A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus
Cytomegalovirus (CMV) is a leading cause of infant hearing loss and neurodevelopmental delay, but there are no clinically licensed vaccines to prevent infection, in part due to challenges eliciting neutralizing antibodies. One of the most well-studied targets for CMV vaccines is the viral fusogen gl...
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| Veröffentlicht in: | PLoS pathogens 2023-01, Vol.19 (1), p.e1011107-e1011107 |
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| creator | Jenks, Jennifer A Amin, Sharmi Sponholtz, Madeline R Kumar, Amit Wrapp, Daniel Venkatayogi, Sravani Tu, Joshua J Karthigeyan, Krithika Valencia, Sarah M Connors, Megan Harnois, Melissa J Hora, Bhavna Rochat, Eric McLellan, Jason S Wiehe, Kevin Permar, Sallie R |
| description | Cytomegalovirus (CMV) is a leading cause of infant hearing loss and neurodevelopmental delay, but there are no clinically licensed vaccines to prevent infection, in part due to challenges eliciting neutralizing antibodies. One of the most well-studied targets for CMV vaccines is the viral fusogen glycoprotein B (gB), which is required for viral entry into host cells. Within gB, antigenic domain 2 site 1 (AD-2S1) is a target of potently neutralizing antibodies, but gB-based candidate vaccines have yet to elicit robust responses against this region. We mapped the genealogy of B cells encoding potently neutralizing anti-gB AD-2S1 antibodies from their inferred unmutated common ancestor (UCA) and characterized the binding and function of early lineage ancestors. Surprisingly, we found that a single amino acid heavy chain mutation A33N, which was an improbable mutation rarely generated by somatic hypermutation machinery, conferred broad CMV neutralization to the non-neutralizing UCA antibody. Structural studies revealed that this mutation mediated key contacts with the gB AD-2S1 epitope. Collectively, these results provide insight into potently neutralizing gB-directed antibody evolution in a single donor and lay a foundation for using this B cell-lineage directed approach for the design of next-generation CMV vaccines. |
| doi_str_mv | 10.1371/journal.ppat.1011107 |
| format | Article |
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Advanced Photon Source (APS)</creatorcontrib><description>Cytomegalovirus (CMV) is a leading cause of infant hearing loss and neurodevelopmental delay, but there are no clinically licensed vaccines to prevent infection, in part due to challenges eliciting neutralizing antibodies. One of the most well-studied targets for CMV vaccines is the viral fusogen glycoprotein B (gB), which is required for viral entry into host cells. Within gB, antigenic domain 2 site 1 (AD-2S1) is a target of potently neutralizing antibodies, but gB-based candidate vaccines have yet to elicit robust responses against this region. We mapped the genealogy of B cells encoding potently neutralizing anti-gB AD-2S1 antibodies from their inferred unmutated common ancestor (UCA) and characterized the binding and function of early lineage ancestors. Surprisingly, we found that a single amino acid heavy chain mutation A33N, which was an improbable mutation rarely generated by somatic hypermutation machinery, conferred broad CMV neutralization to the non-neutralizing UCA antibody. Structural studies revealed that this mutation mediated key contacts with the gB AD-2S1 epitope. Collectively, these results provide insight into potently neutralizing gB-directed antibody evolution in a single donor and lay a foundation for using this B cell-lineage directed approach for the design of next-generation CMV vaccines.