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Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site
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نویسنده
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crooks e.t. ,tong t. ,chakrabarti b. ,narayan k. ,georgiev i.s. ,menis s. ,huang x. ,kulp d. ,osawa k. ,muranaka j. ,stewart-jones g. ,destefano j. ,o’dell s. ,labranche c. ,robinson j.e. ,montefiori d.c. ,mckee k. ,du s.x. ,doria-rose n. ,kwong p.d. ,mascola j.r. ,zhu p. ,schief w.r. ,wyatt r.t. ,whalen r.g. ,binley j.m.
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منبع
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plos pathogens - 2015 - دوره : 11 - شماره : 5
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چکیده
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Eliciting broad tier 2 neutralizing antibodies (nabs) is a major goal of hiv-1 vaccine research. here we investigated the ability of native,membrane-expressed jr-fl env trimers to elicit nabs. unusually potent nab titers developed in 2 of 8 rabbits immunized with virus-like particles (vlps) expressing trimers (trimer vlp sera) and in 1 of 20 rabbits immunized with dna expressing native env trimer,followed by a protein boost (dna trimer sera). all 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of jr-fl gp120. specifically,trimer vlp sera took advantage of the unusual absence of a glycan at residue 197 (present in 98.7% of envs). intriguingly,removing the n197 glycan (with no loss of tier 2 phenotype) rendered 50% or 16.7% (n = 18) of clade b tier 2 isolates sensitive to the two trimer vlp sera,showing broad neutralization via the surface masked by the n197 glycan. neutralizing sera targeted epitopes that overlap with the cd4 binding site,consistent with the role of the n197 glycan in a putative “glycan fence” that limits access to this region. a bioinformatics analysis suggested shared features of one of the trimer vlp sera and monoclonal antibody pg9,consistent with its trimer-dependency. the neutralizing dna trimer serum took advantage of the absence of a glycan at residue 230,also proximal to the cd4 binding site and suggesting an epitope similar to that of monoclonal antibody 8anc195,albeit lacking tier 2 breadth. taken together,our data show for the first time that strain-specific holes in the glycan fence can allow the development of tier 2 neutralizing antibodies to native spikes. moreover,cross-neutralization can occur in the absence of protecting glycan. overall,our observations provide new insights that may inform the future development of a neutralizing antibody vaccine.
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آدرس
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san diego biomedical research institute,san diego,ca, United States, san diego biomedical research institute,san diego,ca, United States, international aids vaccine initiative (iavi) neutralizing antibody center at the scripps research institute,department of immunology and microbial science,la jolla,ca,united states,international aids vaccine initiative hiv vaccine design program,translational health science and technology institute,haryana, India, altravax,inc.,sunnyvale,ca,united states,department of stem cell and regenerative biology,harvard stem cell institute,harvard university,cambridge,ma, United States, vaccine research center,national institutes of health (nih),bethesda,md, United States, international aids vaccine initiative (iavi) neutralizing antibody center at the scripps research institute,department of immunology and microbial science,la jolla,ca,united states,center for hiv/aids vaccine immunology and immunogen discovery,the scripps research institute,la jolla,ca, United States, national laboratory of biomacromolecules,institute of biophysics,chinese academy of sciences,chaoyang district,beijing, China, international aids vaccine initiative (iavi) neutralizing antibody center at the scripps research institute,department of immunology and microbial science,la jolla,ca,united states,center for hiv/aids vaccine immunology and immunogen discovery,the scripps research institute,la jolla,ca, United States, san diego biomedical research institute,san diego,ca, United States, altravax,inc.,sunnyvale,ca, United States, vaccine research center,national institutes of health (nih),bethesda,md,united states,mrc human immunology unit,weatherall institute of molecular medicine,university of oxford,the john radcliffe hospital,oxford, United Kingdom, international aids vaccine initiative,design and development laboratory,brooklyn,ny, United States, vaccine research center,national institutes of health (nih),bethesda,md, United States, department of surgery,duke university,duke university medical center,durham,nc, United States, tulane national primate research center,covington,la, United States, department of surgery,duke university,duke university medical center,durham,nc, United States, vaccine research center,national institutes of health (nih),bethesda,md, United States, altravax,inc.,sunnyvale,ca, United States, vaccine research center,national institutes of health (nih),bethesda,md, United States, vaccine research center,national institutes of health (nih),bethesda,md, United States, vaccine research center,national institutes of health (nih),bethesda,md, United States, national laboratory of biomacromolecules,institute of biophysics,chinese academy of sciences,chaoyang district,beijing, China, international aids vaccine initiative (iavi) neutralizing antibody center at the scripps research institute,department of immunology and microbial science,la jolla,ca,united states,center for hiv/aids vaccine immunology and immunogen discovery,the scripps research institute,la jolla,ca,united states,ragon institute of mgh,mit,and harvard,cambridge,ma, United States, international aids vaccine initiative (iavi) neutralizing antibody center at the scripps research institute,department of immunology and microbial science,la jolla,ca,united states,center for hiv/aids vaccine immunology and immunogen discovery,the scripps research institute,la jolla,ca, United States, altravax,inc.,sunnyvale,ca, United States, san diego biomedical research institute,san diego,ca, United States
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Authors
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