these chemokines. This antiviral effect is related to the ligands’ ability to internalize the receptor and deprive it from being expressed on the cell surface (Cocchi et al 1995). The promise of these modiﬁed chemokines and other novel agents has been difﬁcult to bring to fruition thus far and their future remains uncertain (Simmons et al 1997; Qin et al 2003; Hartley et al 2004; Anderson and Akkina 2007). Another unique approach attempts to employ a zinc ﬁnger nuclease to bind, cleave, and cause mutagenesis in the CCR5 gene and thereby inhibit normal transcription and protein expression (Jouvenot et al 2005; Mani et al 2005). Monoclonal antibodies targeting CCR5 have also been developed with CCR5mAb004 of Human Genome Sci- ences (Rockville, MD, USA), and PRO 140 of Progenics Pharmaceuticals (Tarrytown, NY, USA) progressing to early phase human trials. Each is a mouse-derived but humanized monoclonal antibody capable of blocking CCR5 without activation of the receptor (Olson et al 1999; Roschke et al 2004). A phase I study in 63 HIV-positive patients with CCR5-tropic virus demonstrated CCR5mAb004 to be safe and well tolerated with substantial anti-viral efﬁcacy for up to 28 days after a single dose (Lalezari et al 2006). Subjects were randomized to 5 cohorts with an 8:2 ratio of placebo to active drug. Subjects were infused with a single dose of placebo or CCR5mAb004 at 1 of 5 dosages, 0.4, 2, 8, 20, or 40 mg/kg of body weight, and followed for 8 weeks. Greater antiviral response was observed at higher doses with 55% of subjects receiving doses of 8 mg/kg or greater and 50% in the highest dose cohort demonstrating at least a 1 log10 drop in HIV viral load. Further investigation of a more potent, next generation antibody is anticipated. PRO 140, considered a fast-track product by the FDA, recently reported positive proof-of-concept study results. A phase I study in 39 HIV-positive patients with CCR5-tropic virus demonstrated PRO 140 to be safe, well tolerated and a potent inhibitor of HIV-1 replication with a mean maximal viral load reduction of 1.83 log10 in the highest dose group (5 mg/kg) after a single dose (Jacobson et al 2007). All patients receiving the highest dose had a viral load reduction of at least 1 log10. PRO140 binds to the N terminus and second extracellular domain of CCR5 and acts as a direct competitive inhibitor of HIV binding. The small-molecule antagonists to be discussed bind in a hydrophobic pocket of CCR5 formed by transmembrane helices, and act through allosteric effects. As such, the two classes of CCR5 antagonists work through different mechanisms, and virus resistant to the small mol- ecule antagonists maintain sensitivity to PRO140 (Kuhmann et al 2004; Marozsan et al 2005). In addition, in vitro Therapeutics and Clinical Risk Management 2008:4(2) CCR5 antagonists of HIV-1 infection studies demonstrate potentially synergistic effects with the small-molecule CCR5 antagonists (Murga et al 2006; Ji et al 2007). Though PRO 140 requires parenteral administration, the interval of administration ultimately determined could be long enough to be reasonably convenient. The preliminary results are encouraging. By far the largest group and furthest in development of CCR5 antagonists are the small-molecule inhibitors. Typically cheaper to produce than peptides with better oral bioavailability, these agents also demonstrate signiﬁcant potency across diverse clades with half maximal inhibitory concentrations (IC50) measured in nanomoles. As is the case with many small-molecule inhibitors of G-coupled proteins, these agents appear to bind a pocket within the transmembrane helices, alter extracellular CCR5 conformation, and thereby inhibit HIV-1 binding (Dragic et al 2000). Agents that have progressed from simple labels to scientiﬁc names end in the sufﬁx–viroc, eg, vicriviroc, to denote their action of viral receptor occupancy. Small-molecule antagonists include: TAK-779, TAK-220, Tak-652, AK602/ ONO4128/GSK-873140/aplaviroc, SCH-C/SCH-351125, SCH-D/SCH-417690/vicriviroc, and UK-427,857/maraviroc. In addition to the recently approved maraviroc, which we discuss in greater detail in the following section, a number of other agents merit discussion. The ﬁrst small-molecule CCR5 antagonist published was TAK-779 of Takeda Chemical Industries (Osaka, Japan) (Baba et al 1999). Though a potent inhibitor of CCR5-tropic HIV-1 in vitro, development was curtailed due to the need for subcutaneous administration and the attendant difﬁcul- ties with injection site reactions. More recent focus has been placed on TAK-220 and TAK-652, each with nanomolar inhibition of HIV-1 in vitro and oral bioavailability (Baba et al 2005; Takashima et al 2005). A single-dose phase I study has been completed for TAK-652 and demonstrates favorable initial safety and pharmacokinetic data (Baba et al 2005). Further clinical data are awaited. Spirodiketopiperazine derivatives have been under active development by Ono Pharmaceuticals (Osaka, Japan) in collaboration with GlaxoSmithKline (Research Triangle Park, NC, USA). E913 potently suppresses the replication of laboratory and primary CCR5-tropic HIV-1 strains, including viruses resistant to available antiretroviral medications (Maeda et al 2001). However aplaviroc (AK602/ONO4128/GSK- 873140) demonstrates a 2-fold increase in activity versus HIV-1 isolates at sub-nanomolar concentration both in vitro and in vivo mouse model, and became the lead analogue under development (Maeda et al 2004; Nakata et al 2005). In early phase study, a maximum dose of 600 mg twice a day for 477