IN-VITRO RESISTANCE TO AN INHIBITOR OF HIV PROTEINASE (RO 31-8959) RELATIVE TO INHIBITORS OF REVERSE-TRANSCRIPTASE (AZT AND TIBO)

Serial passage of cell-free human immunodeficiency virus type 1 (HIV-1) strain GB8 on CEM cells was carried out in the presence of increasing concentrations of the HIV proteinase inhibitor Ro 31-8959 in parallel with representative reverse transcriptase (RT) inhibitors (AZT and the TIBO compound, R82150). In all instances, a significant increase in the concentration of compound required to produce a 90% reduction of syncytium formation (IC90) was found after seven to nine passages of virus. Reduced sensitivity to Ro 31-8959 was confirmed by p24 ELISA. Virus passaged in the presence of RT inhibitors did not show a significant change in either the ability to grow in culture supplemented with step-wise increments of inhibitor concentration or the rate of growth in the presence of compound. In contrast, virus passaged in the presence of Ro 31-8959 required, on average, more than 2.5-times the normal passage time and often did not replicate when increases in inhibitor concentration were applied during the initial passages. The results show that reduced sensitivity to an inhibitor of HIV proteinase, Ro 31-8959, can be generated, but it would seem to arise less readily than that found with either of the RT inhibitors studied. While this study indicates the potential for a reduction in sensitivity to proteinase inhibitors, it does not necessarily reflect the ability of mutant virus either to be selected for or to be propagated in the clinic.