J Clin Invest. 2014 Sep 2;124(9):3879-90. doi: 10.1172/JCI75539.

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

Li SS, Gilbert PB, Tomaras GD, Kijak G, Ferrari G, Thomas R, Pyo CW, Zolla-Pazner S, Montefiori D, Liao HX, 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.

 

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 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.

PMID: 25105367

 

SUPPLEMENT:

RV144 trial, which tested the ALVAC-HIV (vCP152) prime and bivalent clade B/E recombinant gp120 boost vaccine regimen, was the first HIV vaccine trial that showed a partial positive efficacy. Correlate analysis (Haynes et al. 2012) showed that IgG binding-antibodies (Abs) to HIV envelope protein correlated inversely with risk of HIV infection whereas plasma IgA binding-Abs correlated positively with risk. Furthermore, Haynes et al. showed IgG avidity, Ab-dependent cellular cytotoxicity (ADCC), neutralizing Abs, and CD4+ T cell response correlated inversely with risk in the group of vaccinees with low plasma IgA, indicating that Env-specific IgA Abs may block the protective IgG Fc-mediated effector function. In this study, we identified polymorphisms in Fc gamma receptor 2C gene (FCGR2C) associated with vaccine efficacy (VE): VE was up to 91% against CRF01_AE circulating HIV-1 strains in Thailand and 64% against any HIV-1 strain in the people carrying CT or TT genotype of one FCGR2C single nucleotide polymorphism locus in contrast to 15% and 11% in the people carrying CC genotype, respectively. We have also found that the positive correlation between plasma Env-specific IgA Abs and risk of HIV-1 infection was observed in the people with CC genotype but not in the people with CT or TT genotype; IgG avidity, neutralizing Abs, and subtype IgG3 correlated inversely with risk of HIV-1 infection only in the people with CT or TT genotype.

These results suggest that Env-specific IgA blocking occurs in people with CC genotype but not people with CT or TT genotypes. They also suggest a potent role of Fc-γ receptors and Fc-mediated Ab function in conferring protection from transmission risk in the RV144 trial. This study will inform/direct future experiments and vaccine trials that can increase knowledge about mechanisms of vaccine protections. Understanding the process of Ab-mediated vaccine protection, where virus neutralization and Fc-FcR interaction together achieve immune protection, is critical for HIV vaccine design.”

Reference:

1. Haynes BF, et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med. 2012;366(14):1275–1286.

 

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