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Virology. 1993 Oct;196(2):576-85.

Knocking-out concentrations of HIV-1-specific inhibitors completely suppress HIV-1 infection and prevent the emergence of drug-resistant virus.

Author information

1
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

Abstract

Treatment of HIV-1-infected cells with the HIV-1-specific inhibitors hydroxyethoxymethylphenylthiothymine (HEPT), tetrahydroimidazobenzodiazepinones (TIBO), nevirapine, pyridinone, bis(heteroaryl)piperazines (BHAP), and tert-butyldimethylsilylspiroaminooxathioledioxide (TSAO) at a concentration of 0.1 microgram/ml resulted in a rapid breakthrough of resistant virus within three to four subcultivations. At drug concentrations of 0.5 to 1 microgram/ml, emergence of resistant virus was delayed. The drug-resistant HIV-1 strains that originated under these conditions were genetically and phenotypically characterized and showed differential sensitivities against the different classes of HIV-1-specific inhibitors depending on the amino acid substitutions in their reverse transcriptase. Novel amino acid substitutions were found in the reverse transcriptase of BHAP- and pyridinone-resistant mutant HIV-1 strains that had not been reported so far. At 2.5 to 10 micrograms/ml, that is at a concentration 100- to 250-fold higher than the 50% effective concentration (EC50), HEPT, TIBO, nevirapine, pyridinone, and BHAP prevented virus breakthrough after 15 subcultivations. In contrast, 3'-azido-2',3'-dideoxythymidine (AZT), even when administered at a 1000-fold higher concentration (i.e., 1.3 micrograms/ml) than its EC50 failed to prevent virus breakthrough after the second subcultivation. HIV-1-infected cell cultures could apparently be cleared from virus by the HIV-1-specific inhibitors when used at the "knocking-out" concentrations (2.5-10 micrograms/ml), as evidenced by (i) the lack of viral cytopathicity, (ii) the lack of virus-specific envelope glycoprotein expression, (iii) the lack of viral p24 antigen production, and (iv) the apparent absence of proviral DNA in the cells. Moreover, uninfected CEM cell cultures to which HIV-1-infected CEM cells (including syncytia) had been added were protected from destruction by high-concentration treatment with the HIV-1-specific inhibitors, but not with AZT and DDI (2',3'-dideoxyinosine).

PMID:
7690501
DOI:
10.1006/viro.1993.1513
[Indexed for MEDLINE]

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