title: New developments in the chemotherapy of lentivirus (human immunodeficiency virus) infections: sensitivity/resistance of HIV-1 to non-nucleoside HIV-1-specific inhibitors.
abstract: Of the different steps of the HIV replicative cycle, the reverse transcription step has received most attention as a target for chemotherapeutic intervention. The reverse transcriptase (RT) can be blocked by both nucleoside (nucleotide) and non-nucleoside type of inhibitors. Whereas the former act as competitive inhibitors with respect to the natural substrates or alternate substrates (chain terminators), the latter act allosterically with a non-substrate binding site of the enzyme. Several non-nucleoside types of RT inhibitors have proved to inhibit HIV-1 replication at nanomolar concentrations that are 10(4)- to 10(5)-fold lower than the cytotoxic concentrations. Although a non-nucleoside HIV-1-specific RT inhibitor may rapidly select for virus-drug resistance in cell culture, the resulting mutant strain may or may not show cross-resistance, and in some instances even hypersensitivity, to other HIV-specific RT inhibitors. When used at the appropriate concentrations, HIV-1-specific RT inhibitors are able to completely shut off ("knock-out") virus replication in vitro, under conditions where dideoxynucleoside analogues such as AZT fail to do so. This apparent "sterilizing effect" achieved by the non-nucleoside type of HIV-1-specific RT inhibitors opens new perspectives for the treatment of HIV infections in patients.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: de Clercq
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000998:Antiviral Agents / Q000627:therapeutic use*; D004352:Drug Resistance, Microbial; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D009705:Nucleosides / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase