Background:  Chemokine (C-C-motif) ligand 5 (CCL5, also known as RANTES) is a potent HIV-1 antagonist that competes with the virus for binding to CCR5. Use of modified RANTES as a microbicide has been tested successfully in primate models. We examined genetic and epigenetic correlates of CCL5 production in HIV-1 seropositive and seronegative adolescents.

Methods:  In 227 HIV-1-seropositive and 184 seronegative adolescents (mostly African Americans), informative single nucleotide polymorphisms in the CCL5 promoter, intron 1 and 3’ untranslated region were detected by DNA sequencing and related techniques. Cytosine (CpG) methylation within promoter sequences derived from CD4⁺ and CD4- cells was quantified using pyrosequencing. Serum (and occasionally plasma) RANTES concentrations were measured using antibody arrays and enzyme-linked immunosorbent assay. Standard statistical procedures suitable for analyses of categorical and continuous variables were applied to test for associations and correlations.

Results:  Major CCL5 haplotypes reported in earlier investigations were readily confirmed in the study population. Serum concentrations of RANTES were usually 2 orders of magnitude higher than those of other C-C and C-X-C chemokines, including macrophage inflammatory proteins (MIP-1a and MIP-1b), which are encoded by multiple genes. Serum RANTES concentrations, which were higher in HIV-1-infected than in uninfected subjects (p <0.001), had weak correlations with early HIV-1 viral load and CD4⁺ T-cell counts in infected patients (Pearson correlation coefficients = 0.37 and  −0.31; p = 0.04 and 0.08, respectively). Statistical adjustment for age, gender, and ethnicity did not alter these relationships. However, neither CCL5 genotypes nor moderate (<50%) promoter CpG methylation could account for inter-individual variability in serum RANTES concentrations.  

Conclusions:  Predominance of RANTES over other chemokines in serum samples may reflect its immunological importance. The mechanisms underlying variable production of RANTES and related chemokines remain elusive.