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3392005 International Medical Press

The human chemokine receptors, CCR5 andCXCR4, are potential host targets for exogenous,small-molecule antagonists for the inhibition ofHIV-1 infection. HIV-1 strains can be categorised byco-receptor tropism their ability to utilise CCR5(CCR5-tropic), CXCR4 (CXCR4-tropic) or both (dual-

tropic) as a co-receptor for entry into susceptiblecells. CCR5 may be the more suitable co-receptortarget for small-molecule antagonists because anatural deletion in the CCR5 gene preventing itsexpression on the cell surface is not associatedwith any obvious phenotype, but can conferresistance to infection by CCR5-tropic strains themost frequently sexually-transmitted strains.The current leading CCR5 antagonists in clinicaldevelopment include maraviroc (UK-427,857,Pfizer), aplaviroc (873140, GlaxoSmithKline) andvicriviroc (SCH-D, Schering-Plough), which havedemonstrated efficacy and tolerability in

HIV-infected patients. Pharmacodynamic data also

suggest that these compounds have a long plasmahalf-life and/or prolonged CCR5 occupancy, whichmay explain the delay in viral rebound observedfollowing compound withdrawal in short-termmonotherapy studies. A switch from CCR5 toCXCR4 tropism occurs spontaneously in approxi-

mately 50% of HIV-infected patients and has beenassociated with, but is not required for, diseaseprogression. The possibility of a co-receptortropism switch occurring under selection pressureby CCR5 antagonists is discussed. The completionof ongoing Phase IIb/III studies of maraviroc,aplaviroc and vicriviroc will provide further insightinto co-receptor tropism, HIV pathogenesis andthe suitability of CCR5 antagonists as a potentnew class of antivirals for the treatment of HIVinfection.

Keywords: co-receptor, chemokine, entry, HIV,

antiretroviral

Antiviral Chemistry & Chemotherapy 16:339354

Review

CCR5 antagonists: host-targeted antivirals for thetreatment 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]

Introduction

Human immunodeficiency virus (HIV), the retrovirus thatcauses acquired immune deficiency syndrome (AIDS), is amajor cause of death worldwide. In 2004 alone, AIDSresulted in the death of an estimated 3.1 million people(WHO, 2004). Highly active antiretroviral therapy(HAART) regimens introduced in the late 1990sprofoundly reduced morbidity and mortality due to HIVinfection in developed countries. These regimens generally

include at least three drugs selected from four classes:nucleoside/nucleotide reverse transcriptase inhibitors(NRTIs), non-nucleoside reverse transcriptase inhibitors(NNRTIs), protease inhibitors (PIs) and fusion inhibitors.Although effective in reducing plasma viral load, delayingdisease progression to AIDS and prolonging survival,HAART has two major limitations. Firstly, drug toxicity(reviewed by Carr, 2003) can often lead to poor treatmentcompliance and treatment failure and facilitates emergenceof resistance. In one study, 58% of patients who

discontinued HAART did so for reasons related to drugtoxicity, which mainly occurred within 3 months of startingtherapy (dArminio et al ., 2000). A further limitation ofHAART is the development of viral resistance, which haslimited the effectiveness of many antiretroviral drugs(Martinez-Picado et al., 2000). In one large study of HIV-positive adults who received treatment yet were viraemicwith >500 HIV RNA copies/ml it was estimated that

approximately 76% of patients had resistance to one ormore HIV drugs within 3 years (Richman et al ., 2004).These limitations highlight the continuing unmet medicalneed for anti-HIV agents with novel mechanisms of action.

Until recently, all licensed anti-HIV drugs have inhib-ited viral replication by acting on intracellular targets.Only one currently licensed drug, enfuvirtide (Fuzeon,Trimeris/Roche; formerly known as T-20) acts at thepoint of virus entry into cells. The licensed approval ofenfuvirtide in 2003 demonstrated that HIV entry is a viable

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therapeutic target for future drug development. Severalnew classes of anti-HIV agents have since emerged, actingon either viral or human target proteins. This reviewoutlines the processes involved in HIV entry and discussesthe development of several promising compounds termedHIV co-receptor antagonists. In particular, the class ofco-receptor antagonists that act on the human chemokinereceptor, CCR5, is discussed in detail.

The process of HIV entry

The process by which HIV-1 attaches to and enters hostcells has been studied extensively (reviewed by Pierson etal., 2004). The interactions between the virus and the cellsurface required for entry are mediated by the viral enve-lope protein, Env. During viral replication, Env is expressedas a 160kDa precursor protein, termed glycoprotein(gp)160, which is later cleaved by a host cell protease into

surface and transmembrane subunits, termed gp120 andgp41, respectively. The gp120 subunit is required forspecific binding to host-cell receptors and possesses fivevariable regions (V1V5) and five constant regions(C1C5) that are conserved among different HIV-1strains. In mature, free virions, gp120 is arranged as innerand outer domains connected by a bridging sheet withconserved and functionally important regions hidden fromhost immune recognition (Kwong et al., 1998; Wyatt et al.,1998). The native gp41 subunit has an N-terminal, glycine-rich fusion peptide which is concealed in a non-fusogenicstate until specific interactions between gp120 and host-

cell receptors have occurred. Each gp120 unit is non-cova-lently associated with a gp41 unit and these heterodimersare arranged as trimers on the outer surface of the maturevirion. The first mandatory step in the process of HIV-1entry is the specific binding of gp120 to CD4, the primaryreceptor for HIV-1 (Figure 1). The CD4 receptor isexpressed mainly on T-lymphocytes and macrophages andis a member of the immunoglobulin (Ig)-like proteinsuperfamily. However, the binding of gp120 to CD4 aloneis not sufficient for HIV-1 entry (Maddon et al., 1986).

