Subtype-specific analysis of the K65R substitution in HIV-1 that confers hypersusceptibility to a novel nucleotide-competing reverse transcriptase inhibitor

Antimicrobial Agents and Chemotherapy
Hongtao XuM A Wainberg

Abstract

Compound A is a novel nucleotide-competing HIV-1 reverse transcriptase (RT) inhibitor (NcRTI) that selects for a unique W153L substitution that confers hypersusceptibility to tenofovir, while the K65R substitution in RT confers resistance against tenofovir and enhances susceptibility to NcRTIs. Although the K65R substitution is more common in subtype C viruses, the impact of subtype variability on NcRTI susceptibility has not been studied. In the present study, we performed experiments with compound A by using purified recombinant RT enzymes and viruses of subtypes B and C and circulating recombinant form CRF_A/G. We confirmed the hypersusceptibility of K65R substitution-containing RTs to compound A for subtype C, CRF_A/G, and subtype B. Steady-state kinetic analysis showed that K65R RTs enhanced the susceptibility to compound A by increasing binding of the inhibitor to the nucleotide binding site of RT in a subtype-independent manner, without significantly discriminating against the natural nucleotide substrate. These data highlight the potential utility of NcRTIs, such as compound A, for treatment of infections with K65R substitution-containing viruses, regardless of HIV-1 subtype.

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Citations

Nov 18, 2015·Antimicrobial Agents and Chemotherapy·Hong-Tao XuMark A Wainberg
Jan 11, 2017·The Journal of Antimicrobial Chemotherapy·Hong-Tao XuMark A Wainberg
Jan 29, 2021·Chemical Reviews·Maria E CilentoStefan G Sarafianos
Oct 12, 2019·Journal of Medicinal Chemistry·F Xavier RuizEddy Arnold

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