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The Effects of Somatic Hypermutation on Neutralization and Binding in the PGT121 Family of Broadly Neutralizing HIV Antibodies
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نویسنده
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sok d. ,laserson u. ,laserson j. ,liu y. ,vigneault f. ,julien j.-p. ,briney b. ,ramos a. ,saye k.f. ,le k. ,mahan a. ,wang s. ,kardar m. ,yaari g. ,walker l.m. ,simen b.b. ,st. john e.p. ,chan-hui p.-y. ,swiderek k. ,kleinstein s.h. ,alter g. ,seaman m.s. ,chakraborty a.k. ,koller d. ,wilson i.a. ,church g.m. ,burton d.r. ,poignard p.
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منبع
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plos pathogens - 2013 - دوره : 9 - شماره : 11
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چکیده
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Broadly neutralizing hiv antibodies (bnabs) are typically highly somatically mutated,raising doubts as to whether they can be elicited by vaccination. we used 454 sequencing and designed a novel phylogenetic method to model lineage evolution of the bnabs pgt121-134 and found a positive correlation between the level of somatic hypermutation (shm) and the development of neutralization breadth and potency. strikingly,putative intermediates were characterized that show approximately half the mutation level of pgt121-134 but were still capable of neutralizing roughly 40-80% of pgt121-134 sensitive viruses in a 74-virus panel at median titers between 15- and 3-fold higher than pgt121-134. such antibodies with lower levels of shm may be more amenable to elicitation through vaccination while still providing noteworthy coverage. binding characterization indicated a preference of inferred intermediates for native env binding over monomeric gp120,suggesting that the pgt121-134 lineage may have been selected for binding to native env at some point during maturation. analysis of glycan-dependent neutralization for inferred intermediates identified additional adjacent glycans that comprise the epitope and suggests changes in glycan dependency or recognition over the course of affinity maturation for this lineage. finally,patterns of neutralization of inferred bnab intermediates suggest hypotheses as to how shm may lead to potent and broad hiv neutralization and provide important clues for immunogen design. © 2013 sok et al.
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آدرس
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department of immunology and microbial science,the scripps research institute,la jolla,ca,united states,iavi neutralizing antibody center,the scripps research institute,la jolla,ca,united states,scripps center for hiv/aids vaccine immunology and immunogen discovery,the scripps research institute,la jolla,ca, United States, department of mathematics,massachusetts institute of technology,cambridge,ma,united states,harvard-mit division of health sciences and technology,massachusetts institute of technology,cambridge,ma,united states,department of genetics,harvard medical school,boston,ma, United States, department of computer science,stanford university,stanford,ca, United States, department of computer science,stanford university,stanford,ca,united states,biomedical informatics training program,stanford university school of medicine,stanford,ca, United States, department of genetics,harvard medical school,boston,ma,united states,abvitro inc.,boston,ma, United States, iavi neutralizing antibody center,the scripps research institute,la jolla,ca,united states,scripps center for hiv/aids vaccine immunology and immunogen discovery,the scripps research institute,la jolla,ca,united states,department of integrative structural and computational biology,the scripps research institute,la jolla,ca, United States, department of immunology and microbial science,the scripps research institute,la jolla,ca,united states,iavi neutralizing antibody center,the scripps research institute,la jolla,ca,united states,scripps center for hiv/aids vaccine immunology and immunogen discovery,the scripps research institute,la jolla,ca, United States, department of immunology and microbial science,the scripps research institute,la jolla,ca,united states,iavi neutralizing antibody center,the scripps research institute,la jolla,ca,united states,scripps center for hiv/aids vaccine immunology and immunogen discovery,the scripps research institute,la jolla,ca,united states,international aids vaccine initiative,new york,ny, United States, department of immunology and microbial science,the scripps research institute,la jolla,ca,united states,iavi neutralizing antibody center,the scripps research institute,la jolla,ca,united states,scripps center for hiv/aids vaccine immunology and immunogen discovery,the scripps research institute,la jolla,ca, United States, department of immunology and microbial science,the scripps research institute,la jolla,ca,united states,iavi neutralizing antibody center,the scripps research institute,la jolla,ca,united states,scripps center for hiv/aids vaccine immunology and immunogen discovery,the scripps research institute,la jolla,ca, United States, ragon institute of massachusetts general hospital,massachusetts institute of technology,and harvard university,boston,ma, United States, department of chemical engineering,massachusetts institute of technology,cambridge,ma,united states,department of physics,massachusetts institute of technology,cambridge,ma, United States, department of physics,massachusetts institute of technology,cambridge,ma, United States, department of pathology,yale university school of medicine,new haven,ct, United States, department of immunology and microbial science,the scripps research institute,la jolla,ca, United States, 454 life sciences - a roche company,branford,ct, United States, 454 life sciences - a roche company,branford,ct, United States, theraclone sciences,inc.,seattle,wa, United States, theraclone sciences,inc.,seattle,wa, United States, department of pathology,yale university school of medicine,new haven,ct, United States, ragon institute of massachusetts general hospital,massachusetts institute of technology,and harvard university,boston,ma, United States, beth israel deaconess medical center,boston,ma, United States, ragon institute of massachusetts general hospital,massachusetts institute of technology,and harvard university,boston,ma,united states,department of chemical engineering,massachusetts institute of technology,cambridge,ma,united states,department of physics,massachusetts institute of technology,cambridge,ma,united states,department of chemistry,institute for medical engineering and science,massachusetts institute of technology,cambridge,ma, United States, department of computer science,stanford university,stanford,ca, United States, iavi neutralizing antibody center,the scripps research institute,la jolla,ca,united states,scripps center for hiv/aids vaccine immunology and immunogen discovery,the scripps research institute,la jolla,ca,united states,department of integrative structural and computational biology,the scripps research institute,la jolla,ca, United States, harvard-mit division of health sciences and technology,massachusetts institute of technology,cambridge,ma,united states,department of genetics,harvard medical school,boston,ma, United States, department of immunology and microbial science,the scripps research institute,la jolla,ca,united states,iavi neutralizing antibody center,the scripps research institute,la jolla,ca,united states,scripps center for hiv/aids vaccine immunology and immunogen discovery,the scripps research institute,la jolla,ca,united states,ragon institute of massachusetts general hospital,massachusetts institute of technology,and harvard university,boston,ma, United States, department of immunology and microbial science,the scripps research institute,la jolla,ca,united states,iavi neutralizing antibody center,the scripps research institute,la jolla,ca,united states,international aids vaccine initiative,new york,ny, United States
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Authors
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