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• W2076297312 abstract "Maraviroc, a recently approved drug for HIV-1 therapy, binds to the chemokine (C–C motif) receptor 5 (CCR5) coreceptor and prevents HIV-1 envelope glycoprotein-mediated entry [1,2]. Some of the pathways leading to an acquired resistance to this drug have been described in vivo in clinical trials assessing its efficacy [3–5], and by using serial passages of viruses in vitro through increasing maraviroc concentrations [6]. One resistance mechanism involves the selection of pre-existing minor chemokine (CXC motif) receptor 4-using strains [5]. An alternative resistance pathway involves the selection of escape mutations in the envelope gene, mainly in the V3 region, without coreceptor switching [3,4,6]. The escape mutations described so far resulted in a reduced maximal inhibition in phenotypic susceptibility assays (i.e. a plateau in dose–inhibition curve), consistent with the virus having acquired the ability to use the maraviroc-bound CCR5 coreceptor for entry, in addition to the free coreceptor [6,7]. We now report a case of acquired resistance to maraviroc involving a competition-based mechanism between the drug and the virus. A 42-year-old HIV-1-infected man with a history of virological failure related to triple-class antiretroviral drug resistance started maraviroc (150 mg twice daily) in 2008, in addition to his previous treatment of abacavir, lamivudine, tenofovir, etravirine, ritonavir-boosted darunavir, and raltegravir. At this time, his plasma viral load was 5.1 log10 copies/ml and his CD4+ T-cell count was 82 cells/μl (5%). Only partial improvement in the patient's immunovirological status was reached following maraviroc introduction, with a transient decrease in plasma viral load down to 3.5 log10 copies/ml and an increase in CD4+ T-cell count up to 552 cells/μl (10%). Then, after 11 months of maraviroc-containing therapy, his plasma viral load re-increased up to 4.4 log10 copies/ml, with a CD4+ T-cell count of 307 cells/μl (11%). HIV-1 coreceptor usage was assessed before starting maraviroc and at months 8, 11, and 13 of maraviroc treatment using the TTT phenotypic entry assay [8]. The virus population remained CCR5-tropic throughout follow-up. Genotyping of V3 env revealed the progressive emergence of minor virus strains harboring escape mutations at month 8, whose frequency increased at month 11, and led to the selection of a fully mutated virus population at month 13. Clonal analysis of the virus population (Fig. 1a) revealed the progressive selection of G306S, N315S, I318Y, and I323V mutations in V3, numbered according to the HXB2 sequence (GenBank #K03455).Fig. 1: Emergence of a virus resistant to maraviroc by competition. (a) V3 amino acid sequence alignment. Clonal analysis of env PCR products revealed the progressive emergence of mutations in V3 between months 8 and 13 following MVC introduction. Dots indicate identity with the consensus sequence. Replacements are indicated by the appropriate code letters. (b) Susceptibility of sensitive and resistant virus clones to MVC. The susceptibility of V3 recombinant molecular clones to MVC was assessed using the TTT phenotypic entry assay on U87 CD4+ CCR5+ cells in the presence of various concentrations of the inhibitor. The sensitive virus clone shown here (open squares, dotted line) corresponds to the major virus found at month 8 (V3 amino acid sequence identical to the consensus); the resistant virus clone shown here (filled triangles, solid line) corresponds to the major virus found at month 13 (V3 amino acid sequence harboring the G306S, N315S, I318Y, and I323V mutations). The values shown are the means ± SEM from two independent experiments. M8, month 8; M13, month 13; MVC, maraviroc.The TTT phenotypic entry assay was adapted to assess the susceptibility to maraviroc of representative molecular clones of this patient. To investigate the impact of the escape mutations observed in V3 independently of the virus backbone, we generated recombinant molecular clones that differ only by their V3 region. The dose–inhibition curves of the mutated molecular clones did not reveal a plateau in maximal inhibition, as has been reported to date for maraviroc-resistant strains [3,4,6,7], but rather showed sigmoidal curves with a 120-fold rightward shift of the half maximal inhibitory concentration between the sensitive and resistant clones (Fig. 1b). At high maraviroc concentrations, a full inhibition of the resistant clones was still obtained. This competitive resistance profile suggests the selection of a virus with an increased affinity of glycoprotein 120 for CCR5 that better competes with maraviroc for binding to CCR5. Further arguing in favor of a competition between the drug and the virus for binding to CCR5, an additional 1 log10 decrease in the plasma viral load was obtained for this patient after doubling his maraviroc daily dose. We used the U87 CD4+ CCR5+ cell line to perform our phenotypic susceptibility assay [9]. This cell line is also used in the commercial profile assay for assessing CCR5 inhibitor resistance [10]. The differences between the inhibition profiles for maraviroc against the resistant virus described here and those described so far are thus unlikely to be due to the assay that had been used. Various escape mutations have been described in the HIV-1 envelope glycoprotein in patients failing maraviroc with CCR5-tropic viruses [3,4]. Most of the mutations lie in the stem and tip of the V3 region but the pattern of amino acid changes seems to be different between patients. The G306S and I323V mutations had previously been reported in a few maraviroc-resistant strains in vivo[3]. However, the high genetic variability of the env gene and the absence of constant pattern of mutations prevent any simple genotypic prediction of resistance to maraviroc, and instead require the use of phenotypic susceptibility assays. The competitive inhibition profile described in this case of acquired resistance to maraviroc in vivo challenges the view that this drug only acts as a noncompetitive allosteric inhibitor. Acknowledgement Financial support for this paper was provided by INSERM U563." @default.
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• W2076297312 date "2010-06-01" @default.
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• W2076297312 title "Shift in phenotypic susceptibility suggests a competition mechanism in a case of acquired resistance to maraviroc" @default.
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• W2076297312 doi "https://doi.org/10.1097/qad.0b013e328338b7a6" @default.
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