title: Recombinant HIV envelope proteins fail to engage germline versions of anti-CD4bs bNAbs.
abstract: Vaccine candidates for HIV-1 so far have not been able to elicit broadly neutralizing antibodies (bNAbs) although they express the epitopes recognized by bNAbs to the HIV envelope glycoprotein (Env). To understand whether and how Env immunogens interact with the predicted germline versions of known bNAbs, we screened a large panel (N:56) of recombinant Envs (from clades A, B and C) for binding to the germline predecessors of the broadly neutralizing anti-CD4 binding site antibodies b12, NIH45-46 and 3BNC60. Although the mature antibodies reacted with diverse Envs, the corresponding germline antibodies did not display Env-reactivity. Experiments conducted with engineered chimeric antibodies combining the mature and germline heavy and light chains, respectively and vice-versa, revealed that both antibody chains are important for the known cross-reactivity of these antibodies. Our results also indicate that in order for b12 to display its broad cross-reactivity, multiple somatic mutations within its VH region are required. A consequence of the failure of the germline b12 to bind recombinant soluble Env is that Env-induced B-cell activation through the germline b12 BCR does not take place. Our study provides a new explanation for the difficulties in eliciting bNAbs with recombinant soluble Env immunogens. Our study also highlights the need for intense efforts to identify rare naturally occurring or engineered Envs that may engage the germline BCR versions of bNAbs.
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Hoot
authors.forename: Andrew T
authors.initials: AT
authors.lastname: McGuire
authors.forename: Kristen W
authors.initials: KW
authors.lastname: Cohen
authors.forename: Roland K
authors.initials: RK
authors.lastname: Strong
authors.forename: Lars
authors.initials: L
authors.lastname: Hangartner
authors.forename: Florian
authors.initials: F
authors.lastname: Klein
authors.forename: Ron
authors.initials: R
authors.lastname: Diskin
authors.forename: Johannes F
authors.initials: JF
authors.lastname: Scheid
authors.forename: D Noah
authors.initials: DN
authors.lastname: Sather
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stamatatos
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000915:Antibody Affinity / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D002460:Cell Line; D000939:Epitopes / Q000276:immunology; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000276:immunology; D007147:Immunoglobulin Light Chains / Q000276:immunology; D008213:Lymphocyte Activation; D009500:Neutralization Tests; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000888:Antibodies, Anti-Idiotypic; D057134:Antibodies, Neutralizing; D000956:Antigens, Viral; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D054299:env Gene Products, Human Immunodeficiency Virus