The observation that human chemokines are capable ofinhibiting HIV-1 infection of T-lymphocytes (Cocchi etal., 1995) and the identification of polymorphisms in the

CCR5 gene leading to resistance to HIV infection (Liu etal., 1996), led to the discovery that a human chemokinereceptor is an essential co-receptor for HIV-1 infection(Feng et al ., 1996). Chemokines are a large family ofsecreted chemoattractant proteins that regulate leukocyteactivation and migration to sites of inflammation via inter-action with a family of chemokine receptors. Thechemokine receptors most commonly utilised by HIV-1 invivo are CCR5 and/or CXCR4 (Choe et al., 1996; Deng etal., 1996; Dragic et al ., 1996; Feng et al ., 1996). The

binding of gp120 to CD4 causes a reconfiguration of theV1/V2 and V3 loops of gp120 to expose the bridging sheetand form a co-receptor binding site (Kwong et al ., 1998;Rizzuto et al ., 1998; Wyatt et al ., 1998). Once this hasoccurred, co-receptor binding triggers conformationalchanges in gp41, which drive the remaining steps in fusionand entry of the viral core (reviewed by Chan & Kim,1998). According to a recent study of HIV-1 entry kinetics,the entry efficiency of cell-attached virus is mainlycontrolled by three kinetic processes: a lag phase caused inpart by the reversible, concentration-dependent associationof virus with CD4 and a co-receptor; a lowering of the acti-vation energy barrier for a co-receptor-dependent confor-mational change in gp41; and a relatively rapid andkinetically dominant process of viral inactivation, possiblyinvolving endocytosis, which competes with viral entry(Platt et al., 2005).

Targeting HIV-1 entry

The development of agents targeting discrete stages of theHIV-1 entry process has been facilitated by two lines ofresearch, namely: the discovery of the cellular receptorsrequired for HIV infection, and an understanding of howviral components interact with these receptors. A potentialadvantage of targeting HIV-1 entry is that the site ofinhibitory action is likely to be extracellular. An extracel-lular target is potentially more accessible and, unlikeNRTIs, there is no requirement for intracellular processingof the agent. Therefore, there is no mechanistic reason for

non-receptor-linked intracellular toxic effects such as mito-chondrial toxicity. A further advantage of entry inhibitors isthat there is no cross-resistance with existing agents thatact on intracellular targets, as demonstrated by the potencyof co-receptor antagonists AMD3100 (Este et al ., 1996),maraviroc (UK-427,857) (Westby et al., 2003) andaplaviroc (Maeda et al ., 2004), and the fusion inhibitorsenfuvirtide and T-1249 (Sista et al ., 2001) against virusesresistant to other classes of anti-HIV drugs.

However, there are potential disadvantages of entryinhibition. Firstly, Env is the most sequence-variable of theHIV-1 proteins (Griffin, 2003). Hence, differences in drugsensitivity between HIV-1 strains are possible, as has been

described for the gp120 inhibitor, BMS-806, which has awide range of activities against panels of B-clade and non-B-clade viruses (Lin et al ., 2003). Secondly, targeting hostreceptors may inhibit their natural function. If this inter-rupts essential host processes then compounds may haveunwanted secondary pharmacological effects.

The inhibition of binding of gp120 to CD4 has beenexplored with mixed results. Early attempts to inhibitthis interaction with soluble, recombinant CD4 wereabandoned because of lack of activity against primary

M Westby & E van der Ryst

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CCR5 antagonists for treatment of HIV infection

HIV-1 isolates. More recent developments includePRO-542 (Progenics Pharmaceuticals, USA), which is atetravalent CD4-IgG2 fusion protein incorporating fourcopies of the Env-binding domains of CD4 (Jacobson etal., 2000), and TNX-355 (Tanox, USA), a humanizedIgG4 monoclonal antibody targeted towards CD4 ratherthan gp120 to prevent post-binding entry (Kuritzkes et al.,2004). Both of these agents are in Phase II developmentand resemble enfuvirtide in that they must be administered

parenterally. Two orally bioavailable compounds, BMS-806and BMS-043 (Bristol-Myers Squibb, USA), target gp120rather than CD4 (Lin PF, Ho HT, Gong YF, Dicker I,Zhou N, Fan L, McAuliffe B, Kimmel B, Nowicka-SansB, Wang T, Kadow J, Yamanaka G, Lin Z, Meanwell N &Colonno R [2004] Characterization of a small moleculeHIV-1 attachment inhibitor BMS-488043: virology, resis-tance and mechanism of action. 11th Conference onRetroviruses and Opportunistic Infections. San Francisco,

Antiviral Chemistry & Chemotherapy 16.6 341

Co-receptor(CCR5 or CXCR4)

Host cellmembrane

gp41

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HIV gp120 binds to CD4 (A). This induces conformational changes in gp120 and exposure of the co-receptor binding site (B), which is acomplex domain comprising the V3 loop and specific amino acid residues in C4, collectively termed the bridging sheet. Exposure of theco-receptor binding site permits binding of gp120 to the co-receptor (C). Co-receptor antagonists inhibit this step by binding the co-receptorand changing its shape such that gp120 cannot recognise it. Co-receptor binding induces conformational changes in gp41 and insertion ofa fusion peptide into the host cell membrane (D), ultimately resulting in fusion of viral and cell membranes. Multiple gp120-co-receptorinteractions are required to form a fusion pore through which the viral core can pass and infect the cell.

