Interactions of CCR5, the Main HIV Coreceptor, with Rantes and Other Ligands

Abstract

The entry of the human immunodeficiency virus 1 (HIV-1) into host cells requires the sequential interaction of the viral envelope glycoprotein 120 (gp120) with the host-cell factor CD4 and with either CCR5 (CC chemokine receptor 5) or CXCR4, both G-protein coupled receptors (GPCR). This leads to the fusion of viral and host cell membranes. The normal physiological role of CCR5, however, is the regulation of immune-cell trafficking upon activation by its endogenous ligands: macrophage inflammatory protein 1α (MIP-1α), MIP-1β and RANTES (Regulated on Activation, Normal T-cell Expressed and Secreted). Since both, viral gp120 and the chemokines bind to the extracellular parts of the receptor, binding of a natural ligand, e.g. RANTES, obstructs the interaction of CCR5 with the viral protein, thereby hindering HIV infection. This makes RANTES and other chemokines potential lead structures for novel anti-HIV agents.Here, we present advances on the study of the interactions of recombinantly-expressed CCR5 with different chemokine variants and the small-molecule inhibitor maraviroc. Experiments are performed by nuclear magnetic resonance (NMR) and surface plasmon resonance (SPR), with CCR5 incorporated in either detergent micelles, lipid bilayers, or the synthetic model membrane system of nanodiscs. Mechanistic implications of these results are discussed.While a 3D structure of CCR5 is still lacking, these data have the potential to shed some new light on our understanding of HIV infection, as well as on the topic of cellular signalling through chemokines. As the quality of preparation of recombinant CCR5 samples improves, further milestones are expected towards structural models of the ligand-CCR5 complexes.