Background:  Macrophage inflammatory protein 1 alpha (MIP-1a) and MIP-1β are unique in that they both consist of non-allelic isoforms encoded by different genes, namely chemokine (C-C-motif) ligand 3 (CCL3), CCL4, CCL3-like 1 (CCL3L1), and CCL4L1. The products of these chemokine genes and of CCL5 (encoding RANTES) can block or interfere with HIV-1 infection through competitive binding to the chemokine (C-C-motif) receptor 5 (CCR5). We evaluated the effect of CCL3L1 and CCL4L1 gene dose on susceptibility and control of HIV-1 infection.

Methods:  Real-time 5’ exonuclease (TaqMan) assays were designed to detect and quantify the CCL3L1, CCL4L1, and related genes for 411 largely African American adolescents from the Reaching for Excellence in Adolescent Care and Health (REACH) study. Serum MIP-1α and MIP-1β concentrations were measured by a commercial multiplex assay. χ² tests and linear regression models were used to evaluate association of CCL3L1 and CCL4L1 gene dose with HIV-1 acquisition, viral load and CD4⁺ T-cell counts. Correlation between CCL3L1 and CCL4L1 gene copies was determined by the Pearson method.

Results:  CCL3 and CCL4 genes occurred invariably as single copies (2 per diploid genome) when adjusted for the housekeeping β globin gene, whereas the copy numbers of CCL3L1 (0 to 11 copies per diploid genome) and CCL4L1 (1 to 6 copies) varied extensively. Neither CCL3L1 nor CCL4L1 gene copy number variation showed appreciable effect on susceptibility to HIV-1 infection or control of disease progression in HIV-1-infected individuals (p ≥0.15 in all analyses). Within individuals, copy numbers of CCL3L1 and CCL4L1 showed moderate linear correlations regardless of ethnicity (pair-wise correlation coefficient r = 0.63 to 0.65, p <0.001). Moreover, serum concentrations of MIP-1a and MIP-1β were persistently low (in the pg/mL range), in contrast with higher concentrations of other related chemokines encoded by single-copy genes.

Conclusions:  Duplication of CCL3L1 and CCL4L1 does not always occur at a 1:1 ratio. Presence of multiple CCL3L1 and CCL4L1 gene copies does not translate directly into increased protein products or a clearly favorable response to HIV-1 infection in the study population.