Fc Gamma Receptor Polymorphisms Modulated the Vaccine Effect on HIV-1 Risk in the HVTN 505 HIV Vaccine Trial

Abstract

HIV Vaccine Trials Network (HVTN) 505 was a phase 2b efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) HIV vaccine regimen. Although the trial was stopped early for lack of overall efficacy, later correlates of risk and sieve analyses generated the hypothesis that the DNA/rAd5 vaccine regimen protected some vaccinees from HIV infection yet enhanced HIV infection risk for others. Here, we assessed whether and how host Fc gamma receptor (FcγR) genetic variations influenced the DNA/rAd5 vaccine regimen's effect on HIV infection risk. We found that vaccine receipt significantly increased HIV acquisition compared with placebo receipt among participants carrying the FCGR2C-TATA haplotype (comprising minor alleles of four FCGR2C single-nucleotide polymorphism [SNP] sites) (hazard ratio [HR] = 9.79, P = 0.035) but not among participants without the haplotype (HR = 0.86, P = 0.67); the interaction of vaccine and haplotype effect was significant (P = 0.034). Similarly, vaccine receipt increased HIV acquisition compared with placebo receipt among participants carrying the FCGR3B-AGA haplotype (comprising minor alleles of the 3 FCGR3B SNPs) (HR = 2.78, P = 0.058) but not among participants without the haplotype (HR = 0.73, P = 0.44); again, the interaction of vaccine and haplotype was significant (P = 0.047). The FCGR3B-AGA haplotype also influenced whether a combined Env-specific CD8⁺ T-cell polyfunctionality score and IgG response correlated significantly with HIV risk; an FCGR2A SNP and two FCGR2B SNPs influenced whether anti-gp140 antibody-dependent cellular phagocytosis correlated significantly with HIV risk. These results provide further evidence that Fc gamma receptor genetic variations may modulate HIV vaccine effects and immune function after HIV vaccination.IMPORTANCE By analyzing data from the HVTN 505 efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) vaccine regimen, we found that host genetics, specifically Fc gamma receptor genetic variations, influenced whether receiving the DNA/rAd5 regimen was beneficial, neutral, or detrimental to an individual with respect to HIV-1 acquisition risk. Moreover, Fc gamma receptor genetic variations influenced immune responses to the DNA/rAd5 vaccine regimen. Thus, Fc gamma receptor genetic variations should be considered in the analysis of future HIV vaccine trials and the development of HIV vaccines.

Keywords: Fc gamma receptor; HIV/AIDS vaccine trial; HVTN 505; genetic polymorphisms.

FIG 1

Assessment of whether and how each of the 33 FcγR SNPs modified the hazard ratio (vaccine/placebo) of HIV acquisition in HVTN 505. (A) Volcano plot of P value for the interaction between genotype and treatment arm (y axis, −log₁₀ scale) versus difference in estimated log(HR) (vaccine/placebo) between genotype groups (x axis). (B) Volcano plot of false discovery rate (FDR) (y axis, −log₁₀ scale) versus difference in estimated log(HR) between genotype groups (x axis). Red dots represent FcγR SNPs that significantly modify the HR (vaccine/placebo). (C) Quantile-quantile plot of the observed and expected P values (−log₁₀ scale for both).

FIG 2

SNP composition of the two haplotype blocks observed in HVTN 505 participants. One of the haplotype blocks was comprised of five FCGR2C SNPs, and the other haplotype block was comprised of three FCGR3B SNPs. (A) Linkage disequilibrium measurements (D′) between the 8 SNP genotypes. (B) Correlation (r²) between the 8 SNP genotypes. (C) Haplotypes and frequencies within FCGR2C and FCGR3B haplotype blocks. Shown in each haplotype block are the haplotypes with a frequency of ≥1%. The haplotype designated with an asterisk in each haplotype block contains all minor alleles from the composite FcγR SNPs. Lines connecting haplotypes across haplotype blocks indicate the frequency of haplotype linkage, where line width represents frequency magnitude (thin lines for a frequency of ≥1% and thick lines for a frequency of ≥10%). Plots were generated using Haploview.

FIG 3

FCGR3B-AGA haplotype modified immune correlates of risk in HVTN 505. (A) Distributions of Env-specific IgG responses, as assessed by binding antibody multiplex assay, plotted according to case/control HIV infection outcome status and FCGR3B-AGA haplotype status. (B) Distributions of Env-specific CD8 polyfunctionality scores (PFS), plotted according to case/control status and FCGR3B-AGA haplotype status. (C) Percentages of HVTN 505 vaccine recipients having medium or high responses for either Env IgG or CD8 PFS in HVTN 505 cases and controls, plotted according to case/control status and FCGR3B-AGA haplotype status.

FIG 4

FcγR SNPs (FCGR2A-intron13-645-G/A [rs2165088], FCGR2B-exon5-523-G/A [rs6665610], and FCGR2B-intron14-352-T/G [rs6666965]) modified the association of Fc effector functions (ConS gp140 ADCP score and FcγRIIa binding) with HIV-1 acquisition risk. (A and B) ConS gp140 ADCP score (A) and ConS gp140 FcγRIIa binding (B). On each panel, distributions of Fc effector functions were plotted according to case/control HIV infection outcome status and genotype groups.