Affinity maturation in an HIV broadly neutralizing B-cell lineage through reorientation of variable domains

Abstract

Rapidly evolving pathogens, such as human immunodeficiency and influenza viruses, escape immune defenses provided by most vaccine-induced antibodies. Proposed strategies to elicit broadly neutralizing antibodies require a deeper understanding of antibody affinity maturation and evolution of the immune response to vaccination or infection. In HIV-infected individuals, viruses and B cells evolve together, creating a virus−antibody “arms race.” Analysis of samples from an individual designated CH505 has illustrated the interplay between an antibody lineage, CH103, and autologous viruses at various time points. The CH103 antibodies, relatively broad in their neutralization spectrum, interact with the CD4 binding site of gp120, with a contact dominated by CDRH3. We show by analyzing structures of progenitor and intermediate antibodies and by correlating them with measurements of binding to various gp120s that there was a shift in the relative orientation of the light- and heavy-chain variable domains during evolution of the CH103 lineage. We further show that mutations leading to this conformational shift probably occurred in response to insertions in variable loop 5 (V5) of the HIV envelope. The shift displaced the tips of the light chain away from contact with V5, making room for the inserted residues, which had allowed escape from neutralization by the progenitor antibody. These results, which document the selective mechanism underlying this example of a virus−antibody arms race, illustrate the functional significance of affinity maturation by mutation outside the complementarity determining region surface of the antibody molecule. Significance An HIV vaccine must induce antibodies [broadly neutralizing antibodies (bnAbs)] that neutralize many viral variants. Determining pathways of antibody affinity maturation that have led to specific bnAbs and tracking coevolution in an infected individual of virus and antibody will define characteristics of immunogens that might elicit broad responses. We have followed, in an infected individual, one round of coevolution of viral envelope with antibodies from a single lineage. Insertions into a loop (V5) in gp120 of autologous viruses allowed escape from neutralization by antibodies in this lineage; antibody affinity maturation shifted the relative orientation of the light- and heavy-chain variable domains, allowing binding to envelopes with augmented V5. The results illustrate a mechanism of affinity maturation through mutation outside the antigen combining site.