SAMHD1 has differential impact on the efficacies of HIV nucleoside reverse transcriptase inhibitors

Antimicrob Agents Chemother. 2014 Aug;58(8):4915-9. doi: 10.1128/AAC.02745-14. Epub 2014 May 27.

Abstract

Sterile alpha motif- and histidine/aspartic acid domain-containing protein 1 (SAMHD1) limits HIV-1 replication by hydrolyzing deoxynucleoside triphosphates (dNTPs) necessary for reverse transcription. Nucleoside reverse transcriptase inhibitors (NRTIs) are components of anti-HIV therapies. We report here that SAMHD1 cleaves NRTI triphosphates (TPs) at significantly lower rates than dNTPs and that SAMHD1 depletion from monocytic cells affects the susceptibility of HIV-1 infections to NRTIs in complex ways that depend not only on the relative changes in dNTP and NRTI-TP concentrations but also on the NRTI activation pathways.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Cell Line
  • Dideoxynucleotides / metabolism*
  • Gene Expression
  • Genes, Reporter
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Host-Pathogen Interactions
  • Humans
  • Lamivudine / pharmacology
  • Luciferases / genetics
  • Luciferases / metabolism
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Monocytes / virology
  • Monomeric GTP-Binding Proteins / antagonists & inhibitors
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Organophosphonates / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology*
  • SAM Domain and HD Domain-Containing Protein 1
  • Stavudine / pharmacology
  • Tenofovir
  • Virus Replication / drug effects
  • Zidovudine / pharmacology

Substances

  • Dideoxynucleotides
  • Organophosphonates
  • RNA, Small Interfering
  • Reverse Transcriptase Inhibitors
  • Lamivudine
  • Zidovudine
  • Tenofovir
  • Stavudine
  • Luciferases
  • HIV Reverse Transcriptase
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • Monomeric GTP-Binding Proteins
  • Adenine