1887

Abstract

The aim of this study was to generate maraviroc (MVC)-resistant viruses using a human immunodeficiency virus type 1 subtype B clinical isolate (HIV-1) to understand the mechanism(s) of resistance to MVC. To select HIV-1 variants resistant to MVC , we exposed high-chemokine (C-C motif) receptor 5 (CCR5)-expressing PM1/CCR5 cells to HIV-1 followed by serial passage in the presence of MVC. We also passaged HIV-1 in PM1 cells, which were low CCR5 expressing to determine low-CCR5-adapted substitutions and compared the Env sequences of the MVC-selected variants. Following 48 passages with MVC (10 µM), HIV-1 acquired a resistant phenotype [maximal per cent inhibition (MPI) 24 %], whilst the low-CCR5-adapted variant had low sensitivity to MVC (IC ~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 quasi-species, in V1, V3 and V5. After 14 passages, the MVC-selected variants harboured 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 mAbs, but not to anti-V3 mAb and autologous plasma IgGs. Conversely, the MVC-selected clone became highly sensitive to the anti-envelope (Env) 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 Env that is associated with a phenotype sensitive to anti-Env neutralizing antibodies.

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2014-08-01
2019-11-22
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