Related Experiment Video
Updated: Jul 30, 2026

Molecular Evolution of the Tre Recombinase
Published on: May 29, 2008
Viral evolution in response to the broad-based retroviral protease inhibitor TL-3
1Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
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.
Related Concept Videos
Retrovirus Life Cycles
Viral Mutations
Retroviruses
Size and Structure of Viral Genomes
Inhibitors of Viral Protein Synthesis
Inhibitors of Virion Maturation and Assembly

