Vaccine-elicited primate antibodies use a distinct approach to the HIV-1 primary receptor binding site informing vaccine redesign
HIV-1 neutralization requires Ab accessibility to the functional envelope glycoprotein (Env) spike. We recently reported the isolation of previously unidentified vaccine-elicited, CD4 binding site (CD4bs)-directed mAbs from rhesus macaques immunized with soluble Env trimers, indicating that this reg...
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| Veröffentlicht in: | Proc. Natl. Acad. Sci. USA 2014-02, Vol.111 (7), p.E738-E747 |
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| creator | Tran, Karen Poulsen, Christian Guenaga, Javier de Val, Natalia de Val Alda, Natalia Wilson, Richard Sundling, Christopher Li, Yuxing Stanfield, Robyn L Wilson, Ian A Ward, Andrew B Karlsson Hedestam, Gunilla B Wyatt, Richard T |
| description | HIV-1 neutralization requires Ab accessibility to the functional envelope glycoprotein (Env) spike. We recently reported the isolation of previously unidentified vaccine-elicited, CD4 binding site (CD4bs)-directed mAbs from rhesus macaques immunized with soluble Env trimers, indicating that this region is immunogenic in the context of subunit vaccination. To elucidate the interaction of the trimer-elicited mAbs with gp120 and their insufficient interaction with the HIV-1 primary isolate spike, we crystallized the Fab fragments of two mAbs, GE136 and GE148. Alanine scanning of their complementarity-determining regions, coupled with epitope scanning of their epitopes on gp120, revealed putative contact residues at the Ab/gp120 interface. Docking of the GE136 and GE148 Fabs to gp120, coupled with EM reconstructions of these nonbroadly neutralizing mAbs (non-bNAbs) binding to gp120 monomers and EM modeling to well-ordered trimers, suggested Ab approach to the CD4bs by a vertical angle of access relative to the more lateral mode of interaction used by the CD4bs-directed bNAbs VRC01 and PGV04. Fitting the structures into the available cryo-EM native spike density indicated clashes between these two vaccine-elicited mAbs and the topside variable region spike cap, whereas the bNAbs duck under this quaternary shield to access the CD4bs effectively on primary HIV isolates. These results provide a structural basis for the limited neutralizing breadth observed by current vaccine-induced, CD4bs-directed Abs and highlight the need for better ordered trimer immunogens. The analysis presented here therefore provides valuable information to guide HIV-1 vaccine immunogen redesign. |
| doi_str_mv | 10.1073/pnas.1319512111 |
| format | Article |
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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>HIV-1 neutralization requires Ab accessibility to the functional envelope glycoprotein (Env) spike. We recently reported the isolation of previously unidentified vaccine-elicited, CD4 binding site (CD4bs)-directed mAbs from rhesus macaques immunized with soluble Env trimers, indicating that this region is immunogenic in the context of subunit vaccination. To elucidate the interaction of the trimer-elicited mAbs with gp120 and their insufficient interaction with the HIV-1 primary isolate spike, we crystallized the Fab fragments of two mAbs, GE136 and GE148. Alanine scanning of their complementarity-determining regions, coupled with epitope scanning of their epitopes on gp120, revealed putative contact residues at the Ab/gp120 interface. Docking of the GE136 and GE148 Fabs to gp120, coupled with EM reconstructions of these nonbroadly neutralizing mAbs (non-bNAbs) binding to gp120 monomers and EM modeling to well-ordered trimers, suggested Ab approach to the CD4bs by a vertical angle of access relative to the more lateral mode of interaction used by the CD4bs-directed bNAbs VRC01 and PGV04. Fitting the structures into the available cryo-EM native spike density indicated clashes between these two vaccine-elicited mAbs and the topside variable region spike cap, whereas the bNAbs duck under this quaternary shield to access the CD4bs effectively on primary HIV isolates. These results provide a structural basis for the limited neutralizing breadth observed by current vaccine-induced, CD4bs-directed Abs and highlight the need for better ordered trimer immunogens. The analysis presented here therefore provides valuable information to guide HIV-1 vaccine immunogen redesign.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1319512111</identifier><identifier>PMID: 24550318</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>AIDS Vaccines - biosynthesis ; AIDS Vaccines - immunology ; alanine ; Animals ; antibodies ; Antibodies, Monoclonal - biosynthesis ; Antibodies, Monoclonal - chemistry ; Antibodies, Monoclonal - immunology ; Antibodies, Neutralizing - biosynthesis ; Antibodies, Neutralizing - chemistry ; Antibodies, Neutralizing - immunology ; Binding sites ; Binding Sites - genetics ; Biological Sciences ; CD4 Antigens - genetics ; CD4 Antigens - metabolism ; Crystallization ; Drug Design ; ducks ; env Gene Products, Human Immunodeficiency Virus - genetics ; epitopes ; Glycoproteins ; HIV ; HIV-1 - immunology ; Human immunodeficiency virus ; Human immunodeficiency virus 1 ; Humans ; Immunization ; Immunoglobulin Fab Fragments - genetics ; Immunoglobulin Fab Fragments - metabolism ; Macaca mulatta ; Macaca mulatta - immunology ; Microscopy, Interference ; Models, Molecular ; Monkeys & apes ; neutralization ; Neutralization Tests ; PNAS Plus ; Primates ; Protein Conformation ; vaccination ; Vaccines</subject><ispartof>Proc. Natl. Acad. Sci. USA, 2014-02, Vol.111 (7), p.E738-E747</ispartof><rights>Copyright National Academy of Sciences Feb 18, 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c669t-d0668b9f6fec5f2d5b0fb799b1f65a49a707aaaa6eec1d2034fafd3e6acddc6e3</citedby><cites>FETCH-LOGICAL-c669t-d0668b9f6fec5f2d5b0fb799b1f65a49a707aaaa6eec1d2034fafd3e6acddc6e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/111/7.cover.gif</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932900/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932900/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,550,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24550318$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1130115$$D View this record in Osti.gov$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:128364537$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Tran, Karen</creatorcontrib><creatorcontrib>Poulsen, Christian</creatorcontrib><creatorcontrib>Guenaga, Javier</creatorcontrib><creatorcontrib>de Val, Natalia</creatorcontrib><creatorcontrib>de Val Alda, Natalia</creatorcontrib><creatorcontrib>Wilson, Richard</creatorcontrib><creatorcontrib>Sundling, Christopher</creatorcontrib><creatorcontrib>Li, Yuxing</creatorcontrib><creatorcontrib>Stanfield, Robyn L</creatorcontrib><creatorcontrib>Wilson, Ian A</creatorcontrib><creatorcontrib>Ward, Andrew B</creatorcontrib><creatorcontrib>Karlsson Hedestam, Gunilla B</creatorcontrib><creatorcontrib>Wyatt, Richard T</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Vaccine-elicited primate antibodies use a distinct approach to the HIV-1 primary receptor binding site informing vaccine redesign</title><title>Proc. Natl. Acad. Sci. USA</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>HIV-1 neutralization requires Ab accessibility to the functional envelope glycoprotein (Env) spike. We recently reported the isolation of previously unidentified vaccine-elicited, CD4 binding site (CD4bs)-directed mAbs from rhesus macaques immunized