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.
View: Text | PDF
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

×

Figure 3

Multiple immune responses among vaccinees contribute to HIV-1 acquisition risk.

Options: View larger image (or click on image) Download as PowerPoint
Multiple immune responses among vaccinees contribute to HIV-1 acquisitio...
(A) Principal components analyses with a scatterplot of the first (PC1) and second (PC2) principal components are shown. In A, summary variables are assessed as described in Supplemental Table 2, with major contributors described in the legend of this figure. Each measurement from an infected vaccinee is represented by a red dot and each measurement from an uninfected vaccinee is represented by a black circle. Ellipses representing 95% confidence regions are shown. **Principal components were significantly inversely correlated with HIV-1 risk (PC1: OR = 0.366, P < 0.001 and PC2: OR = 0.409, P < 0.001). (B) Prediction accuracy of SuperLearner models for different marker sets (all models adjust for the baseline variables age, BMI, and behavioral risk score). CV-AUC is the cross-validated area under the receiver operating characteristic curve. The 95% CI to the right of 0.5 indicates the ability to predict HIV-1 acquisition. Fx Ab = functional antibody variables ADCP, FcγRIIa, FcγRIIIa; no markers = model with baseline variables only. P values were calculated using the Wald test. n = 125 uninfected and 25 infected participants.