1477 ISSN 0269-9370 © 1999 Lippincott Williams & Wilkins Activity of non-nucleoside reverse transcriptase inhibitors against HIV-2 and SIV Myriam Witvrouw, Christophe Pannecouque, Kristel Van Laethem, Jan Desmyter, Erik De Clercq and Anne-Mieke Vandamme 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), α -anilino- phenylacetamides (α-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), α-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. © 1999 Lippincott Williams & Wilkins AIDS 1999, 13:1477–1483 Keywords: HIV-2, SIV, non-nucleoside reverse transcriptase inhibitor, antiretroviral therapy, drug, resistance/resistance mutations, reverse transcriptase From the Rega Institute for Medical Research, KULeuven, Leuven, Belgium. Sponsorship: Supported in part by the Biomedical Research Programme of the European Commission (EC Biomed2 grant BMH4-C5-95-1634) and by grants from the Fonds voor Wetenschappelijk Onderzoek (FWO) Vlaanderen (FWO grant G.0140.98), the Geconcerteerde Onderzoeksacties (GOA 95/5) Vlaamse gemeenschap and the Janssen Research Foundation. Requests for reprints to: M.Witvrouw, Rega Institute for Medical Research, KULeuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Received: 28 October 1998; revised: 7 May 1999; accepted: 12 May 1999.