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Abstract
Allelic variants for the HIV-1 coreceptors chemokine receptor 5 (CCR5) and CCR2, as well as the ligand for the coreceptor CXCR4, stromal-derived factor (SDF-1) that reduce or prevent coreceptor expression are strongly associated with protection against human immunodeficiency virus (HIV) infection and slower disease progression. A polymorphism in the gene encoding CCR5 (named ccr5Δ32) and ccr5Δ32+/- is associated with a delay in progression to AIDS in HIV-infected individuals. Another polymorphism in CCR2 that is named ccr2-V64I, it changes valine (V) 64 of CCR2 to isoleucine (I), and also associated with a delay in progression to AIDS. CCR2-V64I allele is in complete linkage disequilibrium with a point mutation in the ccr5 promoter 59653 (Genbank U95626) of CCR5 regulatory region. An A/G polymorphism was identified at base pair 59029 (Genbank U95626) in the CCR5 promoter as well as sdf-1 3''A (G to A substitution at the 3'' untranslate regiou fromβtype of the SDF-1 mRNA), that affect the rate of progression of HIV-1 infected people to AIDS.
However, it is not clear whether the effect on AIDS progression results from the amino acid change or whether the polymorphism marks a genetically linked, yet unidentified mutation that mediates the effect. Because of the gene encoding CCR5, the major coreceptor for HIV type 1 primary isolates, lies 15 kb 3'' to CCR2, linked mutations in the CCR5 promoter or other regulatory sequences could explain the association of CCR2-64I with slowed AIDS pathogenesis.
In order to realize the allele frequencies for these genes that interfere with HIV-1 pathogenesis in Chinese population. We determinated such polymorphism which related to AIDS progression and tested the hypothesis that polymorphisms of CCR2-V64I or CCR5 promoter mediating the effect of CCR5 expression or transcription. The allele frequency for 59653T (the same as that for CCR2-V64I ), 59029A and sdf-1 3''A in our studied group is15.7% (n=181), 41.1% (n=45) and 31.8% (n=165). FACS determinate panels of peripheral blood mononuclear cells (PBMC) from uninfected donors representing the various CCR5/CCR2 genotypes. We confirmed CCR2-64I is linked to the CCR5 promoter polymorphisms 59653T; however, in FACS and RT-PCR quantitative analysis, ccr5-p59653T and 59029A have higher CCR5 expression on PBMC and CCR5 transcription. Here, we show that CCR2-64I is efficiently expressed on the cell surface but does not have dominant negative activity on CCR5 expression. Taken together, these findings suggest that ccr5-p59653 T/T (CCR2-64I) act by influencing CCR5 translation or mRNA levels, but that may not correlate to the rate of HIV-1 disease progression. Cell surface CCR5 and CCR5 mRNA transcript levels were variable, suggesting that an alternative mechanism may influence cell surface CCR5 levels.
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