Figure 1. A model for HIV entry

A B

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CA, USA, February 2004. Abstract 534; Madani et al .,2004). Both compounds demonstrate variable activitywhen tested in vitro against panels of virus isolates (Lin etal., 2003; Lin et al ., 2004: see above), although BMS-043has shown efficacy in short-term monotherapy in HIV-1infected individuals (Hanna G, Lalezari J, Hellinger J,Wohl D, Masterson T, Fiske W, Kadow J, Lin P, GiordanoM, Colonno R & Grasela D [2004] Antiviral activity,safety, and tolerability of a novel, oral small-molecule HIV-1 attachment inhibitor, BMS-488043, in HIV-1 infectedsubjects. 11th Conference on Retroviruses and Opportunistic

Infections. San Francisco, CA, USA, February 2004.Abstract 141).

As mentioned previously, enfuvirtide is currently theonly licensed HIV-1 entry inhibitor (Arasteh et al., 2004;Lalezari et al., 2003; Lazzarin et al., 2003). Enfuvirtide is a36-amino acid synthetic peptide that targets gp41 toprevent the conformational changes required for fusion

(Clotet et al ., 2004). It is particularly effective when addedto optimized background therapy in viraemic patients witha history of multiple treatment failures (Arasteh et al .,2004; Lalezari et al ., 2003; Lazzarin et al ., 2003). Apartfrom injection site reactions, it has a favourable safetyprofile and no clinically significant drugdrug interactions.However, enfuvirtide use is currently limited to extensivelypre-treated patients who have few treatment options andthis is largely due to its inconvenient route of administra-tion (Clotet et al., 2004).

A similar agent, T-1249 (Roche, Switzerland), whichwas widely regarded as the leading next generation fusion

inhibitor and a successor to enfuvirtide, is no longer indevelopment despite having activity against enfuvirtide-resistant virus (Eron et al ., 2004; Lalezari et al ., 2005).According to its developers, the formulation of T-1249would not be suitable for use in large-scale clinical trials(Martin-Carbonero, 2004). Small-molecule inhibitorstargeting fusion have been described, although theserepresent interesting leads rather than clinical candidates(Jiang et al ., 2004; Salzwedel K, Crisafi K, Jackson T,Castillo A, Kilgore N, Reddick M, Allaway G & Wild C[2004] Identification of small molecule HIV-1 fusioninhibitors. 11th Conference on Retroviruses and Opportunistic

Infections. San Francisco, CA, USA, February 2004.

Abstract 311).The possibility of inhibiting HIV-1 entry bytargeting the co-receptors, specifically CCR5, has been thesubject of increased interest in recent years and will bediscussed in more detail below.

HIV co-receptor tropism

Tropism can be defined as the affinity or specificity for atarget. In the case of HIV-1, tropism is largely determinedby differential co-receptor usage of different HIV strains.

Although several distinct chemokine receptors have beenshown to function as co-receptors for HIV-1 infection invitro, the vast majority of HIV-1 clinical isolates studied todate use CCR5, CXCR4 or both to infect human periph-eral blood mononuclear cells (Berger et al ., 1998; Berger etal., 1999). Historically, HIV-1 strains were classified aseither T-tropic or M-tropic based on their ability to infectT-cells or macrophages, respectively, in vitro. The T-tropicphenotype was later associated with the ability to inducesyncytium formation in MT-2 cells, an in vitro cytopathiceffect which was not apparent with M-tropic strains. Thisled to the phenotypic nomenclature of syncytium-inducing(SI) and non-syncytium-inducing (NSI) strains. Followingthe discovery of the CXCR4 and CCR5 co-receptors, theSI phenotype was shown to most often be associated withvirus that could utilise CXCR4, while most primary NSIisolates use CCR5 for entry. However, there is not anabsolute correlation between cellular tropism, SI/NSI

phenotype and co-receptor tropism (Hendrix et al ., 2004;Todd et al ., 1995). Since CCR5 antagonists target CCR5-using strains, references to virus tropism in this review willfocus on the definition based on co-receptor usage.

In the current system of nomenclature HIV-1 strains arecategorised as R5 (CCR5-tropic), X4 (CXCR4-tropic) orR5X4 (strains using both CCR5 and CXCR4; also referredto as dual-tropic) (Berger et al ., 1998). CCR5 antagonistsonly inhibit strains which are obligate users of CCR5,while X4 and R5X4 strains can be described collectively asCXCR4-using to indicate their ability to infect cells inthe presence or absence of a CCR5-specific antagonist. A

patient serum sample may also contain a heterogeneouspopulation of viruses with different tropism, termed mixedtropism. There is a complex association between HIV-1co-receptor tropism, transmission and pathogenesis whichis not yet fully understood (reviewed by Moore et al., 2004and Philpott et al., 2003). Generally, strains that are trans-mitted and establish new infections in a host are R5(Schuitemaker et al ., 1991; Shankarappa et al ., 1999; Zhuet al ., 1993). In some individuals, CXCR4-tropism evolvesover time and the emergence of X4 virus has been associ-ated with rapid CD4 T-lymphocyte decline and accelerateddisease progression. Although increasing prevalence of X4virus and decreasing prevalence of R5 virus have been asso-

ciated with increasing viral load and decreasing CD4 cellcounts (Brumme et al ., 2005; Moyle et al ., 2005), a switchto CXCR4-tropism is not exclusively required for thedevelopment of AIDS. R5 variants are often the only vari-ants detected in the circulating virus of HIV-1 infectedpatients. This is true at all disease stages (acute, asympto-matic and symptomatic/advanced). Dual/mixed-tropicvirus is more likely to be detected in patients with advanceddisease, but the identification in patients of a circulatingvirus pool that is entirely CXCR4-tropic is rare (Moyle et



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al., 2005; Whitcomb JM, Huang W, Fransen S, Wrin T,Paxinos E, Toma J, Greenberg M, Sista P, Melby T,Matthews T, DeMasi R, Heilek-Snyder G, Cammack N,Hellmann N & Petropoulos C [2003] Analysis of baselineenfuvirtide (T20) susceptibility and co-receptor tropism intwo-phase III study populations. 10th Conference onRetroviruses and Opportunistic Infections. Boston, USA,1014 February 2003. Abstract 557). Whether emergenceof X4 strains is a marker for disease progression rather thanthe cause may only be answered following carefullycontrolled multi-centre clinical trials of CCR5 antagonists(Moore et al., 2004), such as those discussed below.

