Review CCR5 Antagonists: Host-Targeted Antivirals for the Treatment of HIV Infection

Antiviral Chemistry & Chemotherapy 16:339–354 Review CCR5 antagonists: host-targeted antivirals for the treatment of HIV infection Mike Westby* and Elna van der Ryst Pfizer Global R&D, Kent, UK *Corresponding author: Tel: +44 1304 649876; Fax: +44 1304 651819; E-mail: [email protected] The human chemokine receptors, CCR5 and suggest that these compounds have a long plasma CXCR4, are potential host targets for exogenous, half-life and/or prolonged CCR5 occupancy, which small-molecule antagonists for the inhibition of may explain the delay in viral rebound observed HIV-1 infection. HIV-1 strains can be categorised by following compound withdrawal in short-term co-receptor tropism – their ability to utilise CCR5 monotherapy studies. A switch from CCR5 to (CCR5-tropic), CXCR4 (CXCR4-tropic) or both (dual- CXCR4 tropism occurs spontaneously in approxi- tropic) as a co-receptor for entry into susceptible mately 50% of HIV-infected patients and has been cells. CCR5 may be the more suitable co-receptor associated with, but is not required for, disease target for small-molecule antagonists because a progression. The possibility of a co-receptor natural deletion in the CCR5 gene preventing its tropism switch occurring under selection pressure expression on the cell surface is not associated by CCR5 antagonists is discussed. The completion with any obvious phenotype, but can confer of ongoing Phase IIb/III studies of maraviroc, resistance to infection by CCR5-tropic strains – the aplaviroc and vicriviroc will provide further insight most frequently sexually-transmitted strains. into co-receptor tropism, HIV pathogenesis and The current leading CCR5 antagonists in clinical the suitability of CCR5 antagonists as a potent development include maraviroc (UK-427,857, new class of antivirals for the treatment of HIV Pfizer), aplaviroc (873140, GlaxoSmithKline) and infection. vicriviroc (SCH-D, Schering-Plough), which have demonstrated efficacy and tolerability in Keywords: co-receptor, chemokine, entry, HIV, HIV-infected patients. Pharmacodynamic data also antiretroviral Introduction Human immunodeficiency virus (HIV), the retrovirus that discontinued HAART did so for reasons related to drug causes acquired immune deficiency syndrome (AIDS), is a toxicity, which mainly occurred within 3 months of starting major cause of death worldwide. In 2004 alone, AIDS therapy (d’Arminio et al., 2000). A further limitation of resulted in the death of an estimated 3.1 million people HAART is the development of viral resistance, which has (WHO, 2004). Highly active antiretroviral therapy limited the effectiveness of many antiretroviral drugs (HAART) regimens introduced in the late 1990s (Martinez-Picado et al., 2000). In one large study of HIV- profoundly reduced morbidity and mortality due to HIV positive adults who received treatment yet were viraemic infection in developed countries. These regimens generally with >500 HIV RNA copies/ml it was estimated that include at least three drugs selected from four classes: approximately 76% of patients had resistance to one or nucleoside/nucleotide reverse transcriptase inhibitors more HIV drugs within 3 years (Richman et al., 2004). (NRTIs), non-nucleoside reverse transcriptase inhibitors These limitations highlight the continuing unmet medical (NNRTIs), protease inhibitors (PIs) and fusion inhibitors. need for anti-HIV agents with novel mechanisms of action. Although effective in reducing plasma viral load, delaying Until recently, all licensed anti-HIV drugs have inhib- disease progression to AIDS and prolonging survival, ited viral replication by acting on intracellular targets. HAART has two major limitations. Firstly, drug toxicity Only one currently licensed drug, enfuvirtide (Fuzeon®, (reviewed by Carr, 2003) can often lead to poor treatment Trimeris/Roche; formerly known as T-20) acts at the compliance and treatment failure and facilitates emergence point of virus entry into cells. The licensed approval of of resistance. In one study, 58% of patients who enfuvirtide in 2003 demonstrated that HIV entry is a viable ©2005 International Medical Press 339 M Westby & E van der Ryst therapeutic target for future drug development. Several binding of gp120 to CD4 causes a reconfiguration of the new classes of anti-HIV agents have since emerged, acting V1/V2 and V3 loops of gp120 to expose the bridging sheet on either viral or human target proteins. This review and form a co-receptor binding site (Kwong et al., 1998; outlines the processes involved in HIV entry and discusses Rizzuto et al., 1998; Wyatt et al., 1998). Once this has the development of several promising compounds termed occurred, co-receptor binding triggers conformational HIV co-receptor antagonists. In particular, the class of changes in gp41, which drive the remaining steps in fusion co-receptor antagonists that act on the human chemokine and entry of the viral core (reviewed by Chan & Kim, receptor, CCR5, is discussed in detail. 