HIV protease resistance and viral fitness

This review focuses on the evolution of protease inhibitor resistance and replication capacity in the presence and absence of protease inhibitor pressure.

Classically, HIV escapes through mutations in the protease itself causing a decrease in affinity to the inhibitor, leading to resistance. These changes also affect the binding of the enzyme to the natural substrate, and as a consequence cause a decrease in replication capacity of the virus. Continuous replication of these viruses may result in the acquisition of compensatory changes, which will fixate the drug-resistant variant in the viral population. Furthermore, novel treatment strategies have been developed to combat the development of classic protease inhibitor resistance. Using these strategies, the development of resistance in the viral protease is blocked because single or double mutations do not confer significant resistance. Alternative protease inhibitor resistance pathways are described, which enable the virus to escape these novel strategies.

Suboptimal protease inhibitor pressure clearly results in the selection of mutations conferring resistance and in the acquisition of mutations compensating the initial reduction in viral replicative capacity. The major implications of the selection of these compensatory changes on evolution in the absence of protease inhibitor pressure are discussed.