Expression levels of CCR5, the major coreceptor for primary isolates of HIV-1, play a major role in determining susceptibility to infection and disease progression rates. There are several factors that could contribute to person-to-person variability in amounts of CCR5 on the surface of CD4+ T-cells and monocyte/macrophages. Heterozygosity for the ccr532 allele results in a decreased CCR5 expression. However, this two-fold difference in gene dosage does not fully account for the large amount of variability in CCR5 expression that has been found. Differences in CCR5 expression level are also likely to be caused by differences in transcription rate of the gene. The regulatory mechanisms that control CCR5 transcription are not yet understood. CCR5 transcription is regulated both by cell-type and by cellular activation state. It is expressed primarily in memory T-cells and macrophages and is up-regulated by activation of T-cells. The goal of this project is to understand the transcriptional regulation of CCR5. This will involve identifying the CCR5 enhancer and promoter, characterizing the transcription factors that mediate enhancer function and determining which intracellular signaling pathways regulate activity of the transcription factors. These findings should lead an understanding of how CCR5 tissue-specificity is maintained, how the gene is induced by cellular activation and what accounts for person-to-person variability in coreceptor expression level. This could ultimately provide insights into the factors that control HIV transmissibility and pathogenicity and may lead to new strategies for slowing disease progression that are based on reducing CCR5 expression in vivo.
The specific aims of this project are to: 1. Define the regulatory sequences and transcription factors that mediate CCR5 enhancer function. 2. Determine how cell-type and activation-state control CCR5 expression level. 3. Determine what factors account for person-to-person variability in CCR5 expression levels.
