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Article: Structural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120

TitleStructural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120
Authors
Issue Date2009
PublisherAmerican Association for the Advancement of Science. The Journal's web site is located at http://sciencemag.org
Citation
Science, 2009, v. 326 n. 5956, p. 1123-1127 How to Cite?
AbstractThe site on HIV-1 gp120 that binds to the CD4 receptor is vulnerable to antibodies. However, most antibodies that interact with this site cannot neutralize HIV-1. To understand the basis of this resistance, we determined co-crystal structures for two poorly neutralizing, CD4-binding site (CD4BS) antibodies, F105 and b13, in complexes with gp120. Both antibodies exhibited approach angles to gp120 similar to those of CD4 and a rare, broadly neutralizing CD4BS antibody, b12. Slight differences in recognition, however, resulted in substantial differences in F105- and b13-bound conformations relative to b12-bound gp120. Modeling and binding experiments revealed these conformations to be poorly compatible with the viral spike. This incompatibility, the consequence of slight differences in CD4BS recognition, renders HIV-1 resistant to all but the most accurately targeted antibodies.
Persistent Identifierhttp://hdl.handle.net/10722/65597
ISSN
2015 Impact Factor: 34.661
2015 SCImago Journal Rankings: 13.217
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
NIH
International AIDS Vaccine Initiative
Bill and Melinda Gates Foundation Grand Challenges in Global Heath Initiative
Funding Information:

L. Chen produced and assessed for crystallization CD4BS antibodies with unconstrained gp120, crystallized the F105-gp120 complex, assisted with F105-gp120 data collection and structure solution, and carried out mutagenesis and SPR binding experiments. Y. D. K. assisted with F105-gp120 crystallization, data collection, and structure solution and refined and analyzed the F105-gp120 structure. T. Z. purified, crystallized, solved, and analyzed the b13-gp120 complex. X. W., S. O.' D. and J. R. M. assessed neutralization potency and breadth of CD4, patient sera, and CD4BS antibodies. L. Chen and M. P. carried out cell-surface JR-FL binding experiments. M. T. and R. W. provided YU2 core gp120; L. X. and G. J. N. provided stabilized-core gp120; Z.-Y. Y. and G. J. N. converted b13 from Fab to IgG format and provided b13 IgG; L. Cavacini and M. R. P. provided F105; M.-Y. Z. and D. S. D. provided m6, m14, and m18; A. J. H. and D. R. B. provided b3, b6, b11, b12; and J. A. provided dodecameric CD4. J. A., D. R. B., D. S. D., G. J. N., M. R. P., J. S., R. W., and J. R. M. assisted with analysis and writing, and P. D. K. assisted with crystallography and experimental planning and wrote the first draft. Figures, tables, and supporting online material were produced by L. Chen, Y. D. K., M. P., T. Z. and X. W. We thank L. Shapiro and members of the Structural Biology Section, Vaccine Research Center (VRC), for discussions and comments on the manuscript, M. Connors for patient serum, M. Fung for antibodies G3-42 and G3-299, J. Robinson for antibodies 1.5e and F91, J. Stuckey for assistance with figures and tables, S. Subramaniam for EM tomograms, C. Winter and C. Huang for S2 production of core YU2 gp120, X. Yang for preparation of JR-FL gp120, and the Flow Cytometry Core, VRC, for assistance with antibody binding to cell-surface-expressed HIV-1 spikes. Support for this work was provided by the Intramural Research Program of NIH, the International AIDS Vaccine Initiative, a grant from the Bill and Melinda Gates Foundation Grand Challenges in Global Heath Initiative, and grants from NIH. The use of insertion device 22 (Southeast Region Collaborative Access Team) at the Advanced Photon Source was supported by the U. S. Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. Coordinates and structure factors for the F105-gp120 complex (accession code 3HI1) and the b13-gp120 complexes (accession codes 3IDX and 3IDY for C222 and C2221 forms, respectively) have been deposited with the Protein Data Bank.

References

 