with soluble Env trimers, indicating that this region is immunogenic in the context of subunit vaccination. To elucidate the interaction of the trimer-elicited mAbs with gp120 and their insufficient interaction with the HIV-1 primary isolate spike, we crystallized the Fab fragments of two mAbs, GE136 and GE148. Alanine scanning of their complementarity-determining regions, coupled with epitope scanning of their epitopes on gp120, revealed putative contact residues at the Ab/gp120 interface. Docking of the GE136 and GE148 Fabs to gp120, coupled with EM reconstructions of these nonbroadly neutralizing mAbs (non-bNAbs) binding to gp120 monomers and EM modeling to well-ordered trimers, suggested Ab approach to the CD4bs by a vertical angle of access relative to the more lateral mode of interaction used by the CD4bs-directed bNAbs VRC01 and PGV04. Fitting the structures into the available cryo-EM native spike density indicated clashes between these two vaccine-elicited mAbs and the topside variable region spike cap, whereas the bNAbs duck under this quaternary shield to access the CD4bs effectively on primary HIV isolates. These results provide a structural basis for the limited neutralizing breadth observed by current vaccine-induced, CD4bs-directed Abs and highlight the need for better ordered trimer immunogens. The analysis presented here therefore provides valuable information to guide HIV-1 vaccine immunogen redesign.</description><subject>AIDS Vaccines - biosynthesis</subject><subject>AIDS Vaccines - immunology</subject><subject>alanine</subject><subject>Animals</subject><subject>antibodies</subject><subject>Antibodies, Monoclonal - biosynthesis</subject><subject>Antibodies, Monoclonal - chemistry</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Neutralizing - biosynthesis</subject><subject>Antibodies, Neutralizing - chemistry</subject><subject>Antibodies, Neutralizing - immunology</subject><subject>Binding sites</subject><subject>Binding Sites - genetics</subject><subject>Biological Sciences</subject><subject>CD4 Antigens - genetics</subject><subject>CD4 Antigens - metabolism</subject><subject>Crystallization</subject><subject>Drug Design</subject><subject>ducks</subject><subject>env Gene Products, Human Immunodeficiency Virus - genetics</subject><subject>epitopes</subject><subject>Glycoproteins</subject><subject>HIV</subject><subject>HIV-1 - immunology</subject><subject>Human immunodeficiency virus</subject><subject>Human immunodeficiency virus 1</subject><subject>Humans</subject><subject>Immunization</subject><subject>Immunoglobulin Fab Fragments - genetics</subject><subject>Immunoglobulin Fab Fragments - metabolism</subject><subject>Macaca mulatta</subject><subject>Macaca mulatta - immunology</subject><subject>Microscopy, Interference</subject><subject>Models, Molecular</subject><subject>Monkeys & apes</subject><subject>neutralization</subject><subject>Neutralization Tests</subject><subject>PNAS Plus</subject><subject>Primates</subject><subject>Protein Conformation</subject><subject>vaccination</subject><subject>Vaccines</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNqNkj1vFDEQhlcIREKgpgMLGppNxvaud91EQlEgkSJRQNJaXnv2zuHOPmxfECX_HK_2OBIacOOPeeb1aOatqpcUjil0_GTjdTqmnMqWMkrpo-qQgqS1aCQ8rg4BWFf3DWsOqmcp3QKAbHt4Wh2wpm2B0_6w-nmjjXEea1w54zJasolurTMS7bMbgnWYyDaVK7EuZedNJnqziUGbJcmB5CWSi8ubms558QeJaHCTQySD89b5BUlFljg_hriernfzh4WzmNzCP6-ejHqV8MVuP6quP5x_Obuorz59vDx7f1UbIWSuLQjRD3IUI5p2ZLYdYBw6KQc6ilY3UnfQ6bIEoqGWAW9GPVqOQhtrjUB-VNWzbvqOm-2gdvWqoJ3aPX0tJ1Qt4y1rCn868yWyRmvQ56hXD9IeRrxbqkW4U1xyJgGKwJtZIJS-qTR11yxN8B5NVpRyoLQt0LvdLzF822LKau2SwdVKewzbpGhf5lRGK5p_o8UDnPXQy_9AAUTPhOgK-vYv9DZsoy-TmCgqQLK-L9TJTJkYUoo47vtAQU1OVJMT1R8nloxX99u3539b7x4wZe7lKFWdOu_4BLyegVEHpRfRJXX9mU0lAeWyk8B_AWo377k</recordid><startdate>20140218</startdate><enddate>20140218</enddate><creator>Tran, Karen</creator><creator>Poulsen, Christian</creator><creator>Guenaga, Javier</creator><creator>de