title: High-Resolution Longitudinal Study of HIV-1 Env Vaccine-Elicited B Cell Responses to the Virus Primary Receptor Binding Site Reveals Affinity Maturation and Clonal Persistence.
abstract: Because of the genetic variability of the HIV-1 envelope glycoproteins (Env), the elicitation of neutralizing Abs to conserved neutralization determinants including the primary receptor binding site, CD4 binding site (CD4bs), is a major focus of vaccine development. To gain insight into the evolution of Env-elicited Ab responses, we used single B cell analysis to interrogate the memory B cell Ig repertoires from two rhesus macaques after five serial immunizations with Env/adjuvant. We observed that the CD4bs-specific repertoire displayed unique features in the third CDR of Ig H chains with minor alterations along the immunization course. Progressive affinity maturation occurred as evidenced by elevated levels of somatic hypermutation (SHM) in Ab sequences isolated at the late immunization time point compared with the early time point. Abs with higher SHM were associated with increased binding affinity and virus neutralization capacity. Moreover, a notable portion of the CD4bs-specific repertoire was maintained between early and late immunization time points, suggesting that persistent clonal lineages were induced by Env vaccination. Furthermore, we found that the predominant persistent CD4bs-specific clonal lineages had larger population sizes and higher affinities than that from the rest of the repertoires, underscoring the critical role of Ag affinity selection in Ab maturation and clonal expansion. Genetic and functional analyses revealed that the accumulation of SHM in both framework regions and CDRs contributed to the clonal affinity and antigenicity evolution. Our longitudinal study provides high-resolution understanding of the dynamically evolving CD4bs-specific B cell response after Env immunization in primates.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850;
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia;
authors.forename: Christopher
authors.identifier: 0000-0002-6138-690X
authors.initials: C
authors.lastname: Sundling
authors.affiliation: International AIDS Vaccine Initiative Neutralizing Antibody Center at The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Richard
authors.identifier: 0000-0002-7718-5344
authors.initials: R
authors.lastname: Wilson
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Sijy
authors.initials: S
authors.lastname: O'Dell
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Yajing
authors.identifier: 0000-0001-8330-3901
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Kaifan
authors.initials: K
authors.lastname: Dai
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
authors.forename: Ganesh E
authors.identifier: 0000-0002-0047-6899
authors.initials: GE
authors.lastname: Phad
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; Scripps Center for HIV Vaccine Immunogen Discovery, La Jolla, CA 92037; and.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
authors.forename: Gunilla B
authors.initials: GB
authors.lastname: Karlsson Hedestam
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; International AIDS Vaccine Initiative Neutralizing Antibody Center at The Scripps Research Institute, La Jolla, CA 92037; Scripps Center for HIV Vaccine Immunogen Discovery, La Jolla, CA 92037; and.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wyatt
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850; International AIDS Vaccine Initiative Neutralizing Antibody Center at The Scripps Research Institute, La Jolla, CA 92037; yuxingli@umd.edu.
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Li
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D000915:Antibody Affinity; D001666:Binding Sites, Antibody / Q000235:genetics; D015704:CD4 Antigens / Q000378:metabolism; D002470:Cell Survival; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000235:genetics; D019295:Computational Biology; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D011485:Protein Binding; D059010:Single-Cell Analysis; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: D016915:AIDS Vaccines; D000914:Antibodies, Viral; D015704:CD4 Antigens; D022801:Complementarity Determining Regions; D054299:env Gene Products, Human Immunodeficiency Virus