Lack of Duffy Antigen Receptor for Chemokines: No Influence on HIV Disease Progression in an African Treatment-Naive Population

Abstract

Dear Editors: He et al recently reported an association between a single-nucleotide polymorphism (SNP, rs2814778, -46T→C) in the erythroid specific promoter region of the Duffy antigen receptor for chemokine (DARC) and HIV-1 acquisition and disease progression in African Americans (He et al., 2008). The authors described a higher frequency of the null homozygous genotype (-46C/C) in HIV-infected (70%) versus non-infected individuals (60%). Based on these findings they argued that the null allele confers susceptibility to infection with HIV-1 and suggested that up to 11% of the HIV-1 burden in sub-Saharan Africa could be attributed to homozygosity for the null allele. Oddly, however, these authors reported that the null genotype associated with better outcomes amongst those who became infected, including longer survival and more particularly decelerated loss of CD4+ T-lymphocytes. Another report showed an association between the -46C/C genotype and significantly reduced total white blood cells (WBC) in African Americans explaining ∼20% of population variation in WBC (Nalls et al., 2008). The -46C/C genotype is nearly fixed in those sub-Saharan African populations where Plasmodium vivax is endemic, apparently because it confers resistance against P. vivax malaria, but -46C is virtually absent in individuals of European descent (Tournamille et al., 1995; Hamblin and Di Rienzo, 2000). In those regions of sub-Saharan Africa that are not endemic for P. vivax, the -46C allele is not fixed, however, and the wildtype (-46T) allele is frequently observed (Rosenberg et al., 2007). Considering the potential importance of DARC on HIV-1 disease progression in Africans, we studied the effect of the DARC -46 genotype on outcomes to HIV infection in a cohort of untreated black South Africans. This region of Africa is not endemic for P. vivax and lies outside of the area of 96% mean fixation for -46C; thus, the null allele of DARC is not fixed in our study population and the allele frequency of -46T (the wildtype allele) is about 20%. We assessed the effects of the null (C/C), heterozygous (T/C), and wildtype (T/T) genotypes on rates of CD4 decline and mean HIV-1 viral loads in a group of 381 untreated black South Africans. Since the -46C/C genotype has previously been associated significantly with reduced total WBC (Nalls et al., 2008), we also determined WBC in our cohort in order to verify that our cohort is sufficiently powered to detect an effect of the -46 genotype, where -46C/C is expected to associate with low WBC as previously demonstrated.