https://orcid.org/0000-0003-0856-6319</orcidid><orcidid>https://orcid.org/0000-0001-8676-2345</orcidid><orcidid>https://orcid.org/0000-0002-6653-6655</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1553-7374 |
| ispartof | PLoS pathogens, 2018-11, Vol.14 (11), p.e1007431-e1007431 |
| issn | 1553-7374 1553-7366 1553-7374 |
| language | eng |
| recordid | cdi_plos_journals_2251104463 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; PubMed Central Open Access; Public Library of Science (PLoS) |
| subjects | Animal models Antibodies Antibodies, Monoclonal - immunology Antibodies, Neutralizing - immunology Antigens B-Lymphocytes - immunology Binding Sites Biology and Life Sciences Broadly Neutralizing Antibodies Cancer CD4 antigen CD4 Antigens - immunology Clonal deletion env Gene Products, Human Immunodeficiency Virus - immunology Epitopes - immunology Gene deletion Gene mutations Genetic aspects Glycan Glycoproteins Glycosylation HIV HIV (Viruses) HIV Antibodies - immunology HIV Envelope Protein gp120 - immunology HIV Infections - immunology HIV Seropositivity HIV-1 - immunology Human immunodeficiency virus Humans Immunoglobulins Immunology Infectious diseases Lymphocytes B Medical research Medicine Medicine and Health Sciences Mutation N-glycans Neutralization Neutralizing Polysaccharides Polysaccharides - immunology Polysaccharides - metabolism Receptors Research and analysis methods Supervision Surgery Trimers Vaccination Vaccines Viral antibodies Virology Viruses |
| title | HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies |
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