Drug Resistance to HIV-1 Protease Inhibitors: Molecular Mechanisms and Substrate Coevolution

Abstract

HIV-1 protease inhibitors (PIs) are competitive active-site inhibitors that mimic the transition state of the enzyme’s substrate, and are the most potent antiretroviral drugs against HIV infection. HIV-1 protease processes the viral polyproteins at specific cleavage sites and allows infectious mature virions and hence spread of the virus. Unfortunately rapid viral evolution combined with selective pressure of therapy causes selection of many drug-resistant variants that are no longer efficiently inhibited by the PIs. HIV-1 protease can tolerate extensive mutations, with close to half of the 99-residues making up each of the chains in the homodimeric protease and residues at substrate cleavage sites mutating to escape PI pressure. Structural and biophysical studies of many drug-resistant HIV-1 protease variants revealed insights into how mutations at and outside of the protease active site are able to confer PI resistance while still allowing recognition and processing of substrates, and why substrate mutations coevolve with primary protease mutations. We summarize the main molecular mechanisms underlying PI resistance due to primary, secondary, and substrate coevolved mutations and how this knowledge may guide the design of robust inhibitors to avoid resistance.