Val, Natalia</creator><creator>de Val Alda, Natalia</creator><creator>Wilson, Richard</creator><creator>Sundling, Christopher</creator><creator>Li, Yuxing</creator><creator>Stanfield, Robyn L</creator><creator>Wilson, Ian A</creator><creator>Ward, Andrew B</creator><creator>Karlsson Hedestam, Gunilla B</creator><creator>Wyatt, Richard T</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>OTOTI</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope></search><sort><creationdate>20140218</creationdate><title>Vaccine-elicited primate antibodies use a distinct approach to the HIV-1 primary receptor binding site informing vaccine redesign</title><author>Tran, Karen ; Poulsen, Christian ; Guenaga, Javier ; de Val, Natalia ; de Val Alda, Natalia ; Wilson, Richard ; Sundling, Christopher ; Li, Yuxing ; Stanfield, Robyn L ; Wilson, Ian A ; Ward, Andrew B ; Karlsson Hedestam, Gunilla B ; Wyatt, Richard T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c669t-d0668b9f6fec5f2d5b0fb799b1f65a49a707aaaa6eec1d2034fafd3e6acddc6e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>AIDS Vaccines - biosynthesis</topic><topic>AIDS Vaccines - immunology</topic><topic>alanine</topic><topic>Animals</topic><topic>antibodies</topic><topic>Antibodies, Monoclonal - biosynthesis</topic><topic>Antibodies, Monoclonal - chemistry</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Antibodies, Neutralizing - biosynthesis</topic><topic>Antibodies, Neutralizing - chemistry</topic><topic>Antibodies, Neutralizing - immunology</topic><topic>Binding sites</topic><topic>Binding Sites - genetics</topic><topic>Biological Sciences</topic><topic>CD4 Antigens - genetics</topic><topic>CD4 Antigens - metabolism</topic><topic>Crystallization</topic><topic>Drug Design</topic><topic>ducks</topic><topic>env Gene Products, Human Immunodeficiency Virus - genetics</topic><topic>epitopes</topic><topic>Glycoproteins</topic><topic>HIV</topic><topic>HIV-1 - immunology</topic><topic>Human immunodeficiency virus</topic><topic>Human immunodeficiency virus 1</topic><topic>Humans</topic><topic>Immunization</topic><topic>Immunoglobulin Fab Fragments - genetics</topic><topic>Immunoglobulin Fab Fragments - metabolism</topic><topic>Macaca mulatta</topic><topic>Macaca mulatta - immunology</topic><topic>Microscopy, Interference</topic><topic>Models, Molecular</topic><topic>Monkeys & apes</topic><topic>neutralization</topic><topic>Neutralization Tests</topic><topic>PNAS Plus</topic><topic>Primates</topic><topic>Protein Conformation</topic><topic>vaccination</topic><topic>Vaccines</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tran, Karen</creatorcontrib><creatorcontrib>Poulsen, Christian</creatorcontrib><creatorcontrib>Guenaga, Javier</creatorcontrib><creatorcontrib>de Val, Natalia</creatorcontrib><creatorcontrib>de Val Alda, Natalia</creatorcontrib><creatorcontrib>Wilson, Richard</creatorcontrib><creatorcontrib>Sundling, Christopher</creatorcontrib><creatorcontrib>Li, Yuxing</creatorcontrib><creatorcontrib>Stanfield, Robyn L</creatorcontrib><creatorcontrib>Wilson, Ian A</creatorcontrib><creatorcontrib>Ward, Andrew B</creatorcontrib><creatorcontrib>Karlsson Hedestam, Gunilla B</creatorcontrib><creatorcontrib>Wyatt, Richard T</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). 