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J Immunol. 2016 Dec 15;197(12):4603-4612. Epub 2016 Nov 9.

Diversity of Antiviral IgG Effector Activities Observed in HIV-Infected and Vaccinated Subjects.

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Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
Department of Surgery, Duke University Medical Center, Durham, NC 27710.
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139.
Division of Infectious Diseases, University of California School of Medicine, Irvine, CA 92697.
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
Division of Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201.
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
Department of Computer Science, Dartmouth College, Hanover, NH 03755; and.
Thayer School of Engineering, Dartmouth College, Hanover, NH 03755.
Thayer School of Engineering, Dartmouth College, Hanover, NH 03755


Diverse Ab effector functions mediated by the Fc domain have been commonly associated with reduced risk of infection in a growing number of nonhuman primate and human clinical studies. This study evaluated the anti-HIV Ab effector activities in polyclonal serum samples from HIV-infected donors, VAX004 vaccine recipients, and healthy HIV-negative subjects using a variety of primary and cell line-based assays, including Ab-dependent cellular cytotoxicity (ADCC), Ab-dependent cell-mediated viral inhibition, and Ab-dependent cellular phagocytosis. Additional assay characterization was performed with a panel of Fc-engineered variants of mAb b12. The goal of this study was to characterize different effector functions in the study samples and identify assays that might most comprehensively and dependably capture Fc-mediated Ab functions mediated by different effector cell types and against different viral targets. Deployment of such assays may facilitate assessment of functionally unique humoral responses and contribute to identification of correlates of protection with potential mechanistic significance in future HIV vaccine studies. Multivariate and correlative comparisons identified a set of Ab-dependent cell-mediated viral inhibition and phagocytosis assays that captured different Ab activities and were distinct from a group of ADCC assays that showed a more similar response profile across polyclonal serum samples. The activities of a panel of b12 monoclonal Fc variants further identified distinctions among the ADCC assays. These results reveal the natural diversity of Fc-mediated Ab effector responses among vaccine recipients in the VAX004 trial and in HIV-infected subjects, and they point to the potential importance of polyfunctional Ab responses.

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