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

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 LiNicole 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

Research output: Contribution to journalArticlepeer-review

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 TTcarrying 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.

Original languageEnglish (US)
Pages (from-to)3879-3890
Number of pages12
JournalJournal of Clinical Investigation
Volume124
Issue number9
DOIs
StatePublished - Sep 2 2014
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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