Fitness of human immunodeficiency virus type 1 protease inhibitor-selectedsingle mutants

Human immunodeficiency virus type 1 (HIV-1) evolution under chemotherapeuti c selection pressure in vivo involves a complex interplay between an increa sing magnitude of drug resistance and changes in viral replicative capacity To examine the replicative fitness of HIV-I mutants with single, drug-sele cted substitutions in protease (PR), we constructed virus that contained th e most common mutations in indinavir-selected clinical isolates, PR M461 an d V82T, and the most common polymorphic change in drug-naive patients, PR L 63P These mutants were competed in vitro in the absence of drug against the otherwise isogenic WT virus (NL4-3). Phenotypic drug susceptibility was de termined with a recombinant virus assay using a single cycle of virus growt h. PR M461 and L63P were as fit as WT However, PR V82T was out-competed by WT. None of these mutants had appreciable phenotypic resistance to any of t he protease inhibitors, including indinavir. The PRV82T mutant was hypersus ceptible to saquinavir. Thus, the impaired fitness of the V82T single mutan t is consistent with its low frequency in protease inhibitor-naive patients The similar fitness of WT (NL4-3), L63P, and M461 is consistent with the c ommon occurrence of L63P in the absence of protease inhibitor-selection pre ssure, but not with the rare detection of M461 in drug-naive patients. (C) 2000 Academic Press.