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Title: Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial target multiple epitopes and preferentially use the VH1 gene family
Authors: Mattia Bonsignori
Justin Pollara
Anthony A. Moody
Xi Chen
Kwan Ki Hwang
Thaddeus C. Gurley
Daniel M. Kozink
Dawn J. Marshall
John F. Whitesides
Chun Yen Tsao
Georgia D. Tomaras
David C. Montefiori
Guido Ferrari
Hua Xin Liao
Barton F. Haynes
Michael D. Alpert
David T. Evans
Peter B. Gilbert
Ying Huang
Jaranit Kaewkungwal
Sorachai Nitayaphan
Punnee Pitisuttithum
Supachai Rerks-Ngarm
Jerome H. Kim
Nelson L. Michael
George K. Lewis
Anthony DeVico
Duke University School of Medicine
Harvard Medical School
Fred Hutchinson Cancer Research Center
Mahidol University
Armed Forces Research Institute of Medical Sciences, Thailand
Thailand Ministry of Public Health
U.S. Military HIV Research Program
University of Maryland School of Medicine
Keywords: Immunology and Microbiology
Issue Date: 1-Nov-2012
Citation: Journal of Virology. Vol.86, No.21 (2012), 11521-11532
Abstract: The ALVAC-HIV/AIDSVAX-B/E RV144 vaccine trial showed an estimated efficacy of 31%. RV144 secondary immune correlate analysis demonstrated that the combination of low plasma anti-HIV-1 Env IgA antibodies and high levels of antibody-dependent cellular cytotoxicity (ADCC) inversely correlate with infection risk. One hypothesisis that the observed protection in RV144 is partially due to ADCC-mediating antibodies. We found that the majority (73 to 90%) of a representative group of vaccinees displayed plasma ADCC activity, usually (96.2%) blocked by competition with the C1 region-specific A32 Fab fragment.Using memory B-cell cultures and antigen-specific B-cell sorting, we isolated 23 ADCC-mediating nonclonally related antibodies from 6 vaccine recipients. These antibodies targeted A32-blockable conformational epitopes (n=19), a non-A32-blockable conformational epitope (n=1), and the gp120 Env variable loops (n=3). Fourteen antibodies mediated cross-clade target cell killing.ADCC-mediating antibodies displayed modest levels of V-heavy (VH) chain somatic mutation (0.5 to 1.5%) and also displayed a disproportionate usage of VH1 family genes (74%), a phenomenon recently described for CD4-binding site broadly neutralizing antibodies (bNAbs). Maximal ADCC activity of VH1 antibodies correlated with mutation frequency. The polyclonality and low mutation frequency of these VH1 antibodies reveal fundamental differences in the regulation and maturation of these ADCC-mediating responses compared to VH1 bNAbs. © 2012, American Society for Microbiology.
ISSN: 10985514
Appears in Collections:Scopus 2011-2015

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