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The sequence-function landscape of antibody affinity maturation

Banff International Research Station for Mathematical Innovation and Discovery

Antibodies mediate immunity to viruses and other pathogens by binding to specific antigenic targets. Our bodies deploy an evolvable arsenal of naïve antibodies capable of responding to diverse antigens. Upon exposure to a new antigen, potent and mature antibodies emerge from this arsenal through the Darwinian process of affinity maturation, consisting of iterative rounds of mutation and selection for improved binding to the antigen. This work seeks to understand the underlying relationship between sequence and function that guides this somatic evolutionary process by combining bioinformatic analysis of antibody repertoire sequencing data and high-throughput mutational scanning approaches. This framework is being applied to the broadly neutralizing HIV antibody VRC01, a representative of an important class of antibodies that are the subject of ongoing efforts in HIV vaccine design and antiviral therapy. By combining phylogenetic reconstruction of the VRC01 lineage with high-throughput ligand-binding assays, we are uncovering the relationship between sequence and function that guides VRC01 affinity maturation, revealing how epistasis, stochasticity, and historical contingency contribute to the complex maturation trajectory of this antibody. The results will highlight the landscape over which this broad class of therapeutically-important antibodies develop, with key implications for antibody engineering and HIV vaccine design.

Mathematics; Statistical mechanics, structure of matter; Biology and other natural sciences; Mathematical biology

video/mp4

Author affiliation: Fred Hutchinson Cancer Research Center

2020-02-19

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/73566

Unreviewed

http://creativecommons.org/licenses/by-nc-nd/4.0/