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

Hong Tao Xu, Susan P. Colby-Germinario, Peter K. Quashie, Richard Bethell, Mark A. Wainberg

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3189-3196
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume59
Issue number6
DOIs
Publication statusPublished - 1 Jun 2015
Externally publishedYes

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