CCR5 as a therapeutic target

CCR5 is a 352-amino-acid protein with a basic structurethat is consistent with other members of the seven-transmembrane G protein-coupled receptor (GPCR)

superfamily. It consists of three extracellular loops (ECL1,ECL2 and ECL3) and the N terminus, which are involvedin chemokine binding, and three intracellular loops and theC terminus, which participate in G protein-mediatedsignal transduction. Chemokines are the most importantregulators of leukocyte trafficking. The typical cellularresponse to stimulation of chemokine receptors is chemo-taxis up or down a concentration gradient of thechemokine. This is suspected also for CCR5 in light ofchemotaxis observations using recombinant cell lines(Strizki et al ., 2001).The activation of CCR5 also causes anumber of cellular responses that are typical of many

GPCRs, including inhibition of cAMP production, stimu-lation of Ca2+ ion release and activation of MAP kinase andJun-N-terminal kinase (Thelen, 2001). The natural ligandsof CCR5 (reviewed by Mueller & Strange, 2004) includethe chemokines known as macrophage inflammatoryprotein (MIP)-1, MIP-1 and regulated on activation,normal T-cell expressed and secreted (RANTES). Theobservation that these ligands can inhibit HIV-1 entry(Cocchi et al., 1995) led to the identification of CCR5 as aco-receptor for HIV-1 (Alkhatib et al ., 1996). Mutationalanalyses and the inhibition of chemokine and gp120binding to CCR5 by monoclonal antibodies have identifiedECL2 and a tyrosine-rich region within the N terminus of

CCR5 as the major components involved in interactionswith gp120 during HIV-1 entry (Dragic et al ., 1998;Farzan et al ., 1998; Farzan et al ., 1999; Farzan et al., 2000;Farzan et al ., 2002; Lee et al ., 1999; Olson et al ., 1999).These findings prompted the development of an earlydrug candidate, PRO-140 (Progenics Pharmaceuticals,USA), a murine monoclonal antibody that recognisesmultiple extracellular domains of CCR5 (Olson et al .,1999; Trkola et al ., 2001). PRO-140 is currently underinvestigation in Phase I clinical trials (Olson P, Doshan H,

Mezzatesta J, Assumma A, Czarnecky R, Maddon P,Kremer A & Isreal R [2005] First-in-humans trial ofPRO 140, a humanized CCR5 monoclonal antibody forHIV-1 therapy. 3rd International AIDS Society Conference,Rio de Janeiro, Brazil, July 2427, 2005. AbstractWePe6.2C04).

The concept of targeting GPCRs for therapeutic inter-vention is not a new one. The GPCR superfamily is themost prominent class of drug target; approximately 60% ofall commercially available prescription drugs work by selec-tive modulation of a GPCR (Gudermann et al ., 1995) andnew agents are constantly emerging to target GPCRsinvolved in a variety of disease processes (reviewed byGurrath, 2001). Of the two GPCRs acting as the principalHIV-1 co-receptors, CCR5 may be the most suitablecandidate target for novel therapeutic agents. The potentialefficacy of such agents is highlighted by the observationthat individuals with a mutation in their CCR5 gene

showed resistance to HIV-1 infection (Dean et al ., 1996;Huang et al ., 1996; Liu et al ., 1996; Samson et al ., 1996).Approximately 1% of the Caucasian population is homo-zygous for a natural 32-base-pair deletion in the CCR5gene (CCR5-32), which results in complete absence ofCCR5 expression on the cell surface. Furthermore, HIV-positive patients who are heterozygous for the CCR5-32allele have delayed disease progression (Dean et al ., 1996;Huang et al ., 1996), although these patients may show arelatively rapid decline in CD4+ T-cells following AIDSdiagnosis (Garred et al., 1997).

Confidence in safety for the development of a CCR5

antagonist for the treatment of HIV/AIDS was suggestedby the observation that there is no overt phenotype associ-ated with CCR5-32 homozygosity (a natural knockout inhumans) (Samson et al ., 1996). R5 strains are the mostcommonly transmitted (Schuitemaker et al ., 1991;Shankarappa et al . , 1999; Zhu et al ., 1993), they usuallypredominate throughout asymptomatic infection and50% or more of patients who develop AIDS carry onlyR5 strains (Fitzgibbon et al ., 1998; Roda Husman et al .,1999; Tuttle et al . , 2002). Several compounds indevelopment that target CCR5 have been shown to beeffective inhibitors of HIV-1 infection in mouse andmacaque models (Nakata et al ., 2005; Strizki et al ., 2001;

Veazey et al ., 2003) and in humans (Ftkenheuer et al.,2004; Lalezari J, Thompson M, Kumar P, Piliero P, DaveyR, Murtaugh T, Patterson K, Shachoy-Clark A, AdkisonK, Demarest J, Sparks S, Fang L, Lou Y, Berrey M &Piscitelli S [2004] 873140, a novel CCR5 antagonist:antiviral activity and safety during short-term monotherapyin HIV-infected adults. 44th Interscience Conference on

Antimicrobial Agents and Chemotherapy. Washington DC,USA, 30 October2 November 2004. Abstract H-1137b;Reynes J, Rouzier R, Kanouni T, Baillat V, Baroudy B,


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Keung A, Hogan C, Markowitz M & Laughlin M [2002]SCH C: safety and antiviral effects of a CCR5 receptorantagonist in HIV-1-infected subjects. 9th Conference onRetroviruses and Opportunistic Infections. Seattle, USA,February 2002. Abstract 1; Schurmann D, Rouzier R,Nougarede R, Reynes J, Ftkenheuer G, Raffi F, MicheletC, Tarral A, Hoffmann C, Kiunke J, Sprenger H, van LierJ, Sansone A, Jackson M & Laughlin M [2004] SCH-D:antiviral activity of a CCR5 receptor antagonist. 11thConference on Retroviruses and Opportunistic Infections. SanFancisco, USA,8-11 February 2004.Abstract 140LB). Themore promising compounds are discussed in detail below.

