HIV-1 protease is a retroviral aspartyl protease (retropepsin) that is essential for the life-cycle of HIV, the retrovirus that causes AIDS. HIV protease cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion. Without effective HIV protease, HIV virions remain uninfectious. Thus, mutation of HIV protease's active site or inhibition of its activity disrupts HIV’s ability to replicate and infect additional cells, making HIV protease inhibition the subject of considerable pharmaceutical research. 
HIV-1 protease labelled according to its resemblance to an English Bulldog or a fat cat. The blue and cyan-green ribbons depict the peptide backbone of a wild-type (1D4S) and a mutant (1KZK) structure, respectively.
The active site lies between the identical subunits and has the characteristic Asp-Thr-Gly (Asp25, Thr26 and Gly27) sequence common to aspartic proteases. The two Asp25 residues (one from each chain) act as the catalytic residues. According to the mechanism for HIV protease protein cleavage proposed by Mariusz Jaskolski and colleagues, water acts as a nucleophile, which acts in simultaneous conjunction with a well-placed aspartic acid to hydrolyze the scissile peptide bond. Additionally, HIV protease has two molecular "flaps" which move a distance of up to 7 Å when the enzyme becomes associated with a substrate.
The structure of HIV-1 protease (green and cyan) complexed with a polypeptidesubstrate (magenta) based on the 1KJF coordinates. The active site Asp-25 residues are colored red.
The structure of HIV-1 protease complexed with inhibitor BEA369 based on the 1EBY coordinates. The enzyme subunits are colored green and cyan and the active site red. The inhibitor is depicted as a multicolor tube (carbon atoms = white, nitrogen = blue, oxygen = red).
With its integral role in HIV replication, HIV protease has been a prime target for drug therapy. HIV protease inhibitors work by specifically binding to the active site by mimicking the tetrahedral intermediate of its substrate and essentially becoming “stuck,” disabling the enzyme. This results in the production of immature proteins, which cannot assemble into infectious virions. Several protease inhibitors have been licensed for HIV therapy.
HIV-1 Protease has the classic AspThrGly of Aspartyl Proteases. These amino acids are located at position 25, 26, and 27, and are responsible for the catalytic activity.
However, due to the high mutation rates of retroviruses, and considering that changes to a few amino acid within HIV protease can render it much less visible to an inhibitor, the active site of this enzyme can change rapidly when under the selective pressure of replication-inhibiting drugs.
One approach to minimizing the development of drug-resistance in HIV is to administer a combination of drugs which inhibit several key aspects of the HIV replication cycle simultaneously, rather than one drug at a time. Other drug therapy targets include reverse transcriptase, virus attachment, membrane fusion, cDNA integration and virion assembly.
^Jaskólski M, Tomasselli AG, Sawyer TK, Staples DG, Heinrikson RL, Schneider J, Kent SB, Wlodawer A (February 1991). "Structure at 2.5-A resolution of chemically synthesized human immunodeficiency virus type 1 protease complexed with a hydroxyethylene-based inhibitor". Biochemistry30 (6): 1600–9. doi:10.1021/bi00220a023. PMID1993177.