title: Antibodies to a superantigenic glycoprotein 120 epitope as the basis for developing an HIV vaccine.
abstract: Failure to induce synthesis of neutralizing Abs to the CD4 binding determinant (CD4BD) of gp120, a central objective in HIV vaccine research, has been alternately ascribed to insufficient immunogen binding to Abs in their germline V region configuration expressed as BCRs, insufficient adaptive mutations in Ab V regions, and conformational instability of gp120. We employed peptide analogs of gp120 residues 421-433 within the CD4BD (CD4BD(core)) to identify Abs produced without prior exposure to HIV (constitutive Abs). The CD4BD(core) peptide was recognized by single-chain Fv fragments from noninfected humans with lupus that neutralized genetically diverse strains belonging to various HIV subtypes. Replacing the framework region (FR) of a V(H)4-family single-chain Fv with the corresponding V(H)3-family FRs from single-chain Fv JL427 improved the CD4BD(core) peptide-binding activity, suggesting a CD4BD(core) binding site outside the pocket formed by the CDRs. Replacement mutations in the FR site vicinity suggested the potential for adaptive improvement. A very small subset of serum CD4BD(core)-specific serum IgAs from noninfected humans without autoimmune disease isolated by epitope-specific chromatography neutralized the virus potently. A CD4BD(core)-specific, HIV neutralizing murine IgM with H and L chain V regions (V(H) and V(L) regions) free of immunogen-driven somatic mutations was induced by immunization with a CD4BD(core) peptide analog containing an electrophilic group that binds B cells covalently. The studies indicate broad and potent HIV neutralization by constitutive Abs as an innate, germline-encoded activity directed to the superantigenic CD4BD(core) epitope that is available for amplification for vaccination against HIV.
authors.affiliation: Department of Pathology and Laboratory Medicine, Chemical Immunology Research Center, University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Planque
authors.forename: Yukie
authors.initials: Y
authors.lastname: Mitsuda
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nishiyama
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Karle
authors.forename: Stephane
authors.initials: S
authors.lastname: Boivin
authors.forename: Maria
authors.initials: M
authors.lastname: Salas
authors.forename: Mary-Kate
authors.initials: MK
authors.lastname: Morris
authors.forename: Mariko
authors.initials: M
authors.lastname: Hara
authors.forename: Guangling
authors.initials: G
authors.lastname: Liao
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Massey
authors.forename: Carl V
authors.initials: CV
authors.lastname: Hanson
authors.forename: Sudhir
authors.initials: S
authors.lastname: Paul
mesh_terms: D016915:AIDS Vaccines / Q000096:biosynthesis*; D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D015483:HIV Antibodies / Q000096:biosynthesis / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology; D057127:Single-Chain Antibodies / Q000096:biosynthesis / Q000276:immunology; D018089:Superantigens / Q000737:chemistry / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies; D018089:Superantigens