Chemokines represent the largest family of cytokines in the mammalian immune system. Some of these proteins and their receptors have recently been found to be involved in the pathophysiology of HIV-1 infection. One chemokine, stromal cell-derived factor SDF-1a is the natural agonist for the receptor CXCR4. The CXCR4 receptor has also been identified as the co-receptor for T-tropic, syncytium inducing strains of HIV-1. By virtue of its binding to CXCR4, SDR-1a inhibits these viral strains from infecting cells. Physiologically, SDF-1a is a potent chemoattractant for B-cells, neutrophils, and monocytes and also plays a role in cardiac development. Two chemokines, MIP-I and MIP-II, are also encoded by the herpesvirus HHV-8, a virus associated with Kaposi's sarcoma in AIDS patients. The exact role of these proteins in the viral life cycle is not known, but it is interesting that MIP-I and MIP-II are angiogenic, and therefore may be involved in the vascularization that occurs in Kaposi's sarcoma. MIP-II is the only chemokine to possess high affinity binding with CXC and CC chemokine receptors. Three of the receptors to which it binds are HIV-1 co-receptors CCR3, CCR5, and CXCR4. Despite the importance of human SDF-1a and HHV-8 MIP-II in HIV-1 infection, very little is known about their interactions with receptors. The three dimensional structures of SDF-1a and MIP-II will be determined by X-ray crystallography. These structures will form the basis of a structure-based approach using analogues of the chemokines to gain an understanding of the molecular details of chemokine-receptor interactions. The ultimate aim of this work is to use the information generated from these studies in the design of small molecule receptor antagonists for the treatment of HIV-1.
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