CCR5 antagonist discovery

Several major pharmaceutical companies have sought torealise the potential of CCR5 antagonism as a new thera-peutic strategy for HIV infection. The following is an

overview of the development status of the key CCR5antagonists described to date. Key clinical data relating tothe three leading compounds are presented in Table 1.One of the first small-molecule CCR5 antagonists to bedescribed was TAK-779 (Takeda Chemical Industries,Japan; Figure 2) (Baba et al ., 1999). Although activeagainst R5 HIV-1 in vitro (50% effective concentration[EC50] 24 h

Doses of aplaviroc and vicriviroc being evaluated in Phase IIb/III clinical trials were obtained from www.clinicaltrials.gov. *150 mg maravirocdose used in regimens containing HIV-1 protease inhibitors (PIs), with the exception of tipranavir. (Adkison K, Shachoy-Clark A, Fang L, Lou Y,Otto V, Berrey M & Piscitelli S (2005a) The pharmacokinetic interaction between the CCR5 antagonist 873140 and lopinavir/ritonavir inhealthy subjects. 12th Conference on Retroviruses and Opportunistic Infections, Boston, USA. February 2005. Abstract 664; Adkison et al.,2005b; Ftkenheuer et al., 2004; Lalezari et al., 2004: see text; McHale et al., 2005: see text; Sansone A (2005) Pharmacokinetics of SCH417690 administered alone or in combination with ritonavir and efavirenz in healthy volunteers. 6th International Workshop on ClinicalPharmacology of HIV Therapy, Quebec City, Quebec, Canada. April 2830 2005. Abstract 79; Schurmann et al., 2004: see text.)

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Merck has described detailed structure activityrelationships of a series of agents with CCR5 antagonistactivity (Dorn et al ., 2001; Shen et al ., 2004; Willoughbyet al., 2001). However, to date, Merck has not yet reportedon an agent that has progressed into clinical development,although their agents have proved useful tools forunderstanding how small-molecule antagonists bind to thereceptor (Castonguay et al ., 2003) and for investigating

prevention of R5 infection in animal models of HIVinfection (Veazeyet al., 2003; Wolinskyet al ., 2004).

Schering-Plough has been developing CCR5 antago-nists for a number of years. Its first major candidate, SCH-C (SCH-351125; Figure 2), was the first CCR5 antagonistto be studied for clinical efficacy. SCH-C is a small,non-peptidic oxime-piperidine based on a compound iden-tified by high throughput screening of inhibitors of


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TAK-779 SCH-C/SCH-351125

Vicriviroc/SCH-D/SCH-417690

Maraviroc/UK-427,857 Aplaviroc/873140/AK602

Figure 2. Chemical structures of TAK-779, SCH-C, vicriviroc, maraviroc and aplaviroc

Este, 2002; Maeda etal., 2004; Tagat et al., 2004; Takashima et al., 2001; Wood & Armour, 2005. Aplaviroc, GlaxoSmithKline, UK; Maraviroc,Pfizer, UK; TAK-779, Takeda Chemical Industries, Japan; Vicriviroc and SCH-C, Schering-Plough Corporation, USA.

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RANTES-CCR5 binding and was confirmed to be aspecific CCR5 antagonist by receptor binding and signaltransduction assays. The separate binding domains onCCR5 for SCH-C and RANTES (Blanpain et al ., 2003;Tsamis et al., 2003; Wu et al., 1997) strongly suggested thatSCH-C, and potentially other small-molecule CCR5antagonists, act by an allosteric mechanism that alters theconformation of CCR5. In the allosteric model of CCR5antagonism, binding of the antagonist in the transmem-brane domain of CCR5 (Figure 3) induces a conforma-tional change in ECL2 that prevents its interaction withthe V3 crown, thus inhibiting viral entry (Tsamis et al .,2003).In vitro infectivity assays using SCH-C and primaryR5 HIV-1 isolates demonstrated a mean IC50 of less than9 nM, while potent in vivo activity was demonstrated in amurine model (Strizki et al., 2001). Although a study in 12HIV-infected patients demonstrated good oral bioavail-ability and a threefold or greater reduction in viral load at

25 mg BID, observations of QT prolongation in healthyvolunteers receiving 600 mg QD led to the termination offurther studies of SCH-C (Este, 2002; Reynes et al., 2002:see above). The QT interval represents the duration ofventricular depolarization and repolarization a delay incardiac repolarization can lead to the development ofcardiac arrhythmias. Schering-Plough has continued todevelop agents related to SCH-C, most notably vicriviroc(SCH-D, SCH-417690; Figure 2), which is reported to bemore potent than SCH-C and has a more favourable safetyprofile with respect to QTc prolongation. In a clinical studyin HIV-infected patients, more than 80% of patients who

received vicriviroc 50 mg BID achieved at least a1 log10

copies/ml mean reduction in viral load after 14 daysof treatment (Schurmann et al., 2004: see above). Phase IIbstudies of vicriviroc are ongoing.

