title: HIV-1 gp120 vaccine induces affinity maturation in both new and persistent antibody clonal lineages.
abstract: Most antibodies that broadly neutralize HIV-1 are highly somatically mutated in antibody clonal lineages that persist over time. Here, we describe the analysis of human antibodies induced during an HIV-1 vaccine trial (GSK PRO HIV-002) that used the clade B envelope (Env) gp120 of clone W6.1D (gp120(W6.1D)). Using dual-color antigen-specific sorting, we isolated Env-specific human monoclonal antibodies (MAbs) and studied the clonal persistence of antibodies in the setting of HIV-1 Env vaccination. We found evidence of V(H) somatic mutation induced by the vaccine but only to a modest level (3.8% ± 0.5%; range 0 to 8.2%). Analysis of 34 HIV-1-reactive MAbs recovered over four immunizations revealed evidence of both sequential recruitment of naïve B cells and restimulation of previously recruited memory B cells. These recombinant antibodies recapitulated the anti-HIV-1 activity of participant serum including pseudovirus neutralization and antibody-dependent cell-mediated cytotoxicity (ADCC). One antibody (3491) demonstrated a change in specificity following somatic mutation with binding of the inferred unmutated ancestor to a linear C2 peptide while the mutated antibody reacted only with a conformational epitope in gp120 Env. Thus, gp120(W6.1D) was strongly immunogenic but over four immunizations induced levels of affinity maturation below that of broadly neutralizing MAbs. Improved vaccination strategies will be needed to drive persistent stimulation of antibody clonal lineages to induce affinity maturation that results in highly mutated HIV-1 Env-reactive antibodies.
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, USA. moody007@mc.duke.edu
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Moody
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Yates
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Amos
authors.forename: Mark S
authors.initials: MS
authors.lastname: Drinker
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Eudailey
authors.forename: Thaddeus C
authors.initials: TC
authors.lastname: Gurley
authors.forename: Dawn J
authors.initials: DJ
authors.lastname: Marshall
authors.forename: John F
authors.initials: JF
authors.lastname: Whitesides
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Andrew
authors.initials: A
authors.lastname: Foulger
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Yu
authors.forename: Ruijun
authors.initials: R
authors.lastname: Zhang
authors.forename: R Ryan
authors.initials: RR
authors.lastname: Meyerhoff
authors.forename: Robert
authors.initials: R
authors.lastname: Parks
authors.forename: Julia Cavanaugh
authors.initials: JC
authors.lastname: Scull
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Vandergrift
authors.forename: Joy
authors.initials: J
authors.lastname: Pickeral
authors.forename: Justin
authors.initials: J
authors.lastname: Pollara
authors.forename: Garnett
authors.initials: G
authors.lastname: Kelsoe
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
authors.forename: Guido
authors.initials: G
authors.lastname: Ferrari
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Gerald
authors.initials: G
authors.lastname: Voss
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000097:blood / Q000235:genetics / Q000276:immunology; D000915:Antibody Affinity; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity; D001402:B-Lymphocytes / Q000276:immunology; D015483:HIV Antibodies / Q000097:blood / Q000235:genetics / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007115:Immunization Schedule; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory; D022223:Vaccines, Subunit / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007135:Immunoglobulin Variable Region; D022223:Vaccines, Subunit