MCP-1-MCP-3-Eotaxin gene cluster influences HIV-1 transmission.
BACKGROUND
MCP-1 (CCL2), MCP-3 (CCL7), and eotaxin (CCL11) are genes for CC chemokines clustered on the long arm of chromosome 17. Previous studies have implicated these chemokines in monocyte recruitment, viral replication, and anti-HIV cytotoxic T cell responses. An epidemiological analysis identified genetic variants influencing HIV-1 transmission and disease progression.


METHODS
Genomic DNA from over 3000 participants enrolled in five natural history cohorts in the United States were analyzed. Nine single nucleotide polymorphisms (SNP) covering 33 kb containing these three genes were genotyped using the polymerase chain reaction. Distortions in allele, genotype, and haplotype frequencies were assessed with respect to HIV-1 transmission and rates of disease progression using categorical and survival analyses.


RESULTS
Extensive linkage disequilibrium was observed. Three SNP (-2136T located in the MCP-1 promoter region, 767G in intron 1 of MCP-1, and -1385A in the Eotaxin promoter) were nearly always found together on a 31 kb haplotype (H7) containing the three genes. Frequencies of the three variants and the H7 haplotype were significantly elevated (odds ratio, 0.6; P = 0.005-0.01) in uninfected European-Americans repeatedly exposed to HIV-1 through high-risk sexual behavior or contaminated blood products.


CONCLUSIONS
Although the extensive linkage disequilibrium precludes positive identification of the causal variant, the results suggest that genetic variation in the H7 region influences susceptibility to HIV-1 infection. Since these chemokines do not bind the primary HIV-1 coreceptors CCR5 or CXCR4, the observed influence on transmission may result from activation of the immune system in response to infection rather than receptor blockage.
Modi
William S
WS
SAIC Frederick and the Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland, USA.
Goedert
James J
JJ
Strathdee
Steffanie
S
Buchbinder
Susan
S
Detels
Roger
R
Donfield
Sharyne
S
O'Brien
Stephen J
SJ
Winkler
Cheryl
C
D001483:Base Sequence; D054413:Chemokine CCL11; D018932:Chemokine CCL2 / Q000235:genetics; D054410:Chemokine CCL7; D018925:Chemokines / Q000235:genetics*; D019742:Chemokines, CC / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D015331:Cohort Studies; D016207:Cytokines; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000635:transmission; D015497:HIV-1; D006239:Haplotypes; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics; D005810:Multigene Family / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D016019:Survival Analysis
C515456:CCL11 protein, human; C515450:CCL7 protein, human; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; D018945:Monocyte Chemoattractant Proteins