期刊
JOURNAL OF VIROLOGY
卷 86, 期 21, 页码 11521-11532出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01023-12
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资金
- National Institutes of Health (NIH), National Institutes of Allergies and Infectious Diseases (NIAID) [AI07392]
- Division of AIDS with the Center for HIV/AIDS Vaccine Immunology (CHAVI) [U19 AI067854]
- Collaboration for AIDS Vaccine Discovery (CAVD) from the Bill and Melinda Gates Foundation [38619, 38650]
- U.S. Army Medical Research and Materiel Command (USAMRMC) [Y1-AI-2642-12]
- NIAID [Y1-AI-2642-12]
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-07-2-0067]
- U.S. Department of Defense [W81XWH-07-2-0067]
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 hypothesis is 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 poly-clonality 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.
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