J Clin Invest. 2019 Oct 7; NA(NA):NA.

PubMed ID: 31589165

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

Neidich SD, Fong Y, Li SS, Geraghty DE, Williamson BD, Young WC, Goodman D, Seaton KE, Shen X, Sawant S, Zhang L, deCamp AC, Blette BS, Shao M, Yates NL, Feely F, Pyo CW, Ferrari G, HVTN 505 Team., Frank I, Karuna ST, Swann EM, Mascola JR, Graham BS, Hammer SM, Sobieszczyk ME, Corey L, Janes HE, McElrath MJ, Gottardo R, Gilbert PB, Tomaras GD

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.