When this project originated, its purpose was to determine the precise factors that regulate white blood cell migration to sites of infection and inflammation, focusing on the initial interaction of the cell with extracellular signaling molecules known as chemoattractants. We discovered a family of cell surface receptors, specific to different types of leukocytes, that mediate this process. This work was accomplished by gene cloning, which has allowed study of the processes that regulate gene expression and receptor specificity, and study of the precise biological activity of each receptor. Later the scope of the project expanded in an unanticipated direction through the discovery that various microbial pathogens, including HIV, exploit chemoattractant receptors. In particular, we have shown by population genetic studies that HIV uses the receptor CCR5 in person to person transmission, and that CCR5 promoter polymorphisms are associated with altered rates of disease progression. We have also characterized a novel receptor for a chemokine named fractalkine, which mediates both chemotaxis and HIV infection in vitro. This work adds a new chapter to an earlier discovery of how viruses interact with the chemoattractant system, namely through virally-encoded chemoattractant receptor homologues. - Inflammation, Chemotaxis, Leukocyte, Chemokine, AIDS, G Protein-coupled receptor and knock-out mouse. - Human Subjects
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