FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial
Shuying S. Li, … , M. Juliana McElrath, Daniel E. Geraghty
Shuying S. Li, … , M. Juliana McElrath, Daniel E. Geraghty
Published September 2, 2014; First published August 8, 2014
Citation Information: J Clin Invest. 2014;124(9):3879-3890. https://doi.org/10.1172/JCI75539.
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Research Article AIDS/HIV

FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial

Abstract

The phase III RV144 HIV-1 vaccine trial estimated vaccine efficacy (VE) to be 31.2%. This trial demonstrated that the presence of HIV-1–specific IgG-binding Abs to envelope (Env) V1V2 inversely correlated with infection risk, while the presence of Env-specific plasma IgA Abs directly correlated with risk of HIV-1 infection. Moreover, Ab-dependent cellular cytotoxicity responses inversely correlated with risk of infection in vaccine recipients with low IgA; therefore, we hypothesized that vaccine-induced Fc receptor–mediated (FcR-mediated) Ab function is indicative of vaccine protection. We sequenced exons and surrounding areas of FcR-encoding genes and found one FCGR2C tag SNP (rs114945036) that associated with VE against HIV-1 subtype CRF01_AE, with lysine at position 169 (169K) in the V2 loop (CRF01_AE 169K). Individuals carrying CC in this SNP had an estimated VE of 15%, while individuals carrying CT or TT exhibited a VE of 91%. Furthermore, the rs114945036 SNP was highly associated with 3 other FCGR2C SNPs (rs138747765, rs78603008, and rs373013207). Env-specific IgG and IgG3 Abs, IgG avidity, and neutralizing Abs inversely correlated with CRF01_AE 169K HIV-1 infection risk in the CT- or TT-carrying vaccine recipients only. These data suggest a potent role of Fc-γ receptors and Fc-mediated Ab function in conferring protection from transmission risk in the RV144 VE trial.

Authors

Shuying S. Li, Peter B. Gilbert, Georgia D. Tomaras, Gustavo Kijak, Guido Ferrari, Rasmi Thomas, Chul-Woo Pyo, Susan Zolla-Pazner, David Montefiori, Hua-Xin Liao, Gary Nabel, Abraham Pinter, David T. Evans, Raphael Gottardo, James Y. Dai, Holly Janes, Daryl Morris, Youyi Fong, Paul T. Edlefsen, Fusheng Li, Nicole Frahm, Michael D. Alpert, Heather Prentice, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Jaranit Kaewkungwal, Sorachai Nitayaphan, Merlin L. Robb, Robert J. O’Connell, Barton F. Haynes, Nelson L. Michael, Jerome H. Kim, M. Juliana McElrath, Daniel E. Geraghty

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Figure 2

Sieve effects (differential VE against CRF01_AE HIV-1 strains matching versus mismatching the vaccine insert).

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Sieve effects (differential VE against CRF01_AE HIV-1 strains matching v...
Sieve effects at (A) amino acid position 169 and (B) amino acid position 181 of the HIV-1 V2 Env were assessed within each of the 2 genotype subgroups of FCGR2C 126C>T (rs114945036). The error bars are 95% confidence intervals. The P values in the graphs are for comparing genotype-specific VE between and within the CC and CT/TT subgroups. The sieve effect at position 169 differed between the CC and CT/TT subgroups (interaction P = 0.04 at the bottom of A).