Recent advances in human genetics have enabled the identification of various mutations responsible for disease. Such advances include collections of families and populations presenting clinical phenotypes, genome sequence and polymorphism databases, mathematical algorithms and computer programs for computational purposes, and novel applications of pedigree and linkage disequilibrum (LD) analyses. LD is the non-random association between alleles at different loci. By tracking genetic markers in LD with a disease phenotype, a genomic region harboring a causal variant can be localized. Recent studies have demonstrated that many regions of the human genome are characterized by segments or blocks of limited haplotype diversity due to high levels of LD between genetic markers. Chemotactic cytokines are known to direct the migration of specific subsets of leukocytes to sites of infection and inflammation. Further, the natural chemokine receptors CCR5 and CXCR4 are HIV-1 coreceptors. About 40 human chemokine genes are found at eight different chromosomal locations, with major clusters on chromosomes 4 and 17. We are focusing on 16 chemotactic cytokines (CC) genes located at 17q12-21. Nine of these genes (CCL2, CCL7, CCL11, CCL5, CCL14, CCL3, CCL4, CCL3L1, and CCL4L1) have been implicated in HIV-1/AIDS pathogenesis based upon tissue culture, cellular immunological and virus infection assays. In fact, CCL3L1 has the strongest binding affinity of all ligands for CCR5, and is thus an excellent candidate for an HIV-1 entry inhibitor. Approximately 40 'tagged' single nucleotide polymorphisms (SNPs) have been genotyped in 4000 subjects enrolled in HIV-1/AIDS cohorts. CCL3, CCL4, CCL18 are potent chemoattractants produced by macrophages, natural killer (NK) cells, fibroblasts, mast cells, CD4+ and CD8+ T-cells. CCL3 and CCL4 are natural ligands for the primary HIV-1 coreceptor CCR5. Further, CCL3 and CCL4 are known to activate and enhance the cytotoxicity of NK cells. Genomic DNAs from 3000 participants enrolled in five USA-based natural history AIDS cohorts were genotyped for 21 SNPs in the a 46 kb interval containing these genes. Seven of the 21 SNPs had minor allele frequencies less than 0.5% in European-Americans, while all 21 were variable in African-Americans. Four or five haplotype blocks were observed in European-Americans or African-Americans, respectively. Blocks were strongly correlated with each other and haplotype diversity within blocks was limited, indicating strong LD across the entire region. Frequencies of three SNPs and their haplotype in the CCL3 gene were elevated in frequency (p=0.04 to 0.09) among highly exposed, persistently seronegative African Americans compared to seroconvertors. Nine highly correlated SNPs spanning the CCL3 and CCL4 genes were significantly associated (p=0.0008 to 0.05) with more rapid disease progression in European Americans. These results confirm the importance of chemokine gene variation in HIV-1/AIDS pathogenesis. We have completed a survey of 7 SNPs in the SDF1 gene encoding the ligand for CXCR4, the major coreceptor for T tropic, X4 HIV-1 strains in an effort to identify causal SNPs associated with delayed progression to AIDS. Only the single haplotype bearing SDF1-3'A. An allele previously shown to be protective, was associated with delayed progression. This suggests that the SDF1-3'A allele itself is causal or is tracking by LD a causal allele elsewhere on the haplotype.
| Modi, William S; O'Brien, Thomas R; Vlahov, David et al. (2003) Haplotype diversity in the interleukin-4 gene is not associated with HIV-1 transmission and AIDS progression. Immunogenetics 55:157-64 |
| Modi, William S; Goedert, James J; Strathdee, Steffanie et al. (2003) MCP-1-MCP-3-Eotaxin gene cluster influences HIV-1 transmission. AIDS 17:2357-65 |
