Maraviroc: A Coreceptor CCR5 Antagonist for Management of HIV Infection

Raymond Yost; Timothy R. Pasquale; Eric G. Sahloff


Am J Health Syst Pharm. 2009;66(8):715-726. 

In This Article


Mechanism of Action

It is essential for HIV to bind to the host cell in order to enter it, complete replication, and release new virions to further propagate infection. The cell-entry step involves the binding of the HIV glycoprotein gp120 to the host cell's CD4 receptor. Subsequent conformational changes in gp120 uncover additional binding sites that interact with distinct proteins on the host cell membrane, known as β-chemokine coreceptors.[4,5,6,7] Two major coreceptors for viral entry have been identified: CCR5 and CXCR4. CCR5-tropic viral strains (or R5 viruses) are usually predominant during the early stages of HIV infection, while CXCR4-tropic viruses (or X4 viruses) are associated with faster disease progression and are more likely to be encountered in patients with advanced HIV disease.[8] In addition, dual-tropic or mixed-virus populations, which display a broad range of ability to use both CCR5 and CXCR4 coreceptors, may arise over the course of the disease. CCR5 coreceptor antagonists like maraviroc inhibit the attachment of HIV to the host cell by competitively and selectively binding to CCR5 and blocking the interaction between gp120 and CCR5; this prevents infection of the cell (Figure 1).[2,3]

Figure 1.

Mechanism of action of maraviroc. Before fusion of the HIV viral envelope and host cell membrane can occur, an HIV glycoprotein complex consisting of glycoproteins gp41 and gp120 must bind with the CD4 receptor on the membrane of the host cell. This binding causes conformational changes in gp120 that expose coreceptor binding sites (left panel). These sites bind to coreceptor CCR5 or CXCR4 on the membrane of the host cell (center panel), an event that initiates steps that culminate in the fusion of the HIV envelope with the host cell membrane and entry of viral contents into the host cell (inset). Maraviroc binds to and changes the shape of coreceptor CCR5 such that it is not recognized by the gp120 coreceptor binding sites (right panel). Illustration by Taina Litwak, CMI.

Dorr et al.[3] evaluated maraviroc's antiretroviral activity against primary isolates of HIV-1, Group M (clades B and non-B) and Group O. The geometric mean concentration required to inhibit 90% of viral growth (IC90) in 43 primary HIV-1 isolates was 2.0 nM (1.03 ng/mL). An IC50 of > 10 nM (5.14 ng/mL) was noted in CXCR4-tropic HIV-1 laboratory virus, a finding consistent with the lack of maraviroc activity in this viral group. The same investigators used env- recombinant pseudovirus derived from HIV-1 clinical isolates to assess the activity of maraviroc in viruses resistant and susceptible to antiretroviral drugs. They reported no biologically significant difference in susceptibility to maraviroc between pseudovirus with (n = 100) and without (n = 100) genotypic resistance to nucleoside-nucleotide reverse-transcriptase inhibitors and protease inhibitors (PIs), regardless of the number of resistance-associated mutations present in the pseudovirus.

Maraviroc's antagonistic effects are limited to CCR5-tropic virus, with no antiviral activity against CXCR4-tropic or dual- or mixed-tropic HIV-1. The selectivity of maraviroc for the CCR5 coreceptor was evaluated using human immune system in vitro modeling.[3] When exposed to maraviroc concentrations of > 1000 times the IC50, no inhibitory activity was noted for any non-CCR5 chemokines (e.g., CCR2, CCR3, CCR7, CXCR1, CXCR2). Importantly, in vitro evaluations found no antagonistic activity of maraviroc on other human β-chemokines when maraviroc was used in combination with other antiretroviral agents.

Mechanism of Resistance

In clinical trials, treatment failure due to the emergence of maraviroc-resistant isolates, other than CXCR4-tropic virus, was rare.[9,10,11] Mechanisms for resistance are still being identified and include (1) the existence of CXCR4-tropic virus during patient screening in levels below the limit of detection, (2) coreceptor switching or a mutation in the CXCR4-tropic virus arising from a CCR5 virus, and (3) a phenotypic resistance to maraviroc in a CCR5-tropic variant. No cross-resistance with other antiretroviral targets has been noted, as the CCR5 antagonists have a novel target.[3]

Tropism. Up to 50% of treatment-experienced patients may have non-CCR5-tropic virus.[12,13,14] Thus, screening patients with tropism assays (e.g., Trofile, Monogram Biosciences, Inc.) before maraviroc initiation is essential. Tropism assays are used to describe the coreceptor specificity (CCR5, CXCR4, dual, or mixed) of a patient's HIV strain. The Trofile assay requires a minimum plasma viral load of 1000 copies/mL and was found to be extremely sensitive for detecting viral subpopulations constituting at least 10% of the total viral population.[15] However, sensitivity drops to 85% if viral subpopulations are 5% or less of the total viral population. Thus, a viral subpopulation of < 5% may go undetected.

