title: Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies.
abstract: Broadly neutralizing antibodies (bnAbs) against HIV are believed to be a critical component of the protective responses elicited by an effective HIV vaccine. Neutralizing antibodies against the evolutionarily conserved CD4-binding site (CD4-BS) on the HIV envelope glycoprotein (Env) are capable of inhibiting infection of diverse HIV strains, and have been isolated from HIV-infected individuals. Despite the presence of anti-CD4-BS broadly neutralizing antibody (bnAb) epitopes on recombinant Env, Env immunization has so far failed to elicit such antibodies. Here, we show that Env immunogens fail to engage the germline-reverted forms of known bnAbs that target the CD4-BS. However, we found that the elimination of a conserved glycosylation site located in Loop D and two glycosylation sites located in variable region 5 of Env allows Env-binding to, and activation of, B cells expressing the germline-reverted BCRs of two potent broadly neutralizing antibodies, VRC01 and NIH45-46. Our results offer a possible explanation as to why Env immunogens have been ineffective in stimulating the production of such bNAbs. Importantly, they provide key information as to how such immunogens can be engineered to initiate the process of antibody-affinity maturation against one of the most conserved Env regions.
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: McGuire
authors.forename: Sam
authors.initials: S
authors.lastname: Hoot
authors.forename: Anita M
authors.initials: AM
authors.lastname: Dreyer
authors.forename: Adriana
authors.initials: A
authors.lastname: Lippy
authors.forename: Andrew
authors.initials: A
authors.lastname: Stuart
authors.forename: Kristen W
authors.initials: KW
authors.lastname: Cohen
authors.forename: Joseph
authors.initials: J
authors.lastname: Jardine
authors.forename: Sergey
authors.initials: S
authors.lastname: Menis
authors.forename: Johannes F
authors.initials: JF
authors.lastname: Scheid
authors.forename: Anthony P
authors.initials: AP
authors.lastname: West
authors.forename: William R
authors.initials: WR
authors.lastname: Schief
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stamatatos
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology*; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D006031:Glycosylation; D015483:HIV Antibodies / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D015202:Protein Engineering; D017433:Protein Structure, Secondary; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus