Author:

Keywords:

Amino Acid Sequence, Anti-HIV Agents, Cells, Cultured, Cytopathogenic Effect, Viral, Delavirdine, Drug Resistance, Microbial, HIV-1, HIV-1 Reverse Transcriptase, HIV-2, Molecular Sequence Data, RNA-Directed DNA Polymerase, Reverse Transcriptase Inhibitors, Simian immunodeficiency virus, Science & Technology, Life Sciences & Biomedicine, Immunology, Infectious Diseases, Virology, SIV, non-nucleoside reverse transcriptase inhibitor, antiretroviral therapy, drug, resistance/resistance mutations, reverse transcriptase, IMMUNODEFICIENCY-VIRUS TYPE-1, T-LYMPHOTROPIC RETROVIRUS, HTLV-III, ANTIVIRAL ACTIVITY, ESCHERICHIA-COLI, DERIVATIVES, REPLICATION, RESISTANCE, AIDS, MUTATIONS, HIV Reverse Transcriptase, Simian Immunodeficiency Virus, 06 Biological Sciences, 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences, 32 Biomedical and clinical sciences, 42 Health sciences

Abstract:

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.