Abstract
The HIV-1 aspartic protease is an effective target for the treatment of HIV/AIDS. Current therapy utilizes a selection of nine protease inhibitors (PIs) in combination with other classes of antiretroviral drugs. Although PIs were originally developed based on the knowledge of the HIV-1 subtype B protease, the existence of other HIV-1 subtypes and the effects of drug resistance on currently available PIs have become a major challenge in the treatment of HIV/AIDS. Specifically, the HIV-1 subtype C accounts for more than half of the global HIV infections. Considering the importance and relevance of the subtype C virus, in this timely review we discuss the effect of polymorphisms in the HIV-1 subtype C protease on drug resistance, flap flexibility, and hinge region dynamics. We discuss novel paradigms of protease inhibition that attempt to overcome the limitations of currently available inhibitors which fall short considering genetic diversity and resistance mutations.