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

• Published in: The Journal of clinical investigation Vol. 124; no. 9; pp. 3879 - 3890
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.09.2014
• Subjects: Acquired immune deficiency syndrome; Acquired Immunodeficiency Syndrome - genetics; Acquired Immunodeficiency Syndrome - immunology; AIDS; AIDS Vaccines - immunology; Analysis; Biomedical research; Clinical trials; Development and progression; Fc receptors; Genetic aspects; Genetic polymorphisms; Genotype; Genotype & phenotype; Health aspects; HIV Antibodies - immunology; HIV Envelope Protein gp120 - immunology; HIV infection; HIV-1 - immunology; Human immunodeficiency virus 1; Humans; Immune system; Immunoglobulins; Infections; Medical research; Patient outcomes; Polymorphism, Single Nucleotide; Receptors, IgG - genetics; Risk factors; Vaccination; Thailand
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI75539

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.