title: Receptor conformation and constitutive activity in CCR5 chemokine receptor function and HIV infection.
abstract: The CCR5 chemokine receptor mediates the effects of proinflammatory β-chemokines that stimulate chemotaxis, activation, and proliferation of macrophages and T cells. CCR5 is also the major coreceptor that mediates HIV infection in combination with CD4. Chemokine agonists of CCR5 stimulate the activation of cellular calcium and protein kinase signaling pathways that depend on the activation of Gαi and probably also Gαq in some cells. Chemokines also stimulate the recruitment of β-arrestin, which is required for clathrin-dependent receptor internalization and acts as a scaffold protein for the chemotaxis signaling complex that mobilizes the actin cytoskeleton. CCR5 is partially constitutively active for the activation of Gαi, but the physiological significance has not been studied. HIV binding to CCR5 also activates G protein and protein kinase signaling but, in addition, stimulates the production of proinflammatory cytokines, including TNF-α, and mobilizes the actin cytoskeleton to form the fusion pore that allows viral entry and subsequently supports viral replication in the cell. The CCR5 conformation that mediates the fusion of the viral and cell membranes is unknown, but it is probably distinct from the conformation that mediates G protein signaling. Nonpeptide CCR5 blockers are allosteric inverse agonists that increase dissociation of both chemokines and HIV envelope proteins, but this does not correlate with their ability to inhibit HIV infection. Nevertheless, the inverse agonist activity may ameliorate the immune activation that exacerbates AIDS pathogenesis. Inverse agonists of CCR5 have established efficacy for the treatment of AIDS, but may also be useful in preventing HIV infection.
authors.affiliation: School of Physiology and Medical Research Council Receptor Biology Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Private Bag 3, Wits, South Africa. Electronic address: colleen.flanagan@wits.ac.za.
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Flanagan
mesh_terms: D065100:CCR5 Receptor Antagonists / Q000494:pharmacology; D054314:Drug Inverse Agonism; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D006801:Humans; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation; D019713:Receptors, CCR5 / Q000819:agonists / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D065100:CCR5 Receptor Antagonists; D019713:Receptors, CCR5
keywords: CCR5 blockers; CCR5 chemokine receptor; Conformation; HIV coreceptor