The FCGR2C allele that modulated the risk of HIV-1 infection in the Thai RV144 vaccine trial is implicated in HIV-1 disease progression

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, P_Bonf = 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.