The purpose of the project is to clone and characterize novel chemokine receptors in activated lymphocytes. Chemokines are members of a family of more than thirty human cytokines whose best described activities are as chemotactic factors for leukocytes and that act through receptors that are members of the G protein coupled receptor superfamily. Chemokines and their receptors are increasingly recognized as important in the trafficking of lymphocytes in immune and inflammatory responses as well as other aspects of lymphocyte physiology. Because lymphocytes are important in responses to infectious agents as well as in autoimmune diseases, inflammatory disorders, and transplant rejection, secreted factors and receptors that effect lymphocyte recruitment to tissue are potential targets for therapeutic interventions. Characterization of chemokine receptors on lymphocytes is of added medical relevance given the recent discoveries that chemokine receptors function as obligate co-receptors for HIV-1 entry, so that understanding these receptors may lead to novel therapies for preventing and treating HIV infection. Work during the last year has focused on two receptor:ligand groups that have been discovered and/or cloned and characterized in this laboratory: the receptor CCR6 and its ligand CCL20, and the receptor CXCR6 (STRL33), an HIV/SIV co-receptor whose ligand is CXCL16. For CCR6, as well as for other chemokine receptors, we characterized expression and function on resting and activated human and mouse B cells and found that cellular responses to CCL20 and other chemokines differed depending both on the cells? state of activation and on the nature of the activator independently of changes in levels of expression of the cognate receptors. These data suggest novel mechanisms for regulating chemokine receptor activity on lymphocytes. For CXCR6, we have identified and characterized mutations in the envelope glycoprotein (Env) of HIV-1 that are responsible for viral adaptation from using the major CCR5 co-receptor to using CXCR6. Viral adaptation to alternative co-receptors like CXCR6 may be important when anti-HIV therapies are introduced to block chemokine receptor-mediated viral entry.
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