1998). According to a recent study of HIV-1 entry kinetics, the entry efficiency of cell-attached virus is mainly The process of HIV entry controlled by three kinetic processes: a lag phase caused in part by the reversible, concentration-dependent association The process by which HIV-1 attaches to and enters host of virus with CD4 and a co-receptor; a lowering of the acti- cells has been studied extensively (reviewed by Pierson et vation energy barrier for a co-receptor-dependent confor- al., 2004). The interactions between the virus and the cell mational change in gp41; and a relatively rapid and surface required for entry are mediated by the viral enve- kinetically dominant process of viral inactivation, possibly lope protein, Env. During viral replication, Env is expressed involving endocytosis, which competes with viral entry as a 160kDa precursor protein, termed glycoprotein (Platt et al., 2005). (gp)160, which is later cleaved by a host cell protease into surface and transmembrane subunits, termed gp120 and Targeting HIV-1 entry gp41, respectively. The gp120 subunit is required for specific binding to host-cell receptors and possesses five The development of agents targeting discrete stages of the variable regions (V1–V5) and five constant regions HIV-1 entry process has been facilitated by two lines of (C1–C5) that are conserved among different HIV-1 research, namely: the discovery of the cellular receptors strains. In mature, free virions, gp120 is arranged as inner required for HIV infection, and an understanding of how and outer domains connected by a bridging sheet with viral components interact with these receptors. A potential conserved and functionally important regions hidden from advantage of targeting HIV-1 entry is that the site of host immune recognition (Kwong et al., 1998; Wyatt et al., inhibitory action is likely to be extracellular. An extracel- 1998). The native gp41 subunit has an N-terminal, glycine- lular target is potentially more accessible and, unlike rich ‘fusion peptide’ which is concealed in a non-fusogenic NRTIs, there is no requirement for intracellular processing state until specific interactions between gp120 and host- of the agent. Therefore, there is no mechanistic reason for cell receptors have occurred. Each gp120 unit is non-cova- non-receptor-linked intracellular toxic effects such as mito- lently associated with a gp41 unit and these heterodimers chondrial toxicity. A further advantage of entry inhibitors is are arranged as trimers on the outer surface of the mature that there is no cross-resistance with existing agents that virion. The first mandatory step in the process of HIV-1 act on intracellular targets, as demonstrated by the potency entry is the specific binding of gp120 to CD4, the primary of co-receptor antagonists AMD3100 (Este et al., 1996), receptor for HIV-1 (Figure 1). The CD4 receptor is maraviroc (UK-427,857) (Westby et al., 2003) and expressed mainly on T-lymphocytes and macrophages and aplaviroc (Maeda et al., 2004), and the fusion inhibitors is a member of the immunoglobulin (Ig)-like protein enfuvirtide and T-1249 (Sista et al., 2001) against viruses superfamily. However, the binding of gp120 to CD4 alone resistant to other classes of anti-HIV drugs. is not sufficient for HIV-1 entry (Maddon et al., 1986). However, there are potential disadvantages of entry The observation that human chemokines are capable of inhibition. Firstly, Env is the most sequence-variable of the inhibiting HIV-1 infection of T-lymphocytes (Cocchi et HIV-1 proteins (Griffin, 2003). Hence, differences in drug al., 1995) and the identification of polymorphisms in the sensitivity between HIV-1 strains are possible, as has been CCR5 gene leading to resistance to HIV infection (Liu et described for the gp120 inhibitor, BMS-806, which has a al., 1996), led to the discovery that a human chemokine wide range of activities against panels of B-clade and non- receptor is an essential co-receptor for HIV-1 infection B-clade viruses (Lin et al., 2003). Secondly, targeting host (Feng et al., 1996). Chemokines are a large family of receptors may inhibit their natural function. If this inter- secreted chemoattractant proteins that regulate leukocyte rupts essential host processes then compounds may have activation and migration to sites of inflammation via inter- unwanted secondary pharmacological effects. action with a family of chemokine receptors. The The inhibition of binding of gp120 to CD4 has been chemokine receptors most commonly utilised by HIV-1 in explored with mixed results. Early attempts to inhibit vivo are CCR5 and/or CXCR4 (Choe et al., 1996; Deng et this interaction with soluble, recombinant CD4 were al., 1996; Dragic et al., 1996; Feng et al., 1996). The abandoned because of lack of activity against primary 340 ©2005 International Medical Press CCR5 antagonists for treatment of HIV infection Figure 1. A model for HIV entry A B gp41 gp120 CD4 Co-receptor (CCR5 or CXCR4) Host cell membrane C D HIV gp120 binds to CD4 (A). This induces conformational changes in gp120 and exposure of the co-receptor binding site (B), which is a complex domain comprising the V3 loop and specific amino acid residues in C4, collectively termed the ‘bridging sheet’.

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