Genetic Polymorphisms in CX3CR1 predict HIV-1 disease progression in children independently of CD4+ lymphocyte count and HIV-1 RNA load

Background. The impact of CX(3)CR1 polymorphisms on human immunodeficiency virus type 1 (HIV-1) pathogenesis is controversial, with conflicting reports of their role in disease progression in HIV-1-infected adults. Methods. A cohort of 1055 HIV-1-infected children were genotyped for 2 CX(3)CR1 polymorphisms, V/I249 and T/M280, and their impact on HIV-1-related disease progression, including central nervous system (CNS) impairment, was evaluated. Results. Children with the CX(3)CR1 I/I249 genotype experienced more-rapid disease progression (I/I249 vs. V/V249: relative hazard [RH], 2.19 [95% confidence interval {CI}, 1.30-3.68], P = .003; I/I249 vs. V/I249: RH, 1.77 [95% CI, 1.00-3.14],P = .05) and a trend toward more CNS impairment (I/I249 vs. V/V249: RH, 2.19 [ 95% CI, 1.00-4.78], P = .049; I/I249 vs. V/I249: RH, 2.02 [95% CI, 0.85-4.83], P = .11). Children with the V249-T280 haplotype experienced significantly less disease progression (RH, 0.42 [95% CI, 0.24-0.73]; P = .002) and CNS impairment (RH, 0.39 [95% CI, 0.39-0.22]; P = .001). Of note, these effects remained significant after CD4(+) lymphocyte count and plasma HIV-1 RNA load at baseline were adjusted for and in a longitudinal, multivariate analysis. Conclusions. CX(3)CR1 genotypes and haplotypes impact HIV-1 disease progression independently of CD4(+) lymphocyte count and plasma HIV-1 RNA load, suggesting that the fundamental role of CX(3)CR1 in the alteration of disease progression might be the recruitment of immunomodulatory cells responsible for the control of HIV-1.