000006855 001__ 6855 000006855 005__ 20240523043359.0 000006855 02470 $$ahttps://doi.org/10.1371/journal.ppat.1005815$$2doi 000006855 037__ $$aTEXTUAL$$bArticle 000006855 041__ $$aeng 000006855 245__ $$aMinimally Mutated HIV-1 Broadly Neutralizing Antibodies to Guide Reductionist Vaccine Design 000006855 269__ $$a2016-08-25 000006855 336__ $$aArticle 000006855 520__ $$aAn optimal HIV vaccine should induce broadly neutralizing antibodies (bnAbs) that neutralize diverse viral strains and subtypes. However, potent bnAbs develop in only a small fraction of HIV-infected individuals, all contain rare features such as extensive mutation, insertions, deletions, and/or long complementarity-determining regions, and some are polyreactive, casting doubt on whether bnAbs to HIV can be reliably induced by vaccination. We engineered two potent VRC01-class bnAbs that minimized rare features. According to a quantitative features frequency analysis, the set of features for one of these minimally mutated bnAbs compared favorably with all 68 HIV bnAbs analyzed and was similar to antibodies elicited by common vaccines. This same minimally mutated bnAb lacked polyreactivity in four different assays. We then divided the minimal mutations into spatial clusters and dissected the epitope components interacting with those clusters, by mutational and crystallographic analyses coupled with neutralization assays. Finally, by synthesizing available data, we developed a working-concept boosting strategy to select the mutation clusters in a logical order following a germline-targeting prime. We have thus developed potent HIV bnAbs that may be more tractable vaccine goals compared to existing bnAbs, and we have proposed a strategy to elicit them. This reductionist approach to vaccine design, guided by antibody and antigen structure, could be applied to design candidate vaccines for other HIV bnAbs or protective Abs against other pathogens. 000006855 536__ $$oInternational AIDS Vaccine Initiative Neutralizing Antibody Consortium and Center 000006855 536__ $$oBill and Melinda Gates Foundation$$aCAVD award 000006855 536__ $$oBayer Science and Education Foundation 000006855 536__ $$oNational Institute of Allergy and Infectious Diseases$$cP01AI081625 000006855 536__ $$oNational Institute of Allergy and Infectious Diseases$$cCHAVI-ID 1UM1 AI100663 000006855 536__ $$oNational Institute of Allergy and Infectious Diseases$$cP01 AI110657 000006855 536__ $$oNational Institute of Allergy and Infectious Diseases$$cR01 AI084817 000006855 536__ $$oDepartment of Energy$$cDE-AC02-06CH11357 000006855 536__ $$oNCI$$cY1-CO-1020 000006855 536__ $$oNIGMS$$cY1-GM-1104 000006855 540__ $$a<p>© 2016 Jardine et al.</p> <p>This is an open access article distributed under the terms of the <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License</a>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</p> 000006855 542__ $$fCC BY 000006855 594__ $$aCoordinates and structure factors have been deposited with the Protein Data Bank for the two crystal structures reported in this manuscript: (1) eOD-N276Kif + VRC01 (PDB ID: 5KZC) and (2) BG505 SOSIP + PGT122 + NIH45-46 (PDB ID: 5D9Q). All other relevant data are within the paper and its Supporting Information files. 000006855 690__ $$aBiological Sciences Division 000006855 691__ $$aMedicine 000006855 692__ $$aGwen Knapp Center for Lupus and Immunology Research 000006855 7001_ $$aJardine, Joseph G.$$uScripps Research Institute 000006855 7001_ $$aSok, Devin$$uScripps Research Institute 000006855 7001_ $$aJulien, Jean-Philippe$$uScripps Research Institute 000006855 7001_ $$aBriney, Bryan$$uScripps Research Institute 000006855 7001_ $$aSarkar, Anita$$uScripps Research Institute 000006855 7001_ $$aLiang, Chi-Hui$$uScripps Research Institute 000006855 7001_ $$aScherer, Erin A.$$uFred Hutchinson Cancer Research Center 000006855 7001_ $$aHenry Dunand, Carole J.$$uUniversity of Chicago 000006855 7001_ $$aAdachi, Yumiko$$uScripps Research Institute 000006855 7001_ $$aAdachi, Yumiko$$uScripps Research Institute 000006855 7001_ $$aDiwanji, Devan$$uScripps Research Institute 000006855 7001_ $$1http://orcid.org/0000-0002-4070-5270$$2ORCID$$aHsueh, Jessica$$uScripps Research Institute 000006855 7001_ $$aJones, Meaghan$$uScripps Research Institute 000006855 7001_ $$aKalyuzhniy, Oleksandr$$uScripps Research Institute 000006855 7001_ $$aKubitz, Michael$$uScripps Research Institute 000006855 7001_ $$aSpencer, Skye$$uScripps Research Institute 000006855 7001_ $$aPauthner, Matthias$$uScripps Research Institute 000006855 7001_ $$aSaye-Francisco, Karen L.$$uScripps Research Institute 000006855 7001_ $$aSesterhenn, Fabian$$uScripps Research Institute 000006855 7001_ $$aWilson, Patrick C.$$uUniversity of Chicago 000006855 7001_ $$aGalloway, Denise M.$$uFred Hutchinson Cancer Research Center 000006855 7001_ $$aStanfield, Robyn L.$$uScripps Research Institute 000006855 7001_ $$aWilson, Ian A.$$uScripps Research Institute 000006855 7001_ $$aBurton, Dennis R.$$uScripps Research Institute 000006855 7001_ $$aSchief, William R.$$uScripps Research Institute 000006855 773__ $$tPLOS Pathogens 000006855 8564_ $$yArticle$$94fc82a33-3280-4598-809a-410d272166cb$$s5185632$$uhttps://knowledge.uchicago.edu/record/6855/files/journal.ppat.1005815.pdf$$ePublic 000006855 8564_ $$ySupporting information$$9f75dcdc2-6c26-497b-a69e-312724b85b2a$$s7913761$$uhttps://knowledge.uchicago.edu/record/6855/files/ppat.1005815.zip$$ePublic 000006855 908__ $$aI agree 000006855 909CO $$ooai:uchicago.tind.io:6855$$pGLOBAL_SET 000006855 983__ $$aArticle