CCR5 antagonists of HIV-1 infection Figure 2 Development of maraviroc from the high-throughput screening hit UK-107,543. Reprinted with permission from Dorr P,Westby M, Dobbs S, et al 2005. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeﬁciency virus type 1 activity. Antimicrob Agents Chemother, 49:4721-32. Copyright © American Society of Microbiology. Structure, location, and function of CCR5 Similar to other G-protein coupled receptors, chemo- kine receptors have a seven transmembrane structure. The N-terminus is extracellular and participates in bind- ing of the chemokine; the C-terminus is intracellular and serves as the site for β-arrestin binding. β-arrestins facilitate G-protein independent cell signaling in addition to bind- ing the chemokine receptor to clathrin for endocytosis and subsequent recycling (Zhao et al 1998; Oppermann 2004; Signoret et al 2005). Two separate co-receptors for HIV-1 infection have been identiﬁed: CCR5 and CXCR4. There is substantial genetic variability within the amino acid sequence of gp120 molecule on the viral envelope, determining to which chemokine receptor the gp120 will bind (Pastore et al 2006). The ligands for CCR5 and CXCR4 are chemokines, which are small molecules in the cytokine family that promote che- motaxis and cellular activation; on binding to their receptor on the target cell, an intracellular signaling cascade is initiated via a G-protein release from the intracellular domain of the receptor (Oppermann 2004). Native ligands for CCR5 include Therapeutics and Clinical Risk Management 2008:4(2) chemokines MIP-1α (macrophage inﬂammatory protein), MIP-1β, and RANTES (regulated on activation, normal T-cell expressed and secreted), which have been giving standard nomenclature CCL3, CCL4, and CCL5, respectively; CCR5 is expressed on immune cells, including effector and memory T-cells, natural killer cells, and antigen presenting cells (Blanpain et al 1999; Rufﬁng et al 1998). As is exempliﬁed by CCR5 and its ligands, the host defense mechanism is both complex and redundant. A single chemokine receptor can be activated by different chemokines, and similarly, a single chemokine may also activate multiple different chemokine receptors. This redundancy provides a back up plan to coun- teract the strategies and mutations microbes use to circumvent the host defense system. CCR5 is heavily involved in both initiating and amplifying the immune response. At the time of microbial invasion, conserved antigens on the microbe bind to toll-like receptors on the surface of macrophages and immature dendritic cells, which release cytokines and chemokines in response. CCR5 expressing cells are then drawn toward the site of invasion by the high concentration of CCR5 binding chemokines; they ingest 475