Replicative fitness of protease inhibitor-resistant mutants of human immunodeficiency virus type 1

The relative replicative fitness of human immunodeficiency virus type 1 (HI V-1) mutants selected by different protease inhibitors (PIs) in vivo was de termined. Each mutant was compared to wild type (WT), NL4-3, in the absence of drugs by several methods, including clonal genotyping of cultures infec ted with two competing viral variants, kinetics of viral antigen production , and viral infectivity/virion particle ratios. A nelfinavir-selected prote ase D30N substitution substantially decreased replicative capacity relative to WT, while a saquinavir-selected L90M substitution moderately decreased fitness, The D30N mutant virus was also outcompeted by the L90M mutant in t he absence of drugs. A major natural polymorphism of the HIV-1 protease, L6 3P, compensated well for the impairment of fitness caused by L90M but only slightly improved the fitness of D30N, Multiply substituted indinavir-selec ted mutants M46I/L63P/V82T/I84V and L10R/M46I/L63P/V82T/I84V were just as f it as WT. These results indicate that the mutations which are usually initi ally selected by nelfinavir and saquinavir, D30N and L90M, respectively, im pair fitness. However, additional mutations may improve the replicative cap acity of these and other drug-resistant mutants. Hypotheses based on the gr eater fitness impairment of the nelfinavir-selected D30N mutant are suggest ed to explain observations that prolonged responses to delayed salvage regi mens, including alternate PIs, may be relatively common after nelfinavir fa ilure.