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Journal of Virology, September 2002, p. 8659-8666, Vol. 76, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.17.8659-8666.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Nelfinavir-Resistant, Amprenavir-Hypersusceptible Strains of Human Immunodeficiency Virus Type 1 Carrying an N88S Mutation in Protease Have Reduced Infectivity, Reduced Replication Capacity, and Reduced Fitness and Process the Gag Polyprotein Precursor Aberrantly

Wolfgang Resch,1 Rainer Ziermann,2,{dagger} Neil Parkin,2 Andrea Gamarnik,2,{ddagger} and Ronald Swanstrom1,3*

Department of Biochemistry and Biophysics,1 UNC Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,3 ViroLogic Inc., South San Francisco, California2

Received 7 January 2002/ Accepted 5 June 2002

The evolution of human immunodeficiency virus type 1 (HIV-1) strains with reduced susceptibility to protease inhibitors (PIs) is a major cause of PI treatment failure. A subset of subjects failing a therapy regimen containing the PI nelfinavir developed mutations at position 88 in the protease region. The N88S mutation occurring in some of these subjects induces amprenavir hypersusceptibility and a reduction of fitness and replication capacity. Here we demonstrate that substitutions L63P and V77I in protease, in combination, partially compensate for the loss of fitness, loss of replication capacity, loss of specific infectivity, and aberrant Gag processing induced by the N88S mutation. In addition, these mutations partially ablate amprenavir hypersusceptibility. Addition of mutation M46L to a strain harboring mutations L63P, V77I, and N88S resulted in a reduction of fitness and infectivity without changing Gag-processing efficiency, while amprenavir hypersusceptibility was further diminished. The ratio of reverse transcriptase activity to p24 protein was reduced in this strain compared to that in the other variants, suggesting that the M46L effect on fitness occurred through a mechanism different from a Gag-processing defect. We utilized these mutant strains to undertake a systematic comparison of indirect, single, cycle-based measures of fitness with direct, replication-based fitness assays and demonstrated that both yield consistent results. However, we observed that the magnitude of the fitness loss for one of the mutants varied depending on the assay used.

* 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: Bayer Diagnostics, Berkeley, CA 94702.

{ddagger} Present address: Instituto de Investigaciones Bioquimicas F. Le Loir, Buenos Aires (1405), Argentina.

Journal of Virology, September 2002, p. 8659-8666, Vol. 76, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.17.8659-8666.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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