A CCR5 antagonist in development by Pfizer,maraviroc (UK-427,857; Figure 2), has also been shown tobe active in vitro against a wide range of clinical R5 isolates(geometric mean IC90=2.0 nM) (Macartney MJ, Dorr P,Smith MW et al. [2003] In vitro antiviral profile ofUK-427,857, a novel CCR5 antagonist. 43rd InterscienceConference on Antimicrobial Agents and Chemotherapy.Chicago, USA, 1417 September, 2003; Abstract H-875).Pharmacokinetic studies have demonstrated good oral

bioavailability and a terminal half-life of 1623 h followingmultiple dosing, which does not alter significantly withdose. Single doses of up to 900 mg and multiple doses of upto 300 mg BID for 28 days were well tolerated (Abel S,Van der Ryst E, Muihead GJ, Rosario A, Edgington A &Weissgerber G [2003] Pharmacokinetics of single andmultiple oral doses of UK-427,857 a novel CCR5 antag-onist in healthy volunteers. 10th Conference on Retrovirusesand Opportunistic Infections, Boston, USA. February 2003.Abstract 547; Russell D, Bakhtyari A, Jazrawi RP,

Whitlock L, Ridgway C, McHale M & Abel S [2003]Multiple dose study to investigate the safety ofUK-427,857 [100 mg or 300 mg] BID for 28 days inhealthy males and females. 43rd Interscience Conference on

Antimicrobial Agents and Chemotherapy. Chicago, IL, USA,September 2003. Abstract H-874). In Phase IIa studies,treatment-naive HIV patients received maravirocmonotherapy at doses ranging from 25 mg QD to 300 mgBID for 10 days. At 300 mg BID a maximum mean viralload reduction of 1.84 log10 copies/ml was demonstrated(McHale M, Abel S, Russell D, Gallagher J & Van derRyst E [2005] Overview of Phase 1 and 2a safety and effi-cacy data of maraviroc [UK-427,857]. 3rd International

AIDS Society Conference. Rio de Janeiro, Brazil, 24-27 July2005. Abstract TuOA0204). Dosing with food had nosignificant effect on efficacy (Ftkenheuer et al., 2004) andthere was no significant difference in efficacy between150 mg BID and 300 mg QD dosing regimens. The drugis also well tolerated, with headache, nausea and flatulencethe only adverse events occurring at a rate higher thanplacebo at doses up to and including 300 mg BID(Ftkenheuer et al ., 2004; McHale et al ., 2005: see above).Phase IIb/III trials with maraviroc in both treatment-naive



Cell surface

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Binding of the antagonist within the transmembrane domain isthought to alter the conformation of the N-terminus and extracellularloops of CCR5 such that HIV-1 gp120 can no longer bind.

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and treatment-experienced patients are ongoing (McHaleet al ., 2005: see above).

GlaxoSmithKline (GSK) is currently developing small-molecule CCR5 antagonists based on spirodiketopiper-azine (SDP) derivatives. Aplaviroc (licensed from OnoPharmaceuticals, Japan; Figure 2) is effective at inhibitinglaboratory-adapted and primary R5 HIV-1 isolates in vitrowith an IC

50ranging from 0.1 to 0.6 nM (Maeda et al .,

2004) and is currently in Phase IIb/III development.According to mode-of-action studies, aplaviroc does notinhibit RANTES or MIP-1 binding, yet it does inhibitRANTES-mediated signalling and chemotaxis (Maeda etal., 2004; Watson et al ., 2005). Together with the observa-tion that the antagonism of CCR5 by aplaviroc is saturable,these findings are consistent with the allosteric model ofCCR5 antagonism proposed by Tsamis et al. (2003).Indeed, co-administration studies of aplaviroc with SCH-C, vicriviroc, TAK-779 and maraviroc support the theory

that all five of these CCR5 antagonists bind to an allostericsite on CCR5 to alter ECL2 conformation but, asevidenced by their differential effects on RANTESbinding, they do not exert the same allosteric effect(Watson et al ., 2005). This observation highlights theimportance of infectivity assays when assessing new small-molecule CCR5 antagonists because, unlike orthostericinhibitors of receptor binding, the efficacy of a non-competitive, allosteric antagonist is more related to thespecific conformational changes it induces in the targetreceptor rather than a simple function of its receptor-binding efficiency. In a Phase IIa study, patients receiving

an aplaviroc regimen of 600 mg BID for 10 days demon-strated a mean maximum viral load reduction from baselineof 1.66 log10 copies/ml (Lalezari et al ., 2004: see above).The drug appears to be well tolerated when taken orally,apart from mild/moderate gastrointestinal side effectsincluding abdominal cramps, nausea and diarrhoea(Adkison et al ., 2005b).In vivo CCR5 occupancy suggestsa long receptor binding half-life (Demarest J, Adkison K,Shachoy-Clark A, Schell K, Reddy S, Fang L, OMara K,Shibayama S & Piscitelli S [2004] Single and multiple doseescalation study to investigate the safety, pharmacokinetics,and receptor binding of GW873140, a novel CCR5receptor antagonist, in healthy subjects. 11th Conference on

Retroviruses and Opportunistic Infections. San Francisco,USA, 811 February 2004. Abstract 139).

