TY - JOUR
T1 - FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial
AU - Li, Shuying S.
AU - Gilbert, Peter B.
AU - Tomaras, Georgia D.
AU - Kijak, Gustavo
AU - Ferrari, Guido
AU - Thomas, Rasmi
AU - Pyo, Chul Woo
AU - Zolla-Pazner, Susan
AU - Montefiori, David
AU - Liao, Hua Xin
AU - Nabel, Gary
AU - Pinter, Abraham
AU - Evans, David T.
AU - Gottardo, Raphael
AU - Dai, James Y.
AU - Janes, Holly
AU - Morris, Daryl
AU - Fong, Youyi
AU - Edlefsen, Paul T.
AU - Li, Fusheng
AU - Frahm, Nicole
AU - Alpert, Michael D.
AU - Prentice, Heather
AU - Rerks-Ngarm, Supachai
AU - Pitisuttithum, Punnee
AU - Kaewkungwal, Jaranit
AU - Nitayaphan, Sorachai
AU - Robb, Merlin L.
AU - O'Connell, Robert J.
AU - Haynes, Barton F.
AU - Michael, Nelson L.
AU - Kim, Jerome H.
AU - McElrath, M. Juliana
AU - Geraghty, Daniel E.
PY - 2014/9/2
Y1 - 2014/9/2
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI75539
DO - 10.1172/JCI75539
M3 - Article
C2 - 25105367
AN - SCOPUS:84907014639
SN - 0021-9738
VL - 124
SP - 3879
EP - 3890
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 9
ER -