Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk
Scott D. Neidich, … , Peter B. Gilbert, Georgia D. Tomaras
Scott D. Neidich, … , Peter B. Gilbert, Georgia D. Tomaras
Published October 7, 2019
Citation Information: J Clin Invest. 2019;129(11):4838-4849. https://doi.org/10.1172/JCI126391.
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Research Article AIDS/HIV

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

Abstract

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.

Authors

Scott D. Neidich, Youyi Fong, Shuying S. Li, Daniel E. Geraghty, Brian D. Williamson, William Chad Young, Derrick Goodman, Kelly E. Seaton, Xiaoying Shen, Sheetal Sawant, Lu Zhang, Allan C. deCamp, Bryan S. Blette, Mengshu Shao, Nicole L. Yates, Frederick Feely, Chul-Woo Pyo, Guido Ferrari, HVTN 505 Team, Ian Frank, Shelly T. Karuna, Edith M. Swann, John R. Mascola, Barney S. Graham, Scott M. Hammer, Magdalena E. Sobieszczyk, Lawrence Corey, Holly E. Janes, M. Juliana McElrath, Raphael Gottardo, Peter B. Gilbert, Georgia D. Tomaras

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Figure 5

Host genetics (FcγRIIa SNPs) significantly modified the correlation of ADCP with HIV-1 infection risk.

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Host genetics (FcγRIIa SNPs) significantly modified the correlation of A...
**Interaction P = 0.0006 and Q value = 0.026, *within genotype group P < 0.05 after adjusting for all covariates and 2 cellular variables. P values were calculated based on the Wald test. Con S gp140 phagocytosis (A), FcγRIIa binding (B), and Env IgG3 (C) associations with FCGR2A-intron13-645-G/A. Q value was adjusted for 7 × 2 statistical tests with respect to 7 FcγRIIa SNPs and 2 primary Fc effector functions. In the first analysis, we adjusted for age, race, behavior risk, and BMI. In the second analysis, in addition to adjusting these covariates, we also adjusted for 2 cellular responses, Env CD4+ T cell polyfunctionality score (PFS) and Env CD8+ T cell PFS. Box-and-whisker plots show the median line and interquartile ranges. There are 9 infected and 60 uninfected vaccinees with the GG genotype and 16 infected and 62 uninfected in the GA/AA genotype group.