Specific mutations in the HIV-1 G-tract of the 3 '-polypurine tract cause resistance to integrase strand transfer inhibitors
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY(2022)
Abstract
Background In vitro selection experiments identified viruses resistant to integrase strand transfer inhibitors (INSTIs) carrying mutations in the G-tract (six guanosines) of the 3 '-polypurine tract (3 '-PPT). A clinical study also reported that mutations in the 3 '-PPT were observed in a patient receiving dolutegravir monotherapy. However, recombinant viruses with the 3 '-PPT mutations that were found in the clinical study were recently shown to be susceptible to INSTIs. Objectives To identify the specific mutation(s) in the G-tract of the 3 '-PPT for acquiring INSTI resistance, we constructed infectious clones bearing single or multiple mutations and systematically characterized the susceptibility of these clones to both first- and second-generation INSTIs. Methods The infectious clones were tested for their infectivity and susceptibility to INSTIs in a single-cycle assay using TZM-bl cells. Results A single mutation of thymidine (T) at the fifth position (GGG GTG) in the G-tract of the 3 '-PPT had no effect on INSTI resistance. A double mutation, cytidine (C) or 'T' at the second position and 'T' at the fifth position (GCG GTG and GTG GTG), increased resistance to INSTIs, with the appearance of a plateau in the maximal percentage inhibition (MPI) of the dose-response curves, consistent with a non-competitive mechanism of inhibition. Conclusions Mutations at the second and fifth positions in the G-tract of the 3 '-PPT may result in complex resistance mechanism(s), rather than simply affecting INSTI binding at the IN active site.
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Key words
specific mutations,inhibitors,integrase,g-tract
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