HIV-1 protease (PR) and two drug-resistant variants – PR with the V82A mutation (PRV82A) and PR with the I84V mutation (PRI84V) – were studied using reduced peptide analogs of five natural cleavage sites (CA-p2, p2-NC, p6 pol -PR, p1-p6 and NC-p1) to understand the structural and kine-tic changes. The common drug-resistant mutations V82A and I84V alter residues forming the substrate-binding site. Eight crystal structures were refined at resolutions of – A ˚ .