title: HIV-1 Vaccine-elicited Antibodies Reverted to Their Inferred Naive Germline Reveal Associations between Binding Affinity and in vivo Activation.
abstract: The elicitation of HIV-1 broadly neutralizing antibodies following envelope glycoprotein (Env) vaccination is exceedingly difficult. Suboptimal engagement of naïve B cells is suggested to limit these low frequency events, especially at the conserved CD4bs. Here, we analyzed CD4bs-directed monoclonal antibodies (mAbs) elicited by YU2 gp140-foldon trimers in a non-human primate by selective sorting using CD4bs "knock out" trimers. Following two inoculations, the CD4bs-directed mAbs efficiently recognized the eliciting immunogen in their affinity-maturing state but did not recognize CD4bs-defective probes. We reverted these mAbs to their most likely inferred germline (igL) state, leaving the HCDR3 unaltered, to establish correlates of in vitro affinity to in vivo activation. Most igL-reverted mAbs bound the eliciting gp140 immunogen, indicating that CD4bs-directed B cells possessing reasonable affinity existed in the naïve repertoire. We detected relatively high affinities for the majority of the igL mAbs to gp120 and of Fabs to gp140, which, as expected, increased when the antibodies 'matured' following vaccination. Affinity increases were associated with slower off-rates as well as with acquisition of neutralizing capacity. These data reveal in vitro binding properties associated with in vivo activation that result in functional archiving of antigen-specific B cells elicited by a complex glycoprotein antigen following immunization.
authors.affiliation: IAVI Neutralizing Antibody Center at TSRI, La Jolla CA.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA.
authors.forename: Kaifan
authors.initials: K
authors.lastname: Dai
authors.affiliation: IAVI Neutralizing Antibody Center at TSRI, La Jolla CA.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA.
authors.forename: Salar N
authors.initials: SN
authors.lastname: Khan
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA.
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA.
authors.forename: Linling
authors.initials: L
authors.lastname: He
authors.affiliation: IAVI Neutralizing Antibody Center at TSRI, La Jolla CA.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA.
authors.forename: Javier
authors.initials: J
authors.lastname: Guenaga
authors.affiliation: IAVI Neutralizing Antibody Center at TSRI, La Jolla CA.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA.|The Scripps CHAVI-ID, The Scripps Research Institute, La Jolla CA.
authors.forename: Jidnyasa
authors.initials: J
authors.lastname: Ingale
authors.affiliation: Department of Microbiology, and Tumor Cell Biology Karolinska Institutet, Stockholm SE.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sundling
authors.affiliation: Vaccine Research Center, Bethesda MD.
authors.forename: Sijy
authors.initials: S
authors.lastname: O'Dell
authors.affiliation: Vaccine Research Center, Bethesda MD.
authors.forename: Krisha
authors.initials: K
authors.lastname: McKee
authors.affiliation: Department of Microbiology, and Tumor Cell Biology Karolinska Institutet, Stockholm SE.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Phad
authors.affiliation: Department of Microbiology, and Tumor Cell Biology Karolinska Institutet, Stockholm SE.
authors.forename: Martin
authors.initials: M
authors.lastname: Corcoran
authors.affiliation: IAVI Neutralizing Antibody Center at TSRI, La Jolla CA.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA.
authors.forename: Richard
authors.initials: R
authors.lastname: Wilson
authors.affiliation: Vaccine Research Center, Bethesda MD.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: IAVI Neutralizing Antibody Center at TSRI, La Jolla CA.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA.|The Scripps CHAVI-ID, The Scripps Research Institute, La Jolla CA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: IAVI Neutralizing Antibody Center at TSRI, La Jolla CA.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA.
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Microbiology, and Tumor Cell Biology Karolinska Institutet, Stockholm SE.
authors.forename: Gunilla B
authors.initials: GB
authors.lastname: Karlsson Hedestam
authors.affiliation: IAVI Neutralizing Antibody Center at TSRI, La Jolla CA.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA.|The Scripps CHAVI-ID, The Scripps Research Institute, La Jolla CA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wyatt
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D015483:HIV Antibodies / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007114:Immunization; D007700:Kinetics; D008253:Macaca mulatta; D008958:Models, Molecular; D009500:Neutralization Tests; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D020349:Surface Plasmon Resonance; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D022801:Complementarity Determining Regions; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus