The goal of this research project is to identify and characterize genetic polymorphisms within the regulatory regions of the CCR5 and CXCR4 co-receptors for HIV-1 entry, and to determine their influences on the efficiency of HIV-1 transmission and the rate of disease progression in infected individuals. We have shown that CCR5 expression is highly variable on CD4+ T cells from individuals with wild-type CCR5 protein coding alleles. We have identified polymorphisms in the twin promoters for CCR5 and have shown that some of these are associated with reduced CCR5 protein expression and delayed disease progression. We have also found that a polymorphism in the CCR2 chemokine receptor (V641) that is associated with delayed disease progression is 100% genetically linked to a polymorphism in he region containing the CCR5 promoter. There are also partial linkages between CCR5 promoter polymorphisms and the CCR5-32 allele. Our first Specific Aim involves characterizing genetic polymorphisms within the CCR5 and CXCR4 regulatory regions, including their effects on 'transcription efficiency, cell surface protein expression and susceptibility of the target cells to HIV-1 infection. In the second Specific Aim, we will measure the frequencies of CCR5 and CXCR4 promoter polymorphisms (and of the CCR5-32 and CCR2-64I alleles) in AIDS- related cohorts., and determine their association with HIV-1 transmission and disease progression.
In Specific Aim 3, we will study the mechanisms by which CCR5 and CXCR4 gene expression is up- and down-regulated in response to different external stimuli and in different cells, and how this is influence by chemokines.
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