Further analysis of the data from the Maraviroc Versus Efavirenz Regiments As Initial Therapy (MERIT)[16] and Maraviroc Plus Optimized Background Therapy In Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) studies[17] identified 3.5% and 8% of subjects, respectively, as having CCR5-tropic virus at screening but with detectable dual or mixed or CXCR4-tropic populations at baseline (treatment day 1). This phenomenon resulted in diminished virological and immunologic outcomes in maraviroc-treated subjects with the dual or mixed virus at 24 weeks. When CCR5-tropism was present at both screening and baseline, 50%, 50%, and 26% of subjects receiving maraviroc once daily, maraviroc twice daily, and an optimized background regimen (OBR) alone, respectively, were able to achieve HIV-1 RNA levels of < 50 copies/mL.[17] For those subjects with CCR5-tropic virus at screening but dual or mixed virus at baseline, only 27%, 18%, and 18% of subjects in the maraviroc once-daily, maraviroc twice-daily, and OBR groups were able to achieve HIV-1 RNA levels of < 50 copies/mL. Interestingly, virological responses (HIV-1 RNA levels of < 50 copies/mL) were lower in groups receiving efavirenz or maraviroc when baseline assessment showed dual or mixed virus rather than CCR5-tropic virus (efavirenz response: dual or mixed, 54.6% versus CCR5-tropic, 69.3%; maraviroc: dual or mixed, 7.1% versus CCR5-tropic, 68%).[16]

Exposure to CCR5 antagonists suppresses CCR5-tropic virus and may allow for the expansion or selection of CXCR4-tropic populations. In an in vitro study of CCR5-tropic laboratory-adapted strains and primary isolates, serial passage did not lead to the selection of CXCR4-tropic isolates.[18] A study evaluating 10 days of maraviroc monotherapy (dosages ranging from 25 mg once daily to 300 mg twice daily) also addressed the issue of selective pressure.[19,20] Subjects previously identified as having CCR5-tropic virus were again screened on days 1, 10, and 40 for viral tropism. Of 62 evaluable subjects, 2 had detectable mixed- or dual-tropic virus at day 11. By day 40, only 1 of these 2 subjects had a dual- or mixed-tropic virus detected (out to day 443), while the other subject's virus had reverted to CCR5-tropic virus.[19] Viral load reductions comparable to those of others subjects were still noted in these patients. Further, analysis revealed that the emergence of CXCR4-tropic virus was likely due to preexisting variants rather than coreceptor switching.[20]

Coreceptor Switching. The change in tropism from CCR5-tropic virus to CXCR4-tropic virus, which is often seen with disease progression, is also being evaluated as a cause for failure of CCR5 antagonists. The question of why the change from CCR5- to CXCR4-tropic progresses so slowly has yet to be adequately answered. The transition from CCR5- to CXCR4-utilizing variants may be hampered by decreased viral replication fitness, diminished coreceptor-binding efficiency, and the need for specific mutational changes to occur.[21] It has been postulated that the time required to convert to a CXCR4-tropic variant may differ among CCR5-tropic viruses.[21] Whether exposure to CCR5 antagonists could hasten the conversion and, if so, how this might occur have yet to be determined.

CCR5-antagonist Resistance. Resistance to maraviroc in CCR5-utilizing HIV-1 primary isolates (CC1/85 and RU570) has been demonstrated.[18] First, to verify that these isolates were CCR5-tropic variants, a number of tests were performed. Replication of these high-level maraviroc-resistant isolates (IC50, CC1/85 > 5,600 nM [2.9 µg/mL] and RU570 > 50,000 nM [25 µg/mL]) was not inhibited after exposure to the CXCR4 antagonist AMD3100 (with and without maraviroc), and no replication occurred after exposure to peripheral blood lymphocytes (PBLs) from a CCR5 Δ32/Δ32 homozygous donor (with no CCR5 expressed on CD4+ cell surface). Thus, CXCR4 tropism was ruled out. However, replication was documented in the presence of PBLs from a CCR5 wt/wt donor (wild-type express CCR5), supporting the premise that CC1/85 and RU570 were CCR5 tropic.[18]

Once authors established that CC1/85 and RU570 isolates were CCR5 tropic and not mixed-, dual-, or CXCR4 tropic, a second mechanism of resistance was evaluated.[18] Mutations in the V3 loop of gp120 are proposed to be the major determinants of resistance to maraviroc, with mutations in other regions (V1, V2, V4, C3-C5) also playing an isolate-dependent role. These mutations allow maraviroc-resistant virus to bind to and infect CD4+ cells, even in the presence of maraviroc. Interestingly, in this study, cross-resistance was not documented with SCH-C and aplaviroc, which are also CCR5 antagonists.[18]


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