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Natl. Acad. Sci. USA</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tran, Karen</au><au>Poulsen, Christian</au><au>Guenaga, Javier</au><au>de Val, Natalia</au><au>de Val Alda, Natalia</au><au>Wilson, Richard</au><au>Sundling, Christopher</au><au>Li, Yuxing</au><au>Stanfield, Robyn L</au><au>Wilson, Ian A</au><au>Ward, Andrew B</au><au>Karlsson Hedestam, Gunilla B</au><au>Wyatt, Richard T</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Vaccine-elicited primate antibodies use a distinct approach to the HIV-1 primary receptor binding site informing vaccine redesign</atitle><jtitle>Proc. Natl. Acad. Sci. USA</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2014-02-18</date><risdate>2014</risdate><volume>111</volume><issue>7</issue><spage>E738</spage><epage>E747</epage><pages>E738-E747</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>HIV-1 neutralization requires Ab accessibility to the functional envelope glycoprotein (Env) spike. We recently reported the isolation of previously unidentified vaccine-elicited, CD4 binding site (CD4bs)-directed mAbs from rhesus macaques immunized with soluble Env trimers, indicating that this region is immunogenic in the context of subunit vaccination. To elucidate the interaction of the trimer-elicited mAbs with gp120 and their insufficient interaction with the HIV-1 primary isolate spike, we crystallized the Fab fragments of two mAbs, GE136 and GE148. Alanine scanning of their complementarity-determining regions, coupled with epitope scanning of their epitopes on gp120, revealed putative contact residues at the Ab/gp120 interface. Docking of the GE136 and GE148 Fabs to gp120, coupled with EM reconstructions of these nonbroadly neutralizing mAbs (non-bNAbs) binding to gp120 monomers and EM modeling to well-ordered trimers, suggested Ab approach to the CD4bs by a vertical angle of access relative to the more lateral mode of interaction used by the CD4bs-directed bNAbs VRC01 and PGV04. Fitting the structures into the available cryo-EM native spike density indicated clashes between these two vaccine-elicited mAbs and the topside variable region spike cap, whereas the bNAbs duck under this quaternary shield to access the CD4bs effectively on primary HIV isolates. These results provide a structural basis for the limited neutralizing breadth observed by current vaccine-induced, CD4bs-directed Abs and highlight the need for better ordered trimer immunogens. The analysis presented here therefore provides valuable information to guide HIV-1 vaccine immunogen redesign.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>24550318</pmid><doi>10.1073/pnas.1319512111</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0027-8424 |
| ispartof | Proc. Natl. Acad. Sci. USA, 2014-02, Vol.111 (7), p.E738-E747 |
| issn | 0027-8424 1091-6490 |
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| source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; SWEPUB Freely available online; Free Full-Text Journals in Chemistry |
| subjects | AIDS Vaccines - biosynthesis AIDS Vaccines - immunology alanine Animals antibodies Antibodies, Monoclonal - biosynthesis Antibodies, Monoclonal - chemistry Antibodies, Monoclonal - immunology Antibodies, Neutralizing - biosynthesis Antibodies, Neutralizing - chemistry Antibodies, Neutralizing - immunology Binding sites Binding Sites - genetics Biological Sciences CD4 Antigens - genetics CD4 Antigens - metabolism Crystallization Drug Design ducks env Gene Products, Human Immunodeficiency Virus - genetics epitopes Glycoproteins HIV HIV-1 - immunology Human immunodeficiency virus Human immunodeficiency virus 1 Humans Immunization Immunoglobulin Fab Fragments - genetics Immunoglobulin Fab Fragments - metabolism Macaca mulatta Macaca mulatta - immunology Microscopy, Interference Models, Molecular Monkeys & apes neutralization Neutralization Tests PNAS Plus Primates Protein Conformation vaccination Vaccines |
| title | Vaccine-elicited primate antibodies use a distinct approach to the HIV-1 primary receptor binding site informing vaccine redesign |
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