Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk.
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.
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, C-W; 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
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