title: Rational HIV immunogen design to target specific germline B cell receptors.
abstract: Vaccine development to induce broadly neutralizing antibodies (bNAbs) against HIV-1 is a global health priority. Potent VRC01-class bNAbs against the CD4 binding site of HIV gp120 have been isolated from HIV-1-infected individuals; however, such bNAbs have not been induced by vaccination. Wild-type gp120 proteins lack detectable affinity for predicted germline precursors of VRC01-class bNAbs, making them poor immunogens to prime a VRC01-class response. We employed computation-guided, in vitro screening to engineer a germline-targeting gp120 outer domain immunogen that binds to multiple VRC01-class bNAbs and germline precursors, and elucidated germline binding crystallographically. When multimerized on nanoparticles, this immunogen (eOD-GT6) activates germline and mature VRC01-class B cells. Thus, eOD-GT6 nanoparticles have promise as a vaccine prime. In principle, germline-targeting strategies could be applied to other epitopes and pathogens.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Jardine
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Julien
authors.forename: Sergey
authors.initials: S
authors.lastname: Menis
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ota
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Kalyuzhniy
authors.forename: Andrew
authors.initials: A
authors.lastname: McGuire
authors.forename: Devin
authors.initials: D
authors.lastname: Sok
authors.forename: Po-Ssu
authors.initials: PS
authors.lastname: Huang
authors.forename: Skye
authors.initials: S
authors.lastname: MacPherson
authors.forename: Meaghan
authors.initials: M
authors.lastname: Jones
authors.forename: Travis
authors.initials: T
authors.lastname: Nieusma
authors.forename: John
authors.initials: J
authors.lastname: Mathison
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stamatatos
authors.forename: David
authors.initials: D
authors.lastname: Nemazee
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: William R
authors.initials: WR
authors.lastname: Schief
mesh_terms: D016915:AIDS Vaccines / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D005854:Germ Cells / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008251:Macaca; D051379:Mice; D023421:Models, Animal; D008969:Molecular Sequence Data; D053758:Nanoparticles; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D011947:Receptors, Antigen, B-Cell
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