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J Clin Invest. 2019 Oct 7. pii: 126391. doi: 10.1172/JCI126391. [Epub ahead of print]

Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk.

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Duke Human Vaccine Institute, Duke University, Durham, North Carolina, USA.
Statistical Center for HIV/AIDS Research and Prevention.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Department of Biostatistics, University of Washington, Seattle, Washington, USA.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Department of Biostatistics, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina, USA.
Department of Surgery and.
Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA.
Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia Pennsylvania, USA.
Division of AIDS and.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
Division of Infectious Diseases, Department of Medicine, Columbia University, New York, New York, USA.
Department of Immunology, Duke University, Durham, North Carolina, USA.


HVTN 505 is a preventative vaccine efficacy trial testing DNA followed by recombinant adenovirus serotype 5 (rAd5) in circumcised, Ad5-seronegative men and transgendered persons who have sex with men in the United States. Identified immune correlates of lower HIV-1 risk and a virus sieve analysis revealed that, despite lacking overall efficacy, vaccine-elicited responses exerted pressure on infecting HIV-1 viruses. To interrogate the mechanism of the antibody correlate of HIV-1 risk, we examined antigen-specific antibody recruitment of Fcγ receptors (FcγRs), antibody-dependent cellular phagocytosis (ADCP), and the role of anti-envelope (anti-Env) IgG3. In a prespecified immune correlates analysis, antibody-dependent monocyte phagocytosis and antibody binding to FcγRIIa correlated with decreased HIV-1 risk. Follow-up analyses revealed that anti-Env IgG3 breadth correlated with reduced HIV-1 risk, anti-Env IgA negatively modified infection risk by Fc effector functions, and that vaccine recipients with a specific FcγRIIa single-nucleotide polymorphism locus had a stronger correlation with decreased HIV-1 risk when ADCP, Env-FcγRIIa, and IgG3 binding were high. Additionally, FcγRIIa engagement correlated with decreased viral load setpoint in vaccine recipients who acquired HIV-1. These data support a role for vaccine-elicited anti-HIV-1 Env IgG3, antibody engagement of FcRs, and phagocytosis as potential mechanisms for HIV-1 prevention.


AIDS vaccine; AIDS/HIV; Vaccines

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