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.
Highlights
Functional variation in the human leukocyte antigen (HLA) class I genes and in chemokine receptors affects HIV susceptibility, viral load, and rates of disease progression [1,2,3,4]
Our results suggest that genetic variation in CCR3, CCR8 and CCRL2 may contribute additional genetic regulation of HIV-1 disease in addition to that conferred by the major HIV-1 coreceptor gene CCR5
We investigated the impact of genetic variation of 3p21–22 chemokine receptor genes on HIV/AIDS in this population-based association study
Summary
Functional variation in the human leukocyte antigen (HLA) class I genes and in chemokine receptors affects HIV susceptibility, viral load, and rates of disease progression [1,2,3,4]. Recent genome-wide association studies (GWAS) performed in HIV-1 cohorts have shown that the HLA region and the chemokine receptor CCR5 gene have major roles in control of HIV-1 replication and disease progression— together they explain approximately 20% of genetic variability [3,5,6,7,8] (reviewed in [4,5]). These findings from GWAS highlighted the leading role of chemokine receptors among non-HLA genes in HIV-1 pathogenesis and prompted us to assess the role of other chemokine receptor genes on HIV disease using a gene-centric approach to identify common or rare functional variants in the region.
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