Two coselected distal mutations in HIV-1 reverse transcriptase (RT) alter susceptibility to nonnucleoside RT inhibitors and nucleoside analogs

Paul L. Boyer, Kevin Melody, Steven J. Smith, Linda L. Dunn, Chris Kline, Douglas K. Fischer, Richa Dwivedi, Pat Clark, Stephen H. Hughes, Zandrea Ambrose

Research output: Contribution to journalArticle

Abstract

Two mutations, G112D and M230I, were selected in the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) by a novel nonnucleoside reverse transcriptase inhibitor (NNRTI). G112D is located near the HIV-1 polymerase active site; M230I is located near the hydrophobic region where NNRTIs bind. Thus, M230I could directly interfere with NNRTI binding but G112D could not. Biochemical and virological assays were performed to analyze the effects of these mutations individually and in combination. M230I alone caused a reduction in susceptibility to NNRTIs, while G112D alone did not. The G112D/M230I double mutant was less susceptible to NNRTIs than was M230I alone. In contrast, both mutations affected the ability of RT to incorporate nucleoside analogs. We suggest that the mutations interact with each other via the bound nucleic acid substrate; the nucleic acid forms part of the polymerase active site, which is near G112D. The positioning of the nucleic acid is influenced by its interactions with the “primer grip” region and could be influenced by the M230I mutation. IMPORTANCE Although antiretroviral therapy (ART) is highly successful, drug-resistant variants can arise that blunt the efficacy of ART. New inhibitors that are broadly effective against known drug-resistant variants are needed, although such compounds might select for novel resistance mutations that affect the sensitivity of the virus to other compounds. Compound 13 selects for resistance mutations that differ from traditional NNRTI resistance mutations. These mutations cause increased sensitivity to NRTIs, such as AZT.

Original languageEnglish (US)
Article numbere0022419
JournalJournal of virology
Volume93
Issue number11
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Fingerprint

Reverse Transcriptase Inhibitors
RNA-directed DNA polymerase
nucleosides
Human immunodeficiency virus 1
Nucleosides
HIV-1
mutation
Mutation
Nucleic Acids
nucleic acids
active sites
Catalytic Domain
Human immunodeficiency virus 1 reverse transcriptase
drugs
therapeutics
RNA-Directed DNA Polymerase
Hand Strength
Pharmaceutical Preparations
Viruses
viruses

Keywords

  • Drug resistance
  • Nonnucleoside RT inhibitor
  • Nucleic acid repositioning
  • Nucleoside analogs
  • Nucleoside inhibitor

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Two coselected distal mutations in HIV-1 reverse transcriptase (RT) alter susceptibility to nonnucleoside RT inhibitors and nucleoside analogs. / Boyer, Paul L.; Melody, Kevin; Smith, Steven J.; Dunn, Linda L.; Kline, Chris; Fischer, Douglas K.; Dwivedi, Richa; Clark, Pat; Hughes, Stephen H.; Ambrose, Zandrea.

In: Journal of virology, Vol. 93, No. 11, e0022419, 01.01.2019.

Research output: Contribution to journalArticle

Boyer, PL, Melody, K, Smith, SJ, Dunn, LL, Kline, C, Fischer, DK, Dwivedi, R, Clark, P, Hughes, SH & Ambrose, Z 2019, 'Two coselected distal mutations in HIV-1 reverse transcriptase (RT) alter susceptibility to nonnucleoside RT inhibitors and nucleoside analogs', Journal of virology, vol. 93, no. 11, e0022419. https://doi.org/10.1128/JVI.00224-19
Boyer, Paul L. ; Melody, Kevin ; Smith, Steven J. ; Dunn, Linda L. ; Kline, Chris ; Fischer, Douglas K. ; Dwivedi, Richa ; Clark, Pat ; Hughes, Stephen H. ; Ambrose, Zandrea. / Two coselected distal mutations in HIV-1 reverse transcriptase (RT) alter susceptibility to nonnucleoside RT inhibitors and nucleoside analogs. In: Journal of virology. 2019 ; Vol. 93, No. 11.
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