DC FieldValueLanguage
dc.contributor.authorChen, Len_HK
dc.contributor.authorDo Kwon, Yen_HK
dc.contributor.authorZhou, Ten_HK
dc.contributor.authorWu, Xen_HK
dc.contributor.authorO'Dell, Sen_HK
dc.contributor.authorCavacini, Len_HK
dc.contributor.authorHessell, AJen_HK
dc.contributor.authorPancera, Men_HK
dc.contributor.authorTang, Men_HK
dc.contributor.authorXu, Len_HK
dc.contributor.authorYang, ZYen_HK
dc.contributor.authorZhang, MYen_HK
dc.contributor.authorArthos, Jen_HK
dc.contributor.authorBurton, DRen_HK
dc.contributor.authorDimitrov, DSen_HK
dc.contributor.authorNabel, GJen_HK
dc.contributor.authorPosner, MRen_HK
dc.contributor.authorSodroski, Jen_HK
dc.contributor.authorWyatt, Ren_HK
dc.contributor.authorMascola, JRen_HK
dc.contributor.authorKwong, PDen_HK
dc.date.accessioned2010-09-03T01:12:27Z-
dc.date.available2010-09-03T01:12:27Z-
dc.date.issued2009en_HK
dc.identifier.citationScience, 2009, v. 326 n. 5956, p. 1123-1127en_HK
dc.identifier.issn0036-8075en_HK
dc.identifier.urihttp://hdl.handle.net/10722/65597-
dc.description.abstractThe site on HIV-1 gp120 that binds to the CD4 receptor is vulnerable to antibodies. However, most antibodies that interact with this site cannot neutralize HIV-1. To understand the basis of this resistance, we determined co-crystal structures for two poorly neutralizing, CD4-binding site (CD4BS) antibodies, F105 and b13, in complexes with gp120. Both antibodies exhibited approach angles to gp120 similar to those of CD4 and a rare, broadly neutralizing CD4BS antibody, b12. Slight differences in recognition, however, resulted in substantial differences in F105- and b13-bound conformations relative to b12-bound gp120. Modeling and binding experiments revealed these conformations to be poorly compatible with the viral spike. This incompatibility, the consequence of slight differences in CD4BS recognition, renders HIV-1 resistant to all but the most accurately targeted antibodies.en_HK
dc.languageeng-
dc.publisherAmerican Association for the Advancement of Science. The Journal's web site is located at http://sciencemag.orgen_HK
dc.relation.ispartofScienceen_HK
dc.rightsScience. Copyright © American Association for the Advancement of Science.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshAntibodies, Neutralizing - chemistry - immunology - metabolism-
dc.subject.meshAntigens, CD4 - chemistry - metabolism-
dc.subject.meshHIV Antibodies - chemistry - immunology - metabolism-
dc.subject.meshHIV Envelope Protein gp120 - chemistry - immunology - metabolism-
dc.subject.meshImmune Evasion-
dc.titleStructural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120en_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0036-8075&volume=326&issue=5956&spage=1123&epage=1127&date=2009&atitle=Structural+basis+of+immune+evasion+at+the+site+of+CD4+attachment+on+HIV-1+gp120-
dc.identifier.emailZhang, MY:zhangmy@hku.hken_HK
dc.identifier.authorityZhang, MY=rp01409en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1126/science.1175868en_HK
dc.identifier.pmid19965434-
dc.identifier.pmcidPMC2862588-
dc.identifier.scopuseid_2-s2.0-70450182950en_HK
dc.identifier.hkuros185553-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-70450182950&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume326en_HK
dc.identifier.issue5956en_HK
dc.identifier.spage1123en_HK
dc.identifier.epage1127en_HK
dc.identifier.eissn1095-9203-
dc.identifier.isiWOS:000271951000048-
dc.publisher.placeUnited Statesen_HK
dc.identifier.f10001282055-
dc.identifier.scopusauthoridChen, L=7409441567en_HK
dc.identifier.scopusauthoridDo Kwon, Y=24490788600en_HK
dc.identifier.scopusauthoridZhou, T=7402989717en_HK
dc.identifier.scopusauthoridWu, X=11139573200en_HK
dc.identifier.scopusauthoridO'Dell, S=7006539155en_HK
dc.identifier.scopusauthoridCavacini, L=7003582782en_HK
dc.identifier.scopusauthoridHessell, AJ=6506631419en_HK
dc.identifier.scopusauthoridPancera, M=8787874300en_HK
dc.identifier.scopusauthoridTang, M=55205546900en_HK
dc.identifier.scopusauthoridXu, L=7404744597en_HK
dc.identifier.scopusauthoridYang, ZY=7405434139en_HK
dc.identifier.scopusauthoridZhang, MY=35316639300en_HK
dc.identifier.scopusauthoridArthos, J=6603796858en_HK
dc.identifier.scopusauthoridBurton, DR=7401577043en_HK
dc.identifier.scopusauthoridDimitrov, DS=7202564539en_HK
dc.identifier.scopusauthoridNabel, GJ=7103259116en_HK
dc.identifier.scopusauthoridPosner, MR=7201990644en_HK
dc.identifier.scopusauthoridSodroski, J=7102286559en_HK
dc.identifier.scopusauthoridWyatt, R=7402848241en_HK
dc.identifier.scopusauthoridMascola, JR=7005343486en_HK
dc.identifier.scopusauthoridKwong, PD=7006992407en_HK
dc.identifier.citeulike9697595-

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