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HIV-1 gp120 Vaccine Induces Affinity Maturation in both New and Persistent Antibody Clonal Lineages

HIV-1 gp120 Vaccine Induces Affinity Maturation in both New and Persistent Antibody Clonal Lineages HIV-1 gp120 Vaccine Induces Affinity Maturation in both New and Persistent Antibody Clonal Lineages M. Anthony Moody a , b , Nicole L. Yates a , Joshua D. Amos a , Mark S. Drinker a , Joshua A. Eudailey a , Thaddeus C. Gurley a , Dawn J. Marshall a , John F. Whitesides a , c , Xi Chen a , Andrew Foulger a , Jae-Sung Yu a , c , Ruijun Zhang a , R. Ryan Meyerhoff a , Robert Parks a , Julia Cavanaugh Scull e , Lu Wang a , Nathan A. Vandergrift a , c , Joy Pickeral f , Justin Pollara f , Garnett Kelsoe g , S. Munir Alam a , c , d , Guido Ferrari f , David C. Montefiori f , Gerald Voss h , Hua-Xin Liao a , c , Georgia D. Tomaras a , e , f , g and Barton F. Haynes a , c , g a Duke Human Vaccine Institute Departments of b Pediatrics c Medicine d Pathology e Molecular Genetics and Microbiology f Surgery g Immunology, Duke University Medical Center, Durham, North Carolina, USA h GlaxoSmithKline Biologicals, Rixensart, Belgium 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Virology American Society For Microbiology

HIV-1 gp120 Vaccine Induces Affinity Maturation in both New and Persistent Antibody Clonal Lineages

Journal of Virology , Volume 86 (14): 7496 – Jul 15, 2012

Abstract

HIV-1 gp120 Vaccine Induces Affinity Maturation in both New and Persistent Antibody Clonal Lineages M. Anthony Moody a , b , Nicole L. Yates a , Joshua D. Amos a , Mark S. Drinker a , Joshua A. Eudailey a , Thaddeus C. Gurley a , Dawn J. Marshall a , John F. Whitesides a , c , Xi Chen a , Andrew Foulger a , Jae-Sung Yu a , c , Ruijun Zhang a , R. Ryan Meyerhoff a , Robert Parks a , Julia Cavanaugh Scull e , Lu Wang a , Nathan A. Vandergrift a , c , Joy Pickeral f , Justin Pollara f , Garnett Kelsoe g , S. Munir Alam a , c , d , Guido Ferrari f , David C. Montefiori f , Gerald Voss h , Hua-Xin Liao a , c , Georgia D. Tomaras a , e , f , g and Barton F. Haynes a , c , g a Duke Human Vaccine Institute Departments of b Pediatrics c Medicine d Pathology e Molecular Genetics and Microbiology f Surgery g Immunology, Duke University Medical Center, Durham, North Carolina, USA h GlaxoSmithKline Biologicals, Rixensart, Belgium 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.

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Publisher
American Society For Microbiology
Copyright
Copyright © 2012 by the American society for Microbiology.
ISSN
0022-538X
eISSN
1098-5514
DOI
10.1128/JVI.00426-12
pmid
22553329
Publisher site
See Article on Publisher Site

Abstract

HIV-1 gp120 Vaccine Induces Affinity Maturation in both New and Persistent Antibody Clonal Lineages M. Anthony Moody a , b , Nicole L. Yates a , Joshua D. Amos a , Mark S. Drinker a , Joshua A. Eudailey a , Thaddeus C. Gurley a , Dawn J. Marshall a , John F. Whitesides a , c , Xi Chen a , Andrew Foulger a , Jae-Sung Yu a , c , Ruijun Zhang a , R. Ryan Meyerhoff a , Robert Parks a , Julia Cavanaugh Scull e , Lu Wang a , Nathan A. Vandergrift a , c , Joy Pickeral f , Justin Pollara f , Garnett Kelsoe g , S. Munir Alam a , c , d , Guido Ferrari f , David C. Montefiori f , Gerald Voss h , Hua-Xin Liao a , c , Georgia D. Tomaras a , e , f , g and Barton F. Haynes a , c , g a Duke Human Vaccine Institute Departments of b Pediatrics c Medicine d Pathology e Molecular Genetics and Microbiology f Surgery g Immunology, Duke University Medical Center, Durham, North Carolina, USA h GlaxoSmithKline Biologicals, Rixensart, Belgium 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.

Journal

Journal of VirologyAmerican Society For Microbiology

Published: Jul 15, 2012

References