HIV-1 gp120 vaccine induces affinity maturation in both new and persistent antibody clonal lineages |
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Authors: | Moody M Anthony Yates Nicole L Amos Joshua D Drinker Mark S Eudailey Joshua A Gurley Thaddeus C Marshall Dawn J Whitesides John F Chen Xi Foulger Andrew Yu Jae-Sung Zhang Ruijun Meyerhoff R Ryan Parks Robert Scull Julia Cavanaugh Wang Lu Vandergrift Nathan A Pickeral Joy Pollara Justin Kelsoe Garnett Alam S Munir Ferrari Guido Montefiori David C Voss Gerald Liao Hua-Xin Tomaras Georgia D Haynes Barton F |
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Institution: | Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, USA. moody007@mc.duke.edu |
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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 (gp120W6.1D). 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 VH 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, gp120W6.1D 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. |
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