Schlecht et al pathogens, mature, and then migrate to lymphoid tissue where they then prime the adaptive immune response by presenting the microbial antigens to naive B- and T-lymphocytes (Wong et al 2003). Antigen-speciﬁc T-lymphocytes can also release CCR5-binding chemokines, which bind to endothelial cells and components of the extracellular matrix. CCR5 expressing cells roll along the surface of the endothelium and are drawn to the increased chemokine gradient at the site of infection (Wong et al 2003, Luther et al 2001). Of note, while CCR5 has several identiﬁed agonists, CXCR4 has only one (Stromal derived factor-1). Distribution of CCR5-tropic virus in the HIV-positive HIV-1 is capable of using either CCR5 or CXCR4 as a co-receptor in vivo; in vitro, it has been shown to use other chemokine receptors (Unutmaz et al 1998). Some strains of HIV-1, known as R5, use only CCR5 as the co-receptor to gain access to the host cell. Other strains, X4 strains, use only CXCR4 as its co-receptor. Dual or mixed (D/M) strains, also known as R5X4 strains, can use both CCR5 and CXCR4. In early infection, the vast majority (70%–80%) of strains isolated from treatment-naïve patients are CCR5-tropic or R5 viruses (Brumme et al 2005; Moyle et al 2005), whereas X4 strains, previously known as syncytium-inducing variants, are seen in 30%–60% of treatment-experienced patients and arise later in the natural history of HIV-1 infection. They are associated with accelerated progression to AIDS and lymphocyte depletion. It is unclear whether the appearance of variants that use CXCR4 as a co-receptor is a cause or an effect of immunodeﬁciency (Koot et al 1993; Connor et al 1997; Melby et al 2006; Wilkin et al 2007). It should be noted that R5 strains still persist late into the course of disease, so the CCR5 co-receptor may still be an important pharmaceutical target even in advanced stages of disease (Wilkin et al 2007). Natural variant of CCR5 In 1996, a 32 base pair mutation in the gene for CCR5, known as ∆ 32, was shown to protect against HIV-1 infection (Huang et al 1996). The mutant allele codes for a dysfunc- tional truncated protein that is not expressed on the surface of the cell. The frequency of the allele is approximately 10%–14% in the white population, particularly those of Northern European descent, but is seldom seen in Asians or Africans; approximately 1% of the Caucasian population is homozygous for the deletion (Liu et al 1996). Infection of ∆ 32 homozygotes is exceedingly rare, and when it occurs 476 is caused by viruses using CXCR4 as a co-receptor for viral entry; heterozygotes can be infected with the HIV-1 virus but tend to have a longer disease course (Dean et al 1996; Liu et al 1996; Samson et al 1996). Patients who are homo- zygous for the ∆ 32 mutation are phenotypically normal, without readily apparent negative effects or decreased life expectancy. The preserved functional phenotype of ∆ 32 homozygotes is attributable to the redundancy present in the host defense system. Interestingly, mutations in murine CXCR4 (or its only known native ligand, Stromal factor-1) are lethal in the embryo (Lapidot 2001). However, recent evidence suggests ∆ 32 homozygotes may have immunological consequences. Early research- ers proposed that the mutation, in its early age, may have provided protection against Yersinia pestis (Stephens et al 1998), the microbial agent of the bubonic plague; others have suggested that protection against smallpox may have been the survival advantage (Galvani et al 2003). The area remains controversial, and recent population studies indicate that evolution of CCR5 may have been neutral (Sabeti et al 2005). Another study demonstrated longer survival and delayed rejection of renal allografts in ∆ 32 homozygotes (Fischereder et al 2001), and CCR5∆ 32 may be protective against the development of rheumatoid arthritis and persistent hepatitis B infection (Prahalad et al 2006; Thio et al 2007). The ∆ 32 mutation has also been associated with increased mortality from encephalopathy caused by West Nile Virus (Glass et al 2006). Additional studies will likely reveal other previously unrecognized complications or beneﬁts associated with absence, dysfunction, or blockade of CCR5. Targeting CCR5 A number of potential mechanisms are under investigation to inhibit HIV-1 binding and fusion to human cells. These include agents to block CD4 binding by viral gp120, inhibit CCR5 or CXCR4 co-receptor binding by gp120, as well as inhibit gp41 mediated fusion of the viral and cellular lipid bilayers as the Food and Drug Administration (FDA)- approved agent enfuvirtide does (Guo et al 2003; Jacobson et al 2004; Oldﬁeld et al 2005; Kadow et al 2006; Moyle et al 2007). While it is beyond the scope of this review to discuss every agent, we will review developmentally advanced agents and the various tactics under study for the antagonism of CCR5. With the initial discovery that CCR5 was an HIV-1 co- receptor and its endogenous ligands, (MIP-1α, MIP-1β, and RANTES) able to suppress HIV-1 replication, efforts centered on pharmacologically reproducing the effects of Therapeutics and Clinical Risk Management 2008:4(2)