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 increasin g concentrations of the HIV proteinase inhibitor Ro 31-8959 in paralle l with representative reverse transcriptase (RT) inhibitors (AZT and t he 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 v irus. Reduced sensitivity to Ro 31-8959 was confirmed by p24 ELISA. Vi rus passaged in the presence of RT inhibitors did not show a significa nt change in either the ability to grow in culture supplemented with s tep-wise increments of inhibitor concentration or the rate of growth i n the presence of compound. In contrast, virus passaged in the presenc e of Ro 31-8959 required, on average, more than 2.5-times the normal p assage time and often did not replicate when increases in inhibitor co ncentration were applied during the initial passages. The results show that reduced sensitivity to an inhibitor of HIV proteinase, Ro 31-895 9, can be generated, but it would seem to arise less readily than that found with either of the RT inhibitors studied. While this study indi cates the potential for a reduction in sensitivity to proteinase inhib itors, it does not necessarily reflect the ability of mutant virus eit her to be selected for or to be propagated in the clinic.