Engineering catalytically defective forms of HIV protease to modulate its activity.

The protease encoded in the HIV-1 genome plays a crucial role in the life cycle of the virus, cleaving the p55 gag and p160 gag-pol precursors into their mature and functional forms Since either genetic inactivation or chemical inhibition of the protease results in the production of non-infectious viral particles, the development of inhibitors of the HIV-1 protease has been pursued as a means of preventing viral replication. Although many inhibitors now exist that can block viral maturation and slow viral replication in vivo, resistance to the inhibitors over a prolonged period of time is often observed [2–5]. We are interested in defining the role of the protease in the viral life cycle by engineering variant forms of the enzyme with known properties. This approach has led us to consider an alternate method of regulating the activity of HIV protease for potential therapeutic intervention.