Rilpivirine and doravirine have complementary efficacies against NNRTI-resistant HIV-1 mutants

Steven J. Smith, Gary T. Pauly, Aamir Akram, Kevin Melody, Zandrea Ambrose, Joel P. Schneider, Stephen H. Hughes

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: Rilpivirine (RPV) is the latest non-nucleoside reverse transcriptase inhibitor (NNRTI) to be approved by Food and Drug Administration to combat HIV-1 infections. NNRTIs inhibit the chemical step in viral DNA synthesis by binding to an allosteric site located about 10 Å from the polymerase active site of reverse transcriptase (RT). Although NNRTIs potently inhibit the replication of wild-type HIV-1, the binding site is not conserved, and mutations arise in the binding pocket. Doravirine (DOR) is a new NNRTI in phase III clinical trials. Methods: Using a single round HIV-1 infection assay, we tested RPV and DOR against a broad panel of NNRTI-resistant mutants to determine their respective activities. We also used molecular modeling to determine if the susceptibility profile of each compound was related to how they bind RT. Results: Several mutants displayed decreased susceptibility to DOR. However, with the exception of E138K, our data suggest that the mutations that reduce the potency of DOR and RPV are non-overlapping. Thus, these 2 NNRTIs have the potential to be used together in combination therapy. We also show that the location at which DOR and RPV bind with the NNRTI binding pocket of RT correlates with the differences in their respective susceptibility to the panel of NNRTI-resistance mutations. Conclusions: This shows that (1) DOR is susceptible to a number of well-known NNRTI resistance mutations and (2) an understanding of the mutational susceptibilities and binding interactions of NNRTIs with RT could be used to develop pairs of compounds with non-overlapping mutational susceptibilities.

Original languageEnglish (US)
Pages (from-to)485-491
Number of pages7
JournalJournal of Acquired Immune Deficiency Syndromes
Volume72
Issue number5
DOIs
StatePublished - Aug 15 2016
Externally publishedYes

Fingerprint

Rilpivirine
Reverse Transcriptase Inhibitors
HIV-1
RNA-Directed DNA Polymerase
Mutation
HIV Infections
Allosteric Site
Phase III Clinical Trials
Viral DNA
United States Food and Drug Administration
Catalytic Domain
Binding Sites

Keywords

  • antiviral activity
  • HIV-1
  • non-nucleoside reverse transcriptase inhibitor
  • potency
  • resistance
  • susceptibility

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Rilpivirine and doravirine have complementary efficacies against NNRTI-resistant HIV-1 mutants. / Smith, Steven J.; Pauly, Gary T.; Akram, Aamir; Melody, Kevin; Ambrose, Zandrea; Schneider, Joel P.; Hughes, Stephen H.

In: Journal of Acquired Immune Deficiency Syndromes, Vol. 72, No. 5, 15.08.2016, p. 485-491.

Research output: Contribution to journalArticle

Smith, Steven J. ; Pauly, Gary T. ; Akram, Aamir ; Melody, Kevin ; Ambrose, Zandrea ; Schneider, Joel P. ; Hughes, Stephen H. / Rilpivirine and doravirine have complementary efficacies against NNRTI-resistant HIV-1 mutants. In: Journal of Acquired Immune Deficiency Syndromes. 2016 ; Vol. 72, No. 5. pp. 485-491.
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AU - Pauly, Gary T.

AU - Akram, Aamir

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AU - Ambrose, Zandrea

AU - Schneider, Joel P.

AU - Hughes, Stephen H.

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AB - Background: Rilpivirine (RPV) is the latest non-nucleoside reverse transcriptase inhibitor (NNRTI) to be approved by Food and Drug Administration to combat HIV-1 infections. NNRTIs inhibit the chemical step in viral DNA synthesis by binding to an allosteric site located about 10 Å from the polymerase active site of reverse transcriptase (RT). Although NNRTIs potently inhibit the replication of wild-type HIV-1, the binding site is not conserved, and mutations arise in the binding pocket. Doravirine (DOR) is a new NNRTI in phase III clinical trials. Methods: Using a single round HIV-1 infection assay, we tested RPV and DOR against a broad panel of NNRTI-resistant mutants to determine their respective activities. We also used molecular modeling to determine if the susceptibility profile of each compound was related to how they bind RT. Results: Several mutants displayed decreased susceptibility to DOR. However, with the exception of E138K, our data suggest that the mutations that reduce the potency of DOR and RPV are non-overlapping. Thus, these 2 NNRTIs have the potential to be used together in combination therapy. We also show that the location at which DOR and RPV bind with the NNRTI binding pocket of RT correlates with the differences in their respective susceptibility to the panel of NNRTI-resistance mutations. Conclusions: This shows that (1) DOR is susceptible to a number of well-known NNRTI resistance mutations and (2) an understanding of the mutational susceptibilities and binding interactions of NNRTIs with RT could be used to develop pairs of compounds with non-overlapping mutational susceptibilities.

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