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Viral evolution in response to the broad-based retroviral protease inhibitor TL-3

Academic Article
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Overview

authors

  • Buhler, B.
  • Lin, Y. C.
  • Morris, G.
  • Olson, Arthur
  • Wong, Chi-Huey
  • Richman, D. D.
  • Elder, John
  • Torbett, Bruce

publication date

  • October 2001

journal

  • Journal of Virology  Journal

abstract

  • TL-3 is a protease inhibitor developed using the feline immunodeficiency virus protease as a model. It has been shown to efficiently inhibit replication of human, simian, and feline immunodeficiency viruses and therefore has broad-based activity. We now demonstrate that TL-3 efficiently inhibits the replication of 6 of 12 isolates with confirmed resistance mutations to known protease inhibitors. To dissect the spectrum of molecular changes in protease and viral properties associated with resistance to TL-3, a panel of chronological in vitro escape variants was generated. We have virologically and biochemically characterized mutants with one (V82A), three (M46I/F53L/V82A), or six (L24I/M46I/F53L/L63P/V77I/V82A) changes in the protease and structurally modeled the protease mutant containing six changes. Virus containing six changes was found to be 17-fold more resistant to TL-3 in cell culture than was wild-type virus but maintained similar in vitro replication kinetics compared to the wild-type virus. Analyses of enzyme activity of protease variants with one, three, and six changes indicated that these enzymes, compared to wild-type protease, retained 40, 47, and 61% activity, respectively. These results suggest that deficient protease enzymatic activity is sufficient for function, and the observed protease restoration might imply a selective advantage, at least in vitro, for increased protease activity.

subject areas

  • Amino Acid Sequence
  • Animals
  • Cats
  • Evolution, Molecular
  • Genome, Viral
  • Humans
  • Molecular Sequence Data
  • Protease Inhibitors
  • Retroviridae
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Identity

PubMed Central ID

  • PMC114517

International Standard Serial Number (ISSN)

  • 0022-538X

Digital Object Identifier (DOI)

  • 10.1128/jvi.75.19.9502-9508.2001

PubMed ID

  • 11533212
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Additional Document Info

start page

  • 9502

end page

  • 9508

volume

  • 75

issue

  • 19

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