The role of the precursor HIV-1 protease in drug resistance.

Project Abstract This project aims to determine whether the precursor HIV-1 protease (PR) plays an important role in the development of drug resistance to protease inhibitors (PIs). The precursor PR dimer is far less susceptible to inhibition by PIs than the mature PR dimer, leading to the hypothesis that drug resistance mutations may evolve through the relative resistance of the precursor PR. Using innovative techniques ‘locking’ PR in the precursor configuration, we have unexpectedly found that viruses can mature, fuse with target cells, and replicate without formation of mature PR, providing a clear path through which drug resistance can evolve. Aim 1: Assess how mutations within PR or the p6*-PR cleavage site influence dimerization and activity of the precursor and mature PR enzymes. Aim 2: Assess whether PI resistance that develops without canonical mutations in PR alters dimerization and precursor or mature PR function. Aim 3: Perform in vitro viral propagation experiments to better understand how the precursor PR contributes to drug resistance.