The Chemokines are a diverse gene family of chemotactic cytokines that regulate the migration and activation of leukocytes by interacting with cell-surface G-protein coupled receptors. They play a major role in the pathophysiology of many inflammatory disorders such as rheumatoid arthritis, asthma and other lung diseases. Recently, chemokine receptors CCR5 or CXCR4 were identified as essential co-receptors for the entry of human immunodeficiency virus HIV-1 into CD4 positive cells. While CCR5 is the target for the entry of primary viruses CXCR4 may be important in the progression to AIDS from asymptomatic infection. We have developed novel cellular models for understanding the molecular mechanisms of regulation of chemokine receptors. Chemokine receptors including CXCR4 are functionally expressed in a rat basophilic leukemia cell line (RBL-2H3) which displays many leukocyte activities. These studies have provided evidence that chemokine receptors cross-regulate each other's functions at multiple levels. The overall objective of this proposal is to delineate the pathways of CXCR4 signaling, desensitization and internalization using the RBL-2H3 model system. The role of phosphorylation in signaling and desensitization of the receptors will be determined in RBL-cells stably expressing epitope-tagged native or mutated CXCR4. The structural elements on the receptors that regulate internalization will be identified. Interaction of CXCR4 receptors with T-tropic HIV-1 envelope glycoprotein (GP120) and the peptides derived from it will be studied. The mechanisms by which other chemokine receptors and adhesion molecules regulate CXCR4 function and vice versa will be investigated. Cross regulation of chemokine receptors along with differential expression may be responsible for selective leukocyte accumulation in pathological conditions and cell type specificity in viral infection. Understanding the mechanism by which CXCR4 is regulated will provide novel targets and better rationale for therapeutic intervention in HIV-1 infected individuals and in other inflammatory disorders.
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