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1011107</identifier><identifier>PMID: 36662906</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Advertising executives ; Amino acids ; Antibodies ; Antibodies, Neutralizing - genetics ; Antibodies, Neutralizing - immunology ; Antibodies, Viral - genetics ; Antibodies, Viral - immunology ; Antigenic determinants ; Antigens ; B cells ; Biology and Life Sciences ; Care and treatment ; Cell receptors ; Cloning ; Congenital diseases ; Cytomegalovirus ; Cytomegalovirus - genetics ; Cytomegalovirus - immunology ; Cytomegalovirus infections ; Cytomegalovirus Infections - genetics ; Cytomegalovirus Infections - immunology ; Cytomegalovirus Vaccines - therapeutic use ; Development and progression ; Epitopes ; Gene mutations ; Genealogy ; Genetic aspects ; Glycoprotein B ; Glycoproteins ; Health aspects ; Hearing loss ; Host-virus relationships ; Humans ; Immune response ; Infection ; Infections ; Lymphocytes B ; Medical research ; Medicine and Health Sciences ; Medicine, Experimental ; Microbiology ; Mutation ; Neutralization ; Neutralizing ; Parasitology ; Phylogenetics ; Receptors, Antigen, B-Cell - genetics ; Receptors, Antigen, B-Cell - immunology ; Somatic hypermutation ; Vaccines ; Viral antibodies ; Viral Envelope Proteins - genetics ; Viral Envelope Proteins - immunology ; Virology</subject><ispartof>PLoS pathogens, 2023-01, Vol.19 (1), p.e1011107-e1011107</ispartof><rights>Copyright: © 2023 Jenks et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2023 Public Library of Science</rights><rights>2023 Jenks et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Advanced Photon Source (APS)</creatorcontrib><title>A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus</title><title>PLoS pathogens</title><addtitle>PLoS Pathog</addtitle><description>Cytomegalovirus (CMV) is a leading cause of infant hearing loss and neurodevelopmental delay, but there are no clinically licensed vaccines to prevent infection, in part due to challenges eliciting neutralizing antibodies. One of the most well-studied targets for CMV vaccines is the viral fusogen glycoprotein B (gB), which is required for viral entry into host cells. Within gB, antigenic domain 2 site 1 (AD-2S1) is a target of potently neutralizing antibodies, but gB-based candidate vaccines have yet to elicit robust responses against this region. We mapped the genealogy of B cells encoding potently neutralizing anti-gB AD-2S1 antibodies from their inferred unmutated common ancestor (UCA) and characterized the binding and function of early lineage ancestors. Surprisingly, we found that a single amino acid heavy chain mutation A33N, which was an improbable mutation rarely generated by somatic hypermutation machinery, conferred broad CMV neutralization to the non-neutralizing UCA antibody. Structural studies revealed that this mutation mediated key contacts with the gB AD-2S1 epitope. Collectively, these results provide insight into potently neutralizing gB-directed antibody evolution in a single donor and lay a foundation for using this B cell-lineage directed approach for the design of next-generation CMV vaccines.</description><subject>Advertising executives</subject><subject>Amino acids</subject><subject>Antibodies</subject><subject>Antibodies, Neutralizing - genetics</subject><subject>Antibodies, Neutralizing - immunology</subject><subject>Antibodies, Viral - genetics</subject><subject>Antibodies, Viral - immunology</subject><subject>Antigenic determinants</subject><subject>Antigens</subject><subject>B cells</subject><subject>Biology and Life Sciences</subject><subject>Care and treatment</subject><subject>Cell receptors</subject><subject>Cloning</subject><subject>Congenital diseases</subject><subject>Cytomegalovirus</subject><subject>Cytomegalovirus - genetics</subject><subject>Cytomegalovirus - immunology</subject><subject>Cytomegalovirus infections</subject><subject>Cytomegalovirus Infections - genetics</subject><subject>Cytomegalovirus Infections - immunology</subject><subject>Cytomegalovirus Vaccines - therapeutic use</subject><subject>Development and progression</subject><subject>Epitopes</subject><subject>Gene mutations</subject><subject>Genealogy</subject><subject>Genetic aspects</subject><subject>Glycoprotein B</subject><subject>Glycoproteins</subject><subject>Health aspects</subject><subject>Hearing loss</subject><subject>Host-virus relationships</subject><subject>Humans</subject><subject>Immune response</subject><subject>Infection</subject><subject>Infections</subject><subject>Lymphocytes B</subject><subject>Medical research</subject><subject>Medicine and Health Sciences</subject><subject>Medicine, Experimental</subject><subject>Microbiology</subject><subject>Mutation</subject><subject>Neutralization</subject><subject>Neutralizing</subject><subject>Parasitology</subject><subject>Phylogenetics</subject><subject>Receptors, Antigen, B-Cell - genetics</subject><subject>Receptors, Antigen, B-Cell - 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Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2023-01-20</date><risdate>2023</risdate><volume>19</volume><issue>1</issue><spage>e1011107</spage><epage>e1011107</epage><pages>e1011107-e1011107</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>Cytomegalovirus (CMV) is a leading cause of infant hearing loss and neurodevelopmental delay, but there are no clinically licensed vaccines to prevent infection, in part due to challenges eliciting neutralizing antibodies. One of the most well-studied targets for CMV vaccines is the viral fusogen glycoprotein B (gB), which is required for viral entry into host cells. Within gB, antigenic domain 2 site 1 (AD-2S1) is a target of potently neutralizing antibodies, but gB-based candidate vaccines have yet to elicit robust responses against this region. We mapped the genealogy of B cells encoding potently neutralizing anti-gB AD-2S1 antibodies from their inferred unmutated common ancestor (UCA) and characterized the binding and function of early lineage ancestors. Surprisingly, we found that a single amino acid heavy chain mutation A33N, which was an improbable mutation rarely generated by somatic hypermutation machinery, conferred broad CMV neutralization to the non-neutralizing UCA antibody. Structural studies revealed that this mutation mediated key contacts with the gB AD-2S1 epitope. Collectively, these results provide insight into potently neutralizing gB-directed antibody evolution in a single donor and lay a foundation for using this B cell-lineage directed approach for the design of next-generation CMV vaccines.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>36662906</pmid><doi>10.1371/journal.ppat.1011107</doi><tpages>e1011107</tpages><orcidid>https://orcid.org/0000-0002-6865-5615</orcidid><orcidid>https://orcid.org/0000-0003-1438-4554</orcidid><orcidid>https://orcid.org/0000000268655615</orcidid><orcidid>https://orcid.org/0000000314384554</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1553-7374 |
| ispartof | PLoS pathogens, 2023-01, Vol.19 (1), p.e1011107-e1011107 |
| issn | 1553-7374 1553-7366 1553-7374 |
| language | eng |
| recordid | cdi_plos_journals_2777449600 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; PubMed Central Open Access; Public Library of Science (PLoS) |
| subjects | Advertising executives Amino acids Antibodies Antibodies, Neutralizing - genetics Antibodies, Neutralizing - immunology Antibodies, Viral - genetics Antibodies, Viral - immunology Antigenic determinants Antigens B cells Biology and Life Sciences Care and treatment Cell receptors Cloning Congenital diseases Cytomegalovirus Cytomegalovirus - genetics Cytomegalovirus - immunology Cytomegalovirus infections Cytomegalovirus Infections - genetics Cytomegalovirus Infections - immunology Cytomegalovirus Vaccines - therapeutic use Development and progression Epitopes Gene mutations Genealogy Genetic aspects Glycoprotein B Glycoproteins Health aspects Hearing loss Host-virus relationships Humans Immune response Infection Infections Lymphocytes B Medical research Medicine and Health Sciences Medicine, Experimental Microbiology Mutation Neutralization Neutralizing Parasitology Phylogenetics Receptors, Antigen, B-Cell - genetics Receptors, Antigen, B-Cell - immunology Somatic hypermutation Vaccines Viral antibodies Viral Envelope Proteins - genetics Viral Envelope Proteins - immunology Virology |
| title | A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T17%3A07%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20single,%20improbable%20B%20cell%20receptor%20mutation%20confers%20potent%20neutralization%20against%20cytomegalovirus&rft.jtitle=PLoS%20pathogens&rft.au=Jenks,%20Jennifer%20A&rft.aucorp=Argonne%20National%20Laboratory%20(ANL),%20Argonne,%20IL%20(United%20States).%20Advanced%20Photon%20Source%20(APS)&rft.date=2023-01-20&rft.volume=19&rft.issue=1&rft.spage=e1011107&rft.epage=e1011107&rft.pages=e1011107-e1011107&rft.issn=1553-7374&rft.eissn=1553-7374&rft_id=info:doi/10.1371/journal.ppat.1011107&rft_dat=%3Cgale_plos_%3EA737317753%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2777449600&rft_id=info:pmid/36662906&rft_galeid=A737317753&rft_doaj_id=oai_doaj_org_article_111b8730bca84593945e121697cbd932&rfr_iscdi=true |