2012
DOI: 10.1038/nature11371
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Structural and genetic basis for development of broadly neutralizing influenza antibodies

Abstract: Influenza viruses take a yearly toll on human life despite efforts to contain them with seasonal vaccines. These viruses evade human immunity through the evolution of variants that resist neutralization. The identification of antibodies that recognize invariant structures on the influenza haemagglutinin (HA) protein have invigorated efforts to develop universal influenza vaccines. Specifically, antibodies to the highly conserved stem region of HA neutralize diverse viral subtypes. These antibodies largely deri… Show more

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Cited by 249 publications
(314 citation statements)
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“…However, an antibody with a K D of 3 × 10 −4 M could still activate B cells when expressed as a BCR in mice (41). In another study, although somatic mutations were reverted in three affinity-matured antibodies and the unmutated mAbs do not bind to the antigen, when the unmutated mAbs were expressed in a B-cell line as a BCR, they signaled when antigen was added (42). Furthermore, the probability that antibodies that bind to one unrelated antigen should have fortuitous somatic mutations that bind to two or three nonoverlapping epitopes of a DSG3 is small.…”
Section: Discussionmentioning
confidence: 99%
“…However, an antibody with a K D of 3 × 10 −4 M could still activate B cells when expressed as a BCR in mice (41). In another study, although somatic mutations were reverted in three affinity-matured antibodies and the unmutated mAbs do not bind to the antigen, when the unmutated mAbs were expressed in a B-cell line as a BCR, they signaled when antigen was added (42). Furthermore, the probability that antibodies that bind to one unrelated antigen should have fortuitous somatic mutations that bind to two or three nonoverlapping epitopes of a DSG3 is small.…”
Section: Discussionmentioning
confidence: 99%
“…In addition, 65% of the mutations at residue 104, which encodes the serine in the C-terminal end of CDR1, are transitions that would create an alanine, and the rest are transversions that would create a threonine or isoleucine; according to the Pymol program, these changes could also create instability at the bases of both CDR2 and CDR1. These mutations are reminiscent of the mutations at the bases of the CDRs in anti-HIV and anti-influenza antibodies that have no direct contact with the antigen but change the stability of the CDR loops in some cases, converting the antibodies from affinity-matured highly neutralizing antibodies with restricted specificity into broadly neutralizing and protective antibodies to those viruses (1,70,71). The glutamine and leucine encoded by the highly mutated AGCT at residues 9 and 10 ( Fig.…”
Section: Discussionmentioning
confidence: 99%
“…However, the unmutated common ancestor (UCA) and the intermediate (I-2) precursor antibodies in the CH65-CH67 lineage have significantly weaker affinity for the H1 HAs (Schmidt et al, 2013). These studies have suggested that the mutations acquired through affinity maturation dictate the structural conformation of the antibody CDR loops, as for the V H 1-69 stem-targeted antibody CR6261 (Lingwood et al, 2012). Molecular-dynamics simulations and crystal structure comparisons of UCA, I-2, CH65-HA, apo CH67 and CH67-HA have suggested that the maturation pathway leads to a preconfiguration of the antibody HCDR3 conformation that is optimal for antigen recognition and which is observed in the Fab-HA complexes (Schmidt et al, 2013).…”
Section: Introductionmentioning
confidence: 99%
“…These bnAbs bind the influenza hemagglutinin glycoprotein (HA; Wilson et al, 1981) and target functionally conserved epitopes on the HA head and stem regions (Lee & Wilson, 2015). In conjunction with these advances in antibody discovery, the developmental pathways that the HA stem-targeted V H 1-69-encoded antibodies take to convert from germline to affinitymatured forms are an active area of investigation (Lingwood et al, 2012;Avnir et al, 2014;Pappas et al, 2014). These studies show that somatic mutations that arise during the affinitymaturation process can affect the conformations of the antibody complementarity-determining region (CDR) loops.…”
Section: Introductionmentioning
confidence: 99%