MOLECULAR ANALYSIS OF NEUTROPHIL ACTIVATION BY CHEMOATTRACTANTS

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Abstract

The original aim of this project was to define how white blood cells migrate to sites of infection and inflammation. We found that a large family of specific cell surface receptors known collectively as chemoattractant receptors regulates this process. Later we found that a subset of these receptors is used by various microbial pathogens, including HIV, to infect cells and cause disease. In the past year we published new evidence expanding the known roles of specific chemoattractant receptors in inflammation and infection. With regard to AIDS, we published the following new findings: 1.) CX3CR1, which HIV can use to infect cells in the test tube, exists as two genetically determined variants which correlate with different susceptibility to HIV infection and disease progression, suggesting that this receptor is an important regulator of HIV disease in populations, and therefore that it may be a useful drug target. 2.)The genetic variant CCR5D32 of the major HIV receptor CCR5 affects the clinical response of patients to highly active anti-retroviral therapy, which has implications for identifying individuals most likely to respond to this therapy. 3.) A genetic variant that regulates the production of the chemoattractant RANTES, which acts via CCR5, correlates with altered risk of HIV transmission, suggesting that RANTES mimics could be effective therapeutically. 4.)In collaborative work initiated by Hana Golding's group, we found that the receptor CCR8 is expressed on thymus cells where it can facilitate HIV infection, which may be important for understanding the mechanism of immunodeficiency caused by HIV. 5.) In a collaboration initiated by KT Jeang's group, we showed that the HIV protein tat functions as an antagonist specific for the chemoattractant receptor and HIV receptor CXCR4, and proposed a mechanism by which tat could regulate the rate of HIV disease progression. With regard to our inflammation studies, we identified a second subtype of mouse receptor for a bacterial peptide chemoattractant and proposed a mechanism by which the two subtypes act as a signaling relay to facilitate movement of phagocytic cells from the blood to sites of bacterial infection. We also defined additional mouse receptors that mediate activation of white blood cells by specific chemoattractants, which will allow us to study the biological role of these receptors in an animal model.