Background:  Monocyte chemoattractant protein-1 (MCP-1) is the ligand for chemokine receptor, CCR2, a minor co-receptor of HIV-1. MCP-1 modulates immune responses by attracting and activating monocytes, macrophages and lymphocytes to the site of infection, and the MCP-1-2518-G/G genotype is associated with higher MCP-1 expression compared to the wild type A/A genotype. A CCR2-180-G->A (V64I) variant has been shown to be associated with slower disease progression in adults and MCP-1 levels are associated with neuropathogenesis. The current study examined the combined impact of MCP-1 and CCR2 polymorphisms on HIV disease of children.

Methods:  MCP-1-2518-A/G and CCR2-V64I polymorphisms were detected by real-time PCR in 1055 seroprevalent HIV-1 infected children in the United States who participated in clinical trials of mono- or two-drug NRTI treatments. Mantel-Haenszel test was used to evaluate differences in allele frequencies between race/ethnicity groups. Disease progression was analyzed by Kaplan-Meier estimates, log rank test and proportional hazards models.

Results:  MCP-1-2518-G and CCR2-64I allele frequencies were 29.4%, 9.4% in white, 34.8%, 13% in Hispanic, and 21.7%, 16% in black children, respectively. No association of MCP-1-2518 or CCR2-64 genotypes was observed with baseline CD4⁺ count, CD4⁺ percentage or HIV-1 RNA load. None of the MCP-1-2518 genotypes affected HIV-1 disease progression (p = 0.70) or CNS impairment (p = 0.89). In earlier studies, we found that CCR2-64 genotypes did not affect disease progression (p = 0.99) or CNS impairment (p = 0.90) in this cohort. In the present study, presence of combined CCR2-64 and MCP-1-2518 alleles had no impact on disease progression (wt-G vs wt-A, RH = 0.95, 95% CI 0.70 to 1.28, p = 0.71; 64I-A vs wt-A, RH = 0.86, 95% CI 0.56 to 1.30, p = 0.46; and 64I-G vs wt-A, RH = 1.22, 95% CI 0.78 to 1.90, p = 0.38) or CNS impairment (wt-G vs wt/A, RH = 0.96, 95% CI 0.62 to 1.48, p = 0.84; 64I-A vs wt-A, RH = 0.82, 95% CI 0.44 to 1.54, p = 0.54; and 64I-G vs wt-A, RH = 1.47, 95% CI 0.78 to 2.74, p = 0.23). Results did not vary by analyses in children with CCR5-wt/wt genotype or by race/ethnicity.

Conclusions:  Presence of combined MCP-1-2518-A/G and CCR2-V64I alleles did not impact HIV-1 disease progression or CNS impairment in children. These findings differ from that observed in several adult cohort studies and suggest that there may be a specific difference in the immunologic role that the MCP-1-CCR2 interaction plays in HIV pathogenesis of children compared to adults.

Keywords: MCP1-CCR2; polymorphisms; HIV-1