title: Effects of Darwinian Selection and Mutability on Rate of Broadly Neutralizing Antibody Evolution during HIV-1 Infection.
abstract: Accumulation of somatic mutations in antibody variable regions is critical for antibody affinity maturation, with HIV-1 broadly neutralizing antibodies (bnAbs) generally requiring years to develop. We recently found that the rate at which mutations accumulate decreases over time, but the mechanism governing this slowing is unclear. In this study, we investigated whether natural selection and/or mutability of the antibody variable region contributed significantly to observed decrease in rate. We used longitudinally sampled sequences of immunoglobulin transcripts of single lineages from each of 3 donors, as determined by next generation sequencing. We estimated the evolutionary rates of the complementarity determining regions (CDRs), which are most significant for functional selection, and found they evolved about 1.5- to 2- fold faster than the framework regions. We also analyzed the presence of AID hotspots and coldspots at different points in lineage development and observed an average decrease in mutability of less than 10 percent over time. Altogether, the correlation between Darwinian selection strength and evolutionary rate trended toward significance, especially for CDRs, but cannot fully explain the observed changes in evolutionary rate. The mutability modulated by AID hotspots and coldspots changes correlated only weakly with evolutionary rates. The combined effects of Darwinian selection and mutability contribute substantially to, but do not fully explain, evolutionary rate change for HIV-1-targeting bnAb lineages.
authors.affiliation: Department of Biochemistry and Molecular Biophysics and Department of Systems Biology, Columbia University, New York, New York, United States of America.
authors.forename: Zizhang
authors.initials: Z
authors.lastname: Sheng
authors.affiliation: Department of Biochemistry and Molecular Biophysics and Department of Systems Biology, Columbia University, New York, New York, United States of America.
authors.forename: Chaim A
authors.initials: CA
authors.lastname: Schramm
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
authors.affiliation: Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa.|Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.|Center for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, South Africa.
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: Department of Biochemistry and Molecular Biophysics and Department of Systems Biology, Columbia University, New York, New York, United States of America.|Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
mesh_terms: D057134:Antibodies, Neutralizing / Q000235:genetics*; D000915:Antibody Affinity / Q000235:genetics; D022801:Complementarity Determining Regions / Q000235:genetics; D019295:Computational Biology; D019143:Evolution, Molecular; D005803:Genes, Immunoglobulin; D015483:HIV Antibodies / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008137:Longitudinal Studies; D008957:Models, Genetic; D018448:Models, Immunological; D009154:Mutation; D012641:Selection, Genetic; D027041:Somatic Hypermutation, Immunoglobulin
chemical_list: D057134:Antibodies, Neutralizing; D022801:Complementarity Determining Regions; D015483:HIV Antibodies; D007135:Immunoglobulin Variable Region