Pharmacodynamics

In monotherapy trials of CCR5 antagonists the rebound inviral load after treatment discontinuation does not appearto be immediate and viral load may continue to fall aftercessation of the drug. This delayed rebound appears to be aclass effect and its duration varies from 1 to 2 days for

vicriviroc (Schurmann et al., 2004: see above) and aplaviroc(Lalezari et al ., 2004: see above; Sparks S, Adkison K,Shachoy-Clark A, Piscitelli S & Demarest J [2005]Prolonged duration of CCR5 occupancy by 873140 inHIV-negative and HIV-positive subjects. 12th Conferenceon Retroviruses and Opportunistic Infections. Boston, USA,2225 February 2005. Abstract 77) to up to 5 days formaraviroc (Ftkenheuer et al ., 2004), although theseapparent differences may be because of differing frequen-cies of viral load measurement among these studies. Thereare several possible reasons for the rebound delay. A longplasma half-life would result in drug levels remaining highenough to inhibit viral entry for some time after drugdiscontinuation. A similar phenomenon has also been seenwith some of the approved antiretroviral drugs, such as theNNRTIs efavirenz (Taylor S, Allen S, Fidler S, White D,Gibbons S, Fox J, Clarke J,Weber J, Cane P, Wade A, SmitE & Back D [2004] Stop Study: after discontinuation of

efavirenz, plasma concentrations may persist for 2 weeks orlonger. 11th Conference on Retroviruses and Opportunistic

Infections. San Francisco, CA, USA, February 2004.Abstract 131) and nevirapine (Muro et al . , 2005). Thisexplanation may be sufficient to account for the 12 daydelay seen with vicriviroc, which has a plasma half-life ofapproximately 24 h (Schurmann et al ., 2004: see above).However, for maraviroc, a plasma half-life of 1623 h is notsufficient to account for a 5-day prolongation of virologicalresponse. An alternative explanation is that prolongedreceptor occupancy may result in CCR5 moleculesremaining blocked with respect to HIV entry after drug

levels decline. For example, in all patients treated withmaraviroc during the monotherapy studies there was a highdegree of CCR5 occupancy during the dosing period(mean 85%, pre-dose on days 5 and 10) and, at all dosesexcept 25 mg QD, CCR5 occupancy remained >60%5 days after drug discontinuation (Ftkenheuer et al., 2004:see above) (Figure 4). Similarly, 95% CCR5 occupancy byaplaviroc during dosing in vivo has been reported, with anestimated half-life of between 69 and 152 h (Sparks et al .,2005: see above).In vitro data generated using membranespurified from Chinese hamster ovary cells in a MIP-1displacement assay suggested a CCR5 binding half-life ofapproximately 190 h for maraviroc and 200 h for aplaviroc

(Watson et al., 2005). The methods used to measure CCR5occupancy are still under development and can vary widely;the relevance of measurements taken in vitro to the in vivosituation is not clear. For example, whilst it is most practicalto study receptor occupancy ex vivo in peripheral bloodsamples, the majority of virus replication within an infectedindividual occurs in the secondary lymphoid tissue, such asthe gut associated lymphatic tissue (GALT) (Brenchleyetal., 2004; Veazey et al ., 1998). Also, factors such as thedegree of general immune activation in the HIV-infected


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individual will influence the rate ofde novo CCR5 expres-

sion during the dosing interval (Ostrowski et al ., 1998).Receptor occupancy will therefore be affected both by thecompounds ability to remain bound to the receptorspresent at the time of dosing as well as its concentrationbeing sufficiently high during the entire dosing interval tobind to any CCR5 molecules subsequently expressed. Thecombination of prolonged CCR5 occupancy and a longhalf-life may therefore be required for a convenient andefficacious dosing schedule.

Tropism and virus evolution in the contextof CCR5 antagonist therapy

There is a need for reliable assays to assess HIV co-receptortropism in patient samples now that three CCR5 antago-nists have progressed from in vitro development to PhaseIIb/III efficacy studies as components of multi-drug regi-mens. Phenotypic and genotypic-based tropism assays haveboth been described (reviewed by Coakley et al., 2005).Promising phenotypic assays have been developed andthere are two available commercially (Phenoscript,VIRalliance, France; and PhenoSense HIV, MonogramBiosciences Inc., formally ViroLogic Inc., USA). Both

assays use patient-derived envelope sequences amplified

from plasma to infect CD4

+

cell lines expressing eitherCXCR4 or CCR5. Co-receptor usage is determined by thepresence of viral replication in these cell lines, as indicatedby the expression of a reporter gene. The HIV-1 genotypicmethodologies described to date are based on the principlethat the V3 loop is a major determinant of co-receptorusage. For example, an association was identified betweenSI/X4 phenotypes and positively charged amino acids atposition 11 or 25 in the V3 loop, known as the 11/25 rule.A study in 1191 patients to investigate this relationshipdemonstrated a strong association between the X4 pheno-type and the 11/25 genotype (P

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derived V3 loop sequence and a B-clade consensus V3 loopsequence and the presence of evolutionary variants ismeasured by divergence from the consensus. Genotypicassays are generally cheaper and easier to run than theirphenotypic counterparts, although the relative specificityand sensitivity of the approaches in predicting clinicaloutcome will ultimately determine their utility in conjunc-tion with CCR5 antagonists.

In an individual identified as harbouring only R5 virus,X4 virus could emerge under drug selection pressurethrough one of two possible mechanisms: the outgrowth ofa previously undetectable minority reservoir of X4 virus, orthe selection of mutations in an R5 virus leading to a switchto CXCR4 tropism. Interestingly, there have been severalindependent observations in vitro of the selection of virusthat is resistant to a CCR5 antagonist but has retainedCCR5 tropism (Kuhmann et al ., 2004; Maeda et al ., 2004;Maeda et al., 2000; Trkola et al., 2002). In contrast, there is

only one published report of R5 virus switching tropism invitro in the presence of a CCR5 antagonist (Mosier et al .,1999). Indeed, the findings of that study may not be rele-vant to treatment with small-molecule CCR5 antagonists,since the agents used by Mosier and colleagues wereanalogues of the agonist, RANTES. The co-receptor shiftcould, therefore, have been selected as a result of internal-ization of CCR5. Studies showing selection for CXCR4-tropic variants by serial passage of R5 variants in cellcultures expressing low CCR5 levels suggest that the path-ways to tropism shift involve sequential accumulation ofgp120 mutations in both the V1/V2 and V3 regions

(Pastore et al ., 2004). Therefore, emergence of X4 variantsduring CCR5 antagonist treatment in vivo may be morelikely from pre-existing reservoirs than via mutation ofcirculating R5 virus.

