P37.06
Background: A role for the HIV secondary coreceptor, CXCR6, in long-term nonprogression (LTNP) to AIDS has been reported. A single nucleotide polymorphism (SNP), rs2234358, located 42bp downstream from the CXCR6 termination codon, significantly associates with LTNP but not elite control (EC) in cohorts of European descent. In this study we investigated the role of rs2234358 in HIV-1 disease progression in populations of sub-Saharan descent.
Methods: Study participants included HIV-1-infected Black South African individuals with differing disease phenotypes (progressors, n=109; LTNPs, n=47; ECs, n=11) and healthy HIV-uninfected Caucasian (n=28) and Black (n=36) individuals. A continuous region encompassing the CXCR6 open reading frame (ORF) and the untranslated regions (7.0kb) was amplified in 4 overlapping sections. Amplified fragments were sequenced and analysed for the presence of SNPs, indels and intragenic haplotypes to identify potential rs2234358-associated haplotypes. Real-time PCR assays were developed to detect the rs2234358 SNP and another SNP, CXCR6-E3K, also shown to associate with clinical outcome of HIV-1 infected individuals.
Results: The rs2234358 SNP frequency did not differ between LTNPs (51.1%) and progressing (56.9%) Black individuals (P=0.386). CXCR6 gene sequencing failed to detect linkage disequilibrium between rs2234358 and other SNPs within CXCR6. CXCR6-E3K, located in the ORF, was found to be present at high allelic frequencies within control Black individuals (44.4%) and absent in the Caucasian individuals genotyped. In LTNPs heterozygosity for the E3K SNP was overrepresented (72.3%; 85.3% of whom also had rs2234358) compared to progressing (34.9%) individuals (P<0.001, OR=0.17).
Conclusions: The E3K SNP is likely to affect both CXCR6 cell surface expression and/or binding of its ligand. Thus, we hypothesize that the high prevalence and interplay of both these mutations in Black South African individuals may be masking the effect of the rs2234358 SNP on LTNP within this population.
