Li Shuying S, Gilbert Peter B, Tomaras Georgia D, Kijak Gustavo, Ferrari Guido, Thomas Rasmi, Pyo Chul-Woo, Zolla-Pazner Susan, Montefiori David, Liao Hua-Xin, Nabel Gary, Pinter Abraham, Evans David T, Gottardo Raphael, Dai James Y, Janes Holly, Morris Daryl, Fong Youyi, Edlefsen Paul T, Li Fusheng, Frahm Nicole, Alpert Michael D, Prentice Heather, Rerks-Ngarm Supachai, Pitisuttithum Punnee, Kaewkungwal Jaranit, Nitayaphan Sorachai, Robb Merlin L, O'Connell Robert J, Haynes Barton F, Michael Nelson L, Kim Jerome H, McElrath M Juliana, Geraghty Daniel E
J Clin Invest. 2014 Sep;124(9):3879-90. doi: 10.1172/JCI75539. Epub 2014 Aug 8.
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.
III期RV144 HIV-1疫苗试验估计疫苗效力（VE）为31.2%。该试验表明，存在针对包膜（Env）V1V2的HIV-1特异性IgG结合抗体与感染风险呈负相关，而Env特异性血浆IgA抗体的存在与HIV-1感染风险呈正相关。此外，抗体依赖性细胞毒性反应与低IgA疫苗接种者的感染风险呈负相关；因此，我们推测疫苗诱导的Fc受体介导（FcR介导）的抗体功能可指示疫苗的保护作用。我们对FcR编码基因的外显子及周边区域进行了测序，发现一个FCGR2C标签单核苷酸多态性（rs114945036）与针对HIV-1 CRF01_AE亚型的疫苗效力相关，其V2环中第169位为赖氨酸（169K）（CRF01_AE 169K）。该单核苷酸多态性中携带CC的个体估计疫苗效力为15%，而携带CT或TT的个体疫苗效力为91%。此外，rs114945036单核苷酸多态性与其他3个FCGR2C单核苷酸多态性（rs138747765、rs78603008和rs373013207）高度相关。仅在携带CT或TT的疫苗接种者中，Env特异性IgG和IgG3抗体、IgG亲和力及中和抗体与CRF01_AE 169K HIV-1感染风险呈负相关。这些数据表明，在RV144疫苗效力试验中，Fc-γ受体和Fc介导的抗体功能在赋予预防传播风险的保护作用方面具有重要作用。
