IN-VIVO RESISTANCE TO A HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEINASE-INHIBITOR - MUTATIONS, KINETICS, AND FREQUENCIES

Resistance to saquinavir (Ro 31-8959), an inhibitor of human immunodef iciency virus type 1 proteinase, was studied in peripheral blood monon uclear cell-derived proviral DNA from patients undergoing prolonged tr eatment. A Leu90-->Met exchange was the predominant resistance mutatio n in vivo; Gly48-->Val or doubly mutant virus was rarely observed. Aft er 8-12 months of treatment with saquinavir alone (600 mg, 3 times/day ) or in combination with zidovudine (200 mg, 3 times/day), similar to 45% of all patients carried provirus with mutant proteinase; the incid ence was lower (22%) in patients treated with a combination of saquina vir, zidovudine, and dideoxycytidine. There was a good relationship be tween genotypic analysis of saquinavir resistance and data from virus assays, confirming that Leu90-->Met and Gly48-->Val are the essential exchanges in the proteinase that determine loss of sensitivity to this inhibitor. Absence of genotypic resistance correlated with a sustaine d decrease in plasma viral RNA. There was a positive correlation betwe en a Met90 mutation and some residues at natural polymorphic sites (po sitions 10, 36, 63, and 71).