FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial.
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.
Li, SS; Gilbert, PB; Tomaras, GD; Kijak, G; Ferrari, G; Thomas, R; Pyo, C-W; Zolla-Pazner, S; Montefiori, D; Liao, H-X; Nabel, G; Pinter, A; Evans, DT; Gottardo, R; Dai, JY; Janes, H; Morris, D; Fong, Y; Edlefsen, PT; Li, F; Frahm, N; Alpert, MD; Prentice, H; Rerks-Ngarm, S; Pitisuttithum, P; Kaewkungwal, J; Nitayaphan, S; Robb, ML; O'Connell, RJ; Haynes, BF; Michael, NL; Kim, JH; McElrath, MJ; Geraghty, DE
Volume / Issue
Start / End Page
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)