In Vivo Emergence of Vicriviroc Resistance in a Human Immunodeficiency Virus Type 1 Subtype C-Infected Subject

Massachusetts General Hospital, Boston, Massachusetts, USA.
Journal of Virology (Impact Factor: 4.44). 06/2008; 82(16):8210-4. DOI: 10.1128/JVI.00444-08
Source: PubMed


Little is known about the in vivo development of resistance to human immunodeficiency virus type 1 (HIV-1) CCR5 antagonists.
We studied 29 subjects with virologic failure from a phase IIb study of the CCR5 antagonist vicriviroc (VCV) and identified
one individual with HIV-1 subtype C who developed VCV resistance. Studies with chimeric envelopes demonstrated that changes
within the V3 loop were sufficient to confer VCV resistance. Resistant virus showed VCV-enhanced replication, cross-resistance
to another CCR5 antagonist, TAK779, and increased sensitivity to aminooxypentane-RANTES and the CCR5 monoclonal antibody HGS004.
Pretreatment V3 loop sequences reemerged following VCV discontinuation, implying that VCV resistance has associated fitness

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    • "More recent studies have addressed the mechanism of HIV-1 resistance to the CCR5 inhibitors maraviroc (Westby et al., 2007) and vicriviroc (Anastassopoulou et al., 2009; Berro et al., 2009; Ogert et al., 2009) using in vitro-generated drug-resistant strains. Furthermore, the emergence of maraviroc-or vicrivirocresistant HIV-1 in clinical trials has also been reported (Gulick et al., 2008; Tsibris et al., 2008). However, the frequency of natural resistance to CCR5 inhibitors in transmitted or early founder (T/F) viruses has not been characterized. "
    Dataset: Hu's JGV
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    • "The vast majority of studies of HIV-1 resistance to CCR5 antagonists, however, have been conducted on resistant viruses that were generated in vitro[34,37,53,54], or on viruses isolated from subjects failing therapy by CCR5 antagonists that are no longer being pursued for clinical development, such as VVC, APL and TAK-779 [30,32,33,42]. In contrast, there is a paucity of data on MVC-resistant viruses arising in vivo[15,55]. "
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    ABSTRACT: Background The CCR5 antagonist maraviroc (MVC) inhibits human immunodeficiency virus type 1 (HIV-1) entry by altering the CCR5 extracellular loops (ECL), such that the gp120 envelope glycoproteins (Env) no longer recognize CCR5. The mechanisms of HIV-1 resistance to MVC, the only CCR5 antagonist licensed for clinical use are poorly understood, with insights into MVC resistance almost exclusively limited to knowledge obtained from in vitro studies or from studies of resistance to other CCR5 antagonists. To more precisely understand mechanisms of resistance to MVC in vivo, we characterized Envs isolated from 2 subjects who experienced virologic failure on MVC. Results Envs were cloned from subjects 17 and 24 before commencement of MVC (17-Sens and 24-Sens) and after virologic failure (17-Res and 24-Res). The Envs cloned during virologic failure showed broad divergence in resistance levels, with 17-Res Env exhibiting a relatively high maximal percent inhibition (MPI) of ~90% in NP2-CD4/CCR5 cells and peripheral blood mononuclear cells (PBMC), and 24-Res Env exhibiting a very low MPI of ~0 to 12% in both cell types, indicating relatively “weak” and “strong” resistance, respectively. Resistance mutations were strain-specific and mapped to the gp120 V3 loop. Affinity profiling by the 293-Affinofile assay and mathematical modeling using VERSA (Viral Entry Receptor Sensitivity Analysis) metrics revealed that 17-Res and 24-Res Envs engaged MVC-bound CCR5 inefficiently or very efficiently, respectively. Despite highly divergent phenotypes, and a lack of common gp120 resistance mutations, both resistant Envs exhibited an almost superimposable pattern of dramatically increased reliance on sulfated tyrosine residues in the CCR5 N-terminus, and on histidine residues in the CCR5 ECLs. This altered mechanism of CCR5 engagement rendered both the resistant Envs susceptible to neutralization by a sulfated peptide fragment of the CCR5 N-terminus. Conclusions Clinical resistance to MVC may involve divergent Env phenotypes and different genetic alterations in gp120, but the molecular mechanism of resistance of the Envs studied here appears to be related. The increased reliance on sulfated CCR5 N-terminus residues suggests a new avenue to block HIV-1 entry by CCR5 N-terminus sulfopeptidomimetic drugs.
    Retrovirology 04/2013; 10(1):43. DOI:10.1186/1742-4690-10-43 · 4.19 Impact Factor
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    • "Sometimes the escape pathway involves coreceptor switching, the virus now entering cells via CXCR4, but more usually the resistant variant acquires the ability to use the drug-bound conformation of CCR5 (Moore and Kuritzkes, 2009). The determinants of resistance generally map to the V3 region of gp120 (Baba et al., 2007; Berro et al., 2012; Kuhmann et al., 2004; Laakso et al., 2007; Ogert et al., 2008, 2010; Tsibris et al., 2008; Westby et al., 2007). This region plays a role in CCR5 binding but can tolerate a considerable range of sequences without loss of function (Hartley et al., 2005; Kuhmann and Hartley, 2008). "
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    ABSTRACT: A rare pathway of HIV-1 resistance to small molecule CCR5 inhibitors such as Vicriviroc (VCV) involves changes solely in the gp41 fusion peptide (FP). Here, we show that the G516V change is critical to VCV resistance in PBMC and TZM-bl cells, although it must be accompanied by either M518V or F519I to have a substantial impact. Modeling VCV inhibition data from the two cell types indicated that G516V allows both double mutants to use VCV-CCR5 complexes for entry. The model further identified F519I as an independent determinant of preference for the unoccupied, high-VCV affinity form of CCR5. From inhibitor-free reversion cultures, we also identified a substitution in the inner domain of gp120, T244A, which appears to counter the resistance phenotype created by the FP substitutions. Examining the interplay of these changes will enhance our understanding of Env complex interactions that influence both HIV-1 entry and resistance to CCR5 inhibitors.
    Virology 04/2012; 428(2):86-97. DOI:10.1016/j.virol.2012.03.008 · 3.32 Impact Factor
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