The emergence of X4 virus during treatment withCCR5 antagonists has been described for a minority oftreated patients undergoing short-term monotherapy. Inthe Phase IIa trials of maraviroc CXCR4-tropic virus wasdetected in two of 63 patients with CCR5-tropic virus atbaseline following 10 days of monotherapy. Phylogeneticanalysis indicated that the CXCR4-using variants probablyemerged from a pre-existing CXCR4-using reservoir,rather than via co-receptor switch of a CCR5-tropic clone

under selection pressure from maraviroc (Lewis M, Van derRyst E, Youle M, Jenkins T, James I, Medhurst C &Westby M [2004] Phylogenetic analysis and co-receptortropism of HIV-1 envelope sequences from two patientswith emergence of CXCR4 using virus following treatmentwith the CCR5 antagonist UK-427,857. 44th InterscienceConference on Antimicrobial Agents and Chemotherapy.Washington DC, USA, 30 October2 November 2004.Poster H-584b). Similar findings have been presented forvicriviroc (Schurmann et al., 2004: see above) and aplaviroc

(Kitrinos et al ., 2005). The clinical relevance of these find-ings in the context of an optimized multi-drug regimen isnot clear. It is important to note that the emergence of X4variants has been observed in patients receiving HAARTfor 5 years with undetectable viral load (Delobel et al .,2005). Hence, X4 emergence is likely to occur over timewith all HAART regimens and, therefore, it will be impor-tant to understand the net effect of CCR5 antagonistsadded to or as part of a HAART regimen on theemergence of CXCR4-using variants.

Future directions

It will be interesting to see the results of Phase IIb andIIb/III studies to determine the efficacy of CCR5 antago-nists in HIV-infected patients, including patients withdual/mixed-tropic HIV infections, who are receiving back-ground HAART. These data should be available in the near

future, from the large ongoing Phase IIb/III studies ofmaraviroc, aplaviroc and vicriviroc in combination withoptimized background therapy in HIV-1-infected, treat-ment-experienced patients. Resistance to CCR5 antagonistshas been described (Maeda et al ., 2000; Marozsan et al .,2005; Trkola et al ., 2002), although resistance does notappear to be generated easily (Westby M, Mori J, Smith-Burchnell C, Lewis M, Mosley M, Perruccio F, MansfieldR, Dorr P & Perros M [2005] Maraviroc [MVC, UK-427,857]-resistant HIV-1 variants, selected by serialpassage, are sensitive to CCR5 antagonists [GW873140,Schering-C, Schering-D] and T-20 [enfuvirtide]. 14th

International Resistance Workshop, Qubec, Canada. 711June 2004. Abstract 65). In those reports, resistance did notinvolve a switch in co-receptor usage, while Pastore and co-workers (2004) have suggested that co-receptor switching isan inefficient process in many cases. With multiple agentsin advanced clinical development, the issue of cross-resis-tance between CCR5 antagonists will be of interest todetermine whether drug sequencing within this promisingnew class is possible, providing, of course, that clinicalfailure is not always mediated by emergence of or switch toCXCR4-using species. Furthermore, simultaneouslytargeting more than one stage of the process ofHIV-1 entry using drug combinations could be a valuable

treatment option in the future, as implied by earlyin vitrofindings demonstrating synergistic activity of SCH-C withthe fusion inhibitor, enfuvirtide (Tremblayet al., 2002), andby a more recent demonstration of synergy between aCCR5 antagonist (AMD887, AnorMED, Canada) and aCXCR4 antagonist (AMD070) (Schols D, Vermeire K,Hatse S, Princen K, De Clercq E, Calandra G, Fricker S,Nelson K, Labrecque J, Bogucki D, Zhou Y, Skerlj R &Bridger G [2004] In vitro anti-HIV activity profile ofAMD887, a novel CCR5 antagonist, in combination with


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the CXCR4 inhibitor AMD070. 11th Conference onRetroviruses and Opportunistic Infections. Boston, USA, 811February, 2004. Abstract 539). The recent discovery of anantagonist, AMD3451, which has in vitro activity against arange of R5, X4 and R5X4 viruses, may also have an appli-cation in the development of new therapeutic agents(Princen et al., 2004). This compound is the first low mole-cular weight agent that interacts selectively with CCR5 andCXCR4 and is differentiated from other CXCR4 antago-nists by its ability to enhance rather than inhibit the bindingof anti-CXCR4 monoclonal antibodies (Princen et al .,2004). Further studies are required to assess the suitability ofAMD3451 for use in HIV-infected patients.

In conclusion, the point of viral entry is a particularlyattractive target because drug activity is not dependent onintracellular access. Small-molecule CCR5 antagonistshave several potential advantages over agents targetedtowards viral components and have been identified as a

promising new class of entry inhibitor with proven efficacyin HIV-infected patients.

Addendum

GSK has announced that it is terminating further develop-ment of its CCR5 antagonist, aplaviroc. The decision wasmade following the observation of elevated liver enzymesand total bilirubin in one of the HIV-1 infected patientsreceiving aplaviroc as part of their Phase IIb/III clinicalprogram. Liver enzymes and bilirubin are biochemicalmarkers of liver function and elevated levels are often

associated with hepatotoxicity.

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Received 10 August 2005, accepted 6 October 2005

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