Background:  CX₃CR1, the receptor for the chemokine, fractalkine, is a minor co-receptor of HIV-1 and is thought to modulate the immune response to viral infections. The effect of CX₃CR1 polymorphisms on HIV-1 pathogenesis is controversial with conflicting reports on its role in disease progression in HIV-1-infected adults. This research examined the effect of CX₃CR1 polymorphisms on HIV-1 infection of children.

Methods:  CX₃CR1 V/I249 and T/M280 polymorphisms were detected by real-time PCR in 1055 seroconverted children in the United States. HIV-1 disease progression was defined as weight growth failure, CNS impairment, development of 2 opportunistic infections or death. Mental Developmental Index of Bayley scales, the General Cognitive Index of the McCarthy scales, and the full-scale IQ of the revised Wechsler Intelligence Scale for Children or Wechsler Adult Intelligence Scale were used to assess cognitive function. ANOVA and ANCOVA were used to compare markers of disease status at trial entry. The Mantel-Haenszel test was used to evaluate differences in genotype frequencies between race/ethnicity groups. Progression to a study endpoint was analyzed by Kaplan-Meier estimates, log rank test, and proportional hazards models stratified by study and randomized treatment.

Results:  The CX₃CR1 I249 and M280 allelic frequencies varied by race/ethnicity, being most common in non-Hispanic white children (28% and 16%, respectively), intermediate in Hispanics (17% and 7%), and least common in non-Hispanic, black children (13% and 4%) (p = 0.001).  More rapid disease progression (p = 0.008) and a trend for CNS impairment (p = 0.13) were observed for children with the  I/I249 genotype. Notably, these effects were independent of the protective effects observed with the CCR5-wt/d32 genotype.  The M/M280 genotype did not have a significant effect on disease progression. However, children with the V249-T280 haplotype were significantly less likely to experience disease progression (RH = 0.48, CI: 0.29, 0.80, p = 0.004) and CNS impairment (RH = 0.46, CI: 0.21, 1.01, p = 0.046). 

Conclusions:  The CX₃CR1 I/I249 genotype is associated with more rapid disease progression and CNS impairment in HIV-1-infected children, while the V249-T280 haplotype is associated with improved outcome.  Because CX₃CR1 is a minor co-receptor for HIV-1 attachment and entry, we believe that the fundamental role of CX₃CR1 in altering HIV-1 infection is the recruitment of immunomodulatory cells responsible for the control of HIV-1 infection.

Keywords: CX3CR1 polymorphisms; HIV-1 disease progression; children