New developments in the chemotherapy of lentivirus (human immunodeficiency virus) infections: sensitivity/resistance of HIV-1 to non-nucleoside HIV-1-specific inhibitors.


Of the different steps of the HIV replicative cycle, the reverse ...
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.




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