Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression

Abstract

CCL3 (MIP-1 alpha), CCL4 (MIP-1 beta), and CCL18 (DC-CK1/PARC/AMAC-1) are potent chemoattractants produced by macrophages, natural killer cells, fibroblasts, mast cells, CD4(+) T cells, and CD8(+) T cells. CCL3 and CCL4 are natural ligands for the primary human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 and are also known to activate and enhance the cytotoxicity of natural killer cells. Genomic DNAs from >3,000 participants enrolled in five United States-based natural-history cohorts with acquired immunodeficiency syndrome (AIDS) were genotyped for 21 single-nucleotide polymorphisms (SNPs) in a 47-kb interval on chromosome 17q12 containing the genes CCL3, CCL4, and CCL18. All 21 SNPs were polymorphic in African Americans (AAs), whereas 7 of the 21 had minor-allele frequencies <0.01 in European Americans (EAs). Substantial linkage disequilibrium was observed in a 37-kb interval containing 17 SNPs where many pairwise D' values exceeded 0.70 in both racial groups, but particularly in EAs. Four and three haplotype blocks were observed in AAs and EAs, respectively. Blocks were strongly correlated with each other, and common haplotype diversity within blocks was limited. Two significant associations are reported that replicate an earlier study. First, among AA members of the AIDS Link to the Intravenous Experience cohort of injection drug users, frequencies of three correlated SNPs covering 2,231 bp in CCL3 were significantly elevated among highly exposed, persistently HIV-1-uninfected individuals compared with HIV-1-infected seroconvertors (P = .02-.03). Second, seven highly correlated SNPs spanning 36 kb and containing all three genes were significantly associated with more-rapid disease progression among EAs enrolled in the Multicenter AIDS Cohort Study cohort (P = .01-.02). These results reiterate the importance of chemokine gene variation in HIV-1/AIDS pathogenesis and emphasize that localized linkage disequilibrium makes the identification of causal mutations difficult.

Figure 1.

Molecular map of the CCL18, CCL3, and CCL4 genes. Each gene has three exons, depicted as blackened boxes, and SNPs are numbered 1–21. The distance between SNPs 1 and 21 is 47,637 bp. Below the map are pairwise D^′ plots and haplotype blocks obtained from HAPLOVIEW for 420 AAs (A) and 972 EAs (B) (in panel B, seven tracks are blank because of MAFs <0.01). Dark-red squares signify high D′ values, light-blue squares indicate high D′ values with low LOD scores, and light-red and white squares indicate low D′ values. Block boundaries are based on the 95% CIs for D′. Panels C and D show the structure of haplotype blocks found in AAs and EAs, respectively. Haplotype-tagging SNPs identified by HAPLOVIEW are indicated by arrowheads. Numbers below the blocks are interblock, multiallelic D′ values.

Figure 2.

Kaplan-Meier survival curves showing the dependence of AIDS-87 progression (the proportion surviving who did not reach the disease end point) on the dominant rs1719130 genotype in all EAs (A) and the dominant rs1719153 genotype in the MACS cohort (B). A, The black curve (C/C) represents all individuals homozygous for the wild-type allele, and the blue curve (C/T and T/T) includes individuals with one or two copies of the minor allele. The total number of individuals was 636; 291 developed AIDS, and 345 were censored. RH=1.50; log-rank P=.0065; Wilcoxon P=.0023; −2log(likelihood ratio) P=.009. B, The black curve (A/A) represents individuals carrying two copies of the wildtype allele, and the blue curve (A/T and T/T) represents individuals with one or two copies of the variant allele. The total number of individuals was 402; 184 developed AIDS, and 218 were censored. RH=1.51; log-rank P=.0072; Wilcoxon P=.0159; −2log(likelihood ratio) P=.0149. RH values were obtained from Cox proportional hazards regression, and the P values were obtained from the Kaplan-Meier survival analyses.