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EFFECT OF INTERFERON REGULATORY FACTOR-1 POLYMORPHISMS, ASSOCIATED WITH RESISTANCE TO HIV-1 INFECTION IN HIGHLY EXPOSED UNINFECTED KENYAN SEX WORKERS
A Sivro1, TB Ball1, H Ji1, J Kimani2, FA Plummer1
1Winnipeg, MB; 2Nairobi, Kenya
Objectives: Previous studies have shown an association of three polymorphisms in Interferon Regulatory Factor-1 (IRF-1), located at 619, the microsatelite region, and 6516 of the gene, with the resistance to HIV-1 infection and a reduced likelihood of serconverson. Peripheral blood mononuclear cells (PBMC's) from patients with protective IRF-1 genotypes exhibited significantly lower basal IRF-1 expression and reduced responsiveness to exogenous Interferon-gamma (IFN-gamma) stimulation. Preliminary results show that IRF-1 polymorphisms cause increased exon skipping. This project will further characterize the effect of three IRF-1 polymorphisms associated with the resistance to HIV-1 infection, on exon shipping and the subsequent expression of IRF-1 regulated genes.
Methods: Exon skipping and the functional impact of IRF-1 polymorphisms on expression of IRF-1 regulated genes were analysed using the Affymetrix Human Exon 1.0 ST microarrays. Quantitative RT-PCR was used to investigate IRF-1 mRNA levels, as well as to confirm the microarray results. Analysis of protein levels and protein phosphorylation will be conducted using flow cytometric techniques.
Results: Preliminary analysis of the effect of IRF-1 polymorphisms on exon skipping indicates links between specific IRF-1 polymorphisms and skipping in exon 2, 3 and 7. Skipped exons were adjacent to the IRF-1 polymorphisms that correlated with the HIV-1 resistance phenotype. Further functional analysis of the effects of these polymorphisms on IRF-1 protein expression and HIV resistance is underway.
Conclusions: IRF-1 polymorphisms that associate with protection may play an important role in modulating HIV infection and disease progression. The complete characterization of the effects of IRF-1 polymorphism will further our understanding of mechanisms of HIV resistance and could potentially be used in the development of novel HIV prevention and treatment strategies.