Abstract
Understanding affinity maturation of antibodies that can target many variants of HIV-1 is important for vaccine development. While the antigen-binding site of antibodies is known to mutate throughout the co-evolution of antibodies and viruses in infected individuals, the roles of the mutations in the antibody framework region are not well understood. Throughout affinity maturation, the CH103 broadly neutralizing antibody lineage, from an individual designated CH505, altered the orientation of one of its antibody variable domains. The change in orientation was a response to insertions in the variable loop 5 (V5) of the HIV envelope. In this study, we generated CH103 lineage antibody variants in which residues in the variable domain interface were mutated, and measured the binding to both autologous and heterologous HIV-1 envelopes. Our data show that very few mutations in an early intermediate antibody of the lineage can improve binding toward both autologous and heterologous HIV-1 envelopes. We also crystallized an antibody mutant to show that framework mutations alone can result in a shift in relative orientations of the variable domains. Taken together, our results demonstrate the functional importance of residues located outside the antigen-binding site in affinity maturation.
Highlights
A well-recognized aspect of antibody affinity maturation is the somatic hypermutation (SHM) of the antigen binding regions, i.e., the complementarity determining regions, or CDRs [1]
While the unmutated common ancestor (UCA) and early intermediate antibodies had a structure whose variable domain (VL) domain, the antibody DE loop residues 65L-67L, would clash with variable loop 5 (V5) loops that were longer than that of the CH505 transmitted founder (T/F) Env, the relative shift in VL with respect to VH appeared to accommodate these V5 loop insertions as well as the longer V5 loops found in heterologous HIV-1 Envs (Figure 1A)
Autologous CH505 Envs with longer V5 loops displayed differential binding to different members of the CH103 antibody lineage, whereas the CH505 T/F Env bound with similar affinity to all CH103 lineage members (Table 1) [22]
Summary
A well-recognized aspect of antibody affinity maturation is the somatic hypermutation (SHM) of the antigen binding regions, i.e., the complementarity determining regions, or CDRs [1]. This is even observed in antibodies that target rapidly evolving pathogens, such as HIV-1 and influenza. The long time frame is partly due to the fact that the virus rapidly develops escape mutations to avoid antibody recognition [4, 5]. This results in bnAbs with high mutation frequencies
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