This chapter discusses the application of C-C chemokine receptor type 5 (CCR5) antagonists for the treatment of HIV infection and AIDS. Several CCR5 antagonists have been shown to be effective inhibitors of HIV-1 infection in humans. CCR5 is a 352-amino-acid protein with a basic structure that is typical of a seven-transmembrane G protein-coupled receptor (GPCR). It consists of three extracellular loops and the N terminus, which are involved in chemokine binding and interactions with the viral protein gp120, and three intracellular loops and the C terminus, which participate in G protein-mediated signal transduction. The activation of CCR5 by its endogenous ligands activates cellular responses including inhibition of cyclic adenosine monophosphate (cAMP) production, stimulation of Ca2+ ion release and activation of mitogen-activated protein (MAP) kinase and Jun-N-terminal kinase. The endogenous ligands of CCR5 include the chemokines known as macrophage inflammatory protein (MIP)-1α, Macrophage inflammatory protein (MIP)-1β and “regulated upon activation, normal T-cell expressed and secreted” (RANTES). It is worth noting that RANTES and (MIP)-1α can recognise multiple chemokine receptors in addition to CCR5, in contrast to CXCR4 that has an exclusive 1–1 association with stromal cell-derived factor (SDF)1-α. The observation that CCR5 ligands can inhibit HIV-1 entry led to the identification of CCR5 as a coreceptor for HIV-1.
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