Abstract
In the HIV-1 Thai RV144 vaccine trial—the only trial to demonstrate anyvaccine efficacy to date—a three-variant haplotype within the Fc gamma receptor 2Cgene (FCGR2C) modified the risk of HIV-1acquisition. A similar vaccine regimen is currently being evaluated in South Africain the HVTN702 trial, where the predominant population is polymorphic for only asingle variant in the haplotype, c.134-96C>T. To investigate the significance ofc.134-96C>T in HIV-specific immunity in South Africans, this study assessed itsrole in HIV-1 disease progression. In a cohort of HIV-1-infected South Africancontrollers (n = 71) and progressors (n = 73), the c.134-96C>T minor allele significantlyassociated with increased odds of HIV-1 disease progression (odds ratio 3.80, 95%confidence interval 1.90–7.62; P = 2.0 × 10–4, PBonf = 2.4 × 10–3).It is unlikely that the underlying mechanism involves wild-type FcγRIIc function,since only a single study participant was predicted to express wild-type FcγRIIc asdetermined by the FCGR2C c.798+1A>Gsplice-site variant. Conversely, in silico analysis revealed a potential role forc.134-96C> T in modulating mRNA transcription. In conclusion, these data provideadditional evidence towards a role for FCGR2Cc.134-96C>T in the context of HIV-1 and underscore the need to investigate itssignificance in the HVTN702 efficacy trial in South Africa.
Highlights
It is unclear if the population differences will differentially affect HIV-1 vaccine protection in Thais and South Africans, since the causal variant associated with the Thai Fc gamma receptor 2C gene (FCGR2C) haplotype is unknown and the significance of the c.134-96C>T variant in Africans has not been studied
A weaker association was observed for the c.169T>C (p.X57Q) variant (P = 0.019, PBonf > 0.05; Fig. 1)
Complete linkage disequilibrium (D′ = 1 and r2 = 1) was observed between c.134-96C>T, c.1131058T>C, c.113-684C>T, p.T118I and c.391+111G>A in two mainland Southeast Asia populations (Kinh in Vietnam and Chinese Dai in China) that share common ancestry with Thai populations [13]. These additional linkage patterns may be of significance for elucidating the mechanisms underlying the association of c.134-96C>T with vaccine efficacy in the Thai RV144 vaccine trial and HIV-1 disease progression; it requires confirmation with FCGR2C gene-specific approaches that account for gene copy number variability
Summary
Immune effector functions recruited through the Fc portion of immunoglobulin G (IgG) are increasingly recognised as an important component of HIV-1 protective immunity [1]. In the phase 3 Thai RV144 vaccine trial, which evaluated a prime-boost vaccination regimen of ALVAC-HIV (vCP1521) and HIV1 gp120 AIDSVAX B/E, a novel FCGR2C haplotype significantly modified vaccine efficacy [8, 9]. This haplotype —hereafter referred to as the Thai FCGR2C haplotype— comprised three single-nucleotide variants that were in complete linkage disequilibrium, including c.353C>T It is unclear if the population differences will differentially affect HIV-1 vaccine protection in Thais and South Africans, since the causal variant associated with the Thai FCGR2C haplotype is unknown and the significance of the c.134-96C>T variant in Africans has not been studied. Gender and age did not differ significantly between the HIV-1 controllers (total and individual controller groups) and HIV1 progressors (P > 0.05 for all comparisons)
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