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: 4.65). 06/2008; 82(16):8210-4. DOI: 10.1128/JVI.00444-08
Source: PubMed

ABSTRACT 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 costs.

  • The Journal of Infectious Diseases 11/2013; DOI:10.1093/infdis/jit656 · 5.78 Impact Factor
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    Retrovirology 11/2014; 11(1):106. DOI:10.1186/s12977-014-0106-8 · 4.77 Impact Factor
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    ABSTRACT: The aim of this study was to generate maraviroc (MVC)-resistant viruses in vitro using a subtype B clinical isolate (HIV-1KP-5) to understand the mechanism(s) of resistance to MVC. To select HIV-1 variants resistant to MVC in vitro, we exposed the CCR5 high expressing PM1/CCR5 cells to the HIV-1KP-5 followed by serial passage in the presence of MVC. We also passaged HIV-1KP-5 in PM1 cells, which were low expressing CCR5 to determine low CCR5 adapted substitutions and compared the Env sequences of the MVC-selected variants. Following 48 passages with MVC (10 µM), HIV-1KP-5 acquired a resistant phenotype (maximal percent inhibition [MPI]: 24%), while the low CCR5 adapted variant had low sensitivity to MVC (IC50: around 200 nM), but not reduction of the MPI. The common substitutions observed in both the MVC selected and low CCR5 adapted variants were selected from the quasispecies, in V1, V3 and V5. After 14 passages, the MVC selected variants harbored substitutions around the CCR5 N-terminal binding site and V3 (V200I, T297I, K305R and M434I). The low CCR5 adapted infectious clone became sensitive to anti-CD4bs and CD4i monoclonal antibodies (mAbs), but not to anti-V3 mAb and autologous plasma IgGs. Conversely, the MVC selected clone became highly sensitive to the anti-envelope mAbs tested and the autologous plasma IgGs. These findings suggest that the four MVC-resistant mutations required for entry using MVC-bound CCR5 result in a conformational change of envelope protein that is associated with a phenotype sensitive to anti-envelope neutralizing antibodies.
    Journal of General Virology 05/2014; DOI:10.1099/vir.0.062885-0 · 3.53 Impact Factor


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