Evolution of human immunodeficiency virus type 1 protease genotypes and phenotypes in vivo under selective pressure of the protease inhibitor ritonavir.
We examined the population dynamics of human immunodeficiency virus type 1 pro variants during the evolution of resistance to the protease inhibitor ritonavir (RTV) in vivo. pro variants were followed in subjects who had added RTV to their previously failed reverse transcriptase inhibitor therapy using a heteroduplex tracking assay designed to detect common resistance-associated mutations. In most cases the initial variant appeared rapidly within 2 to 3 months followed by one or more subsequent population turnovers. Some of the subsequent transitions between variants were rapid, and some were prolonged with the coexistence of multiple variants. In several cases variants without resistance mutations persisted despite the emergence of new variants with an increasing number of resistance-associated mutations. Based on the rate of turnover of pro variants in the RTV-treated subjects we estimated that the mean fitness of newly emerging variants was increased 1.2-fold (range, 1.02 to 1.8) relative to their predecessors. A subset of pro genes was introduced into infectious molecular clones. The corresponding viruses displayed impaired replication capacity and reduced susceptibility to RTV. A subset of these clones also showed increased susceptibility to two nonnucleoside reverse transcriptase inhibitors and the protease inhibitor saquinavir. Finally, a significant correlation between the reduced replication capacity and reduced processing at the gag NC-p1 processing site was noted. Our results reveal a complexity of patterns in the evolution of resistance to a protease inhibitor. In addition, these results suggest that selection for resistance to one protease inhibitor can have pleiotropic effects that can affect fitness and susceptibility to other drugs.
Resch
Wolfgang
W
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
Parkin
Neil
N
Watkins
Terri
T
Harris
Janera
J
Swanstrom
Ronald
R
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D015683:Gene Products, gag / Q000737:chemistry / Q000378:metabolism; D005838:Genotype; D016333:HIV Protease / Q000032:analysis / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D020180:Heteroduplex Analysis; D006801:Humans; D010641:Phenotype; D019438:Ritonavir / Q000627:therapeutic use*; D014779:Virus Replication / Q000187:drug effects
D015683:Gene Products, gag; D017320:HIV Protease Inhibitors; D016333:HIV Protease; D019438:Ritonavir