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Journal of Virology, August 2005, p. 10638-10649, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10638-10649.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Evolution of Human Immunodeficiency Virus Type 1 Protease Genotypes and Phenotypes In Vivo under Selective Pressure of the Protease Inhibitor Ritonavir

Wolfgang Resch,{dagger} Neil Parkin,3 Terri Watkins,2 Janera Harris,2 and Ronald Swanstrom1,2*

Department of Biochemistry and Biophysics,1 UNC Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,2 ViroLogic Inc., South San Francisco, California3

Received 4 July 2004/ Accepted 11 February 2005

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.

* Corresponding author. Mailing address: University of North Carolina, Lineberger Bldg., Rm. 22-006, Mason Farm Rd., CB 7295, Chapel Hill, NC 27599-7295. Phone: (919) 966-5710. Fax: (919) 966-8212. E-mail: risunc{at}med.unc.edu.

{dagger} Present address: NIAID, MSC 0445, NIH, Bethesda, MD 20892.

Journal of Virology, August 2005, p. 10638-10649, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10638-10649.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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