Activity of non-nucleoside reverse transcriptase inhibitors against HIV-2 and SIV

AIDS. 1999 Aug 20;13(12):1477-83. doi: 10.1097/00002030-199908200-00006.


Background: After the initial discovery of 1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) and tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and thione (TIBO) derivatives, several other non-nucleoside reverse transcriptase (RT) inhibitors (NNRTI), including nevirapine (BI-RG-587), pyridinone derivatives (L-696,229 and L-697,661), delavirdine (U-90152), alpha-anilinophenylacetamides (alpha-APA) and various other classes of NNRTI have been described. The hallmark of NNRTI has been based on their ability to interact with a specific site ('pocket') of HIV-1 RT.

Objective: To investigate whether, in addition to HIV-1, different strains of HIV-2 (ROD and EHO) and SIV (mac251, agm3 and mndGB1) are sensitive to a selection of NNRTI i.e. delavirdine, the HEPT derivative I-EBU (MKC-442), 8-chloro-TIBO (tivirapine), alpha-APA (loviride), nevirapine and the pyridinone derivative L-697,661.

Methods and results: The NNRTI tested inhibited the replication of the different strains of HIV-2 and SIV at micromolar concentrations. The inhibitory effects of the NNRTI on HIV-2-induced cytopathicity correlated well with their inhibitory effects on HIV-2 RT activity. Drug-resistant HIV-2 (EHO) variants containing the Ser102Leu and/or Glu219Asp mutations in their RT were selected after passaging the virus in MT-4 cells in the presence of increasing concentrations of delavirdine. The EHO virus mutants were at least 20-fold less susceptible to the antiviral effects of delavirdine. Some cross-resistance, depending on the mutant strain, was observed with the other NNRTI tested (i.e. MKC-442, tivirapine, loviride and pyridinone L-697,661).

Conclusions: Our data demonstrate that NNRTI are not exclusively specific for HIV-1 but are also inhibitory to different HIV-2 and SIV strains. These observations will have important implications for the development of new NNRTI with higher activity against both HIV-1 and HIV-2. Furthermore, in view of their anti-SIV activity, NNRTI could be evaluated further for their in vivo anti-retrovirus efficacy in non-human primate models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anti-HIV Agents / pharmacology*
  • Cells, Cultured / virology
  • Cytopathogenic Effect, Viral
  • Delavirdine / pharmacology*
  • Drug Resistance, Microbial
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects
  • HIV-1 / physiology
  • HIV-2 / drug effects*
  • HIV-2 / physiology
  • Molecular Sequence Data
  • RNA-Directed DNA Polymerase / genetics
  • RNA-Directed DNA Polymerase / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Simian Immunodeficiency Virus / drug effects*
  • Simian Immunodeficiency Virus / physiology


  • Anti-HIV Agents
  • Reverse Transcriptase Inhibitors
  • Delavirdine
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase