Role of exonic variation in chemokine receptor genes on AIDS: CCRL2 F167Y association with pneumocystis pneumonia

Abstract

Chromosome 3p21-22 harbors two clusters of chemokine receptor genes, several of which serve as major or minor coreceptors of HIV-1. Although the genetic association of CCR5 and CCR2 variants with HIV-1 pathogenesis is well known, the role of variation in other nearby chemokine receptor genes remain unresolved. We genotyped exonic single nucleotide polymorphisms (SNPs) in chemokine receptor genes: CCR3, CCRL2, and CXCR6 (at 3p21) and CCR8 and CX3CR1 (at 3p22), the majority of which were non-synonymous. The individual SNPs were tested for their effects on disease progression and outcomes in five treatment-naïve HIV-1/AIDS natural history cohorts. In addition to the known CCR5 and CCR2 associations, significant associations were identified for CCR3, CCR8, and CCRL2 on progression to AIDS. A multivariate survival analysis pointed to a previously undetected association of a non-conservative amino acid change F167Y in CCRL2 with AIDS progression: 167F is associated with accelerated progression to AIDS (RH = 1.90, P = 0.002, corrected). Further analysis indicated that CCRL2-167F was specifically associated with more rapid development of pneumocystis pneumonia (PCP) (RH = 2.84, 95% CI 1.28-6.31) among four major AIDS-defining conditions. Considering the newly defined role of CCRL2 in lung dendritic cell trafficking, this atypical chemokine receptor may affect PCP through immune regulation and inducing inflammation.

Figure 1. Polymorphisms in seven chemokine receptor genes on the Chromosome 3p21–22.

Schematics at bottom show the configuration of the receptors in the cell membrane, with circles representing the position and type of the polymorphisms. White circle indicates a synonymous substitution, colors nonsynonymous substitutions: yellow, conservative; blue, hydrophobic—hydrophilic; orange, hydrophilic—hydrophobic; red, charge changing (acidic—basic), purple, shape changing. Also indicated are Δ32 in CCR5 (rectangle) and the polymorphic CCR5 promoter (red triangle in the gene map). CCR5-2459 promoter allele (rs1799987).

Figure 2. Genetic effect of CCR3-255C and CCRL2-243V on AIDS progression.

Kaplan-Meier survival curves of time progression since HIV-1 infection to AIDS (1987 CDC definition) were plotted for genotypes of CCR3-255C (A) and CCRL2-243V (B). Circles on the curves indicate those censored.

Figure 3. Genetic effect of CCRL2-167F on AIDS progression and PCP.

Kaplan-Meier survival curves of time progression since HIV-1 infection to AIDS (1987 CDC definition) (A) or to PCP (B) were plotted for CCRL2-Y167F genotypes. Circles on the curves indicate those censored.