Background:  FcγRIIIa—an IgG receptor found on natural killer cells, monocytes, macrophages, and dendritic cells—is encoded by a gene with a functional polymorphism affecting IgG binding affinity. The valine/valine (VV) form of the receptor binds IgG1 and IgG3 with higher affinity than the phenylalanine/phenylalanine (FF) form; the heterozygous FV receptor has intermediate affinity. FcγRIIIa genotype has been associated with susceptibility to or severity of autoimmune and infectious diseases and with the efficacy of monoclonal antibody treatment. We tested the hypothesis that FcγRIIIa genotype is associated with the risk of acquiring HIV infection.

Methods:  Participants in the Multicenter AIDS Cohort Study (MACS) were genotyped. The sample included 555 infected subjects and 555 uninfected controls, matched by age and number of anal sex partners; 430 infected subjects had known seroconversion dates, whereas 125 were seroprevelant cases. Conditional logistic regression analysis, including race as a covariate, was used to analyze associations between genotype and infection risk.

Results:  Among seroconverters and their matched controls, FV were significantly more likely to become infected than FF (OR =1.7; 95%CI 1.2 to 2.3; p = 0.001); VV had a risk similar to that of FF (OR = 0.9; 95%CI 0.7 to 1.3; p = 0.7). When both the seroconverter and seroprevalent groups were analyzed together, again, FV were more likely to be infected than FF (OR = 1.5; 95%CI 1.1 to 1.9; p = 0.007), and VV and FF had similar risks (OR = 0.9; 95%CI 0.7 to 1.2; p = 0.5). There was no association between FcγRIIIa genotype and infection risk in the seroprevalent group alone (whose sample size was much smaller than that of the seroconverter group).

Conclusions:  FcγRIIIa appears to be an HIV-1 restriction gene that confers a heterozygous disadvantage. The association between FcγRIIIa genotype and infection risk is striking because it implies that virus or infected cells opsonized with antibody (the ligand for FcγRIIIa) are key determinants of successful infection. The antibody is likely to be donor-derived, but could also be a pre-existing, recipient antibody that binds to virions or infected cells.