Rev is a key regulatory protein of HIV-1. Its function is to bind to viral transcripts and effect export from the nucleus of unspliced mRNA, thereby allowing the production of structural proteins. In our previous work, the structure of Rev was solved for first time by complexing it with an antibody fragment (Fab). The anti-Rev Fab stabilized Rev allowing the formation of protein crystals suitable for X-ray structural analysis. The anti-Rev Fab was shown to have anti-HIV activity, presumably by binding tightly to Rev and blocking its functional interactions. Regions of the Fab antibody in contact with Rev are known collectively as the paratope (regions of Rev in contact with the Fab are known as the epitope). The paratope consists of six complementary determining region (CDR) loop-like regions, three each from the antibody heavy and light chains. The CDRs are relatively short consisting of 6 to 14 amino acid residues. Analyses of the epitope-paratope interface from the X-ray structure allowed for the prediction of key contacts (hot spots which bind most tightly) among the CDR sequences which stabilize the Rev: Fab complex. Peptides were synthesized which corresponded to the CDRs: the peptides were cyclized N- to C-terminal to give them a structure approximating to their loop-like conformation in the intact antibody. Of the CDRs peptides tested, one from the light chain (LCDR3) exhibited tight binding to Rev. Analogous to the antibody; the peptide was capable of depolymerizing a highly associated form of Rev (filaments) by specifically disrupting Rev protein-protein interactions. Mutations of residues in Fab, corresponding to the predicted hot spots in LCDR3, dramatically reduced its binding to Rev, confirming their key role in stabilizing the interaction. The LCDR3 peptide and other peptides selected for their binding to Rev are being assessed for their anti-HIV activity. HIV protease, a homodimeric protein, is essential in the viral life cycle and a major anti-HIV drug target. We have expressed and purified a number of wild type and drug resistant forms of the protease which have been used in structural studies. Novel drugs which bind to the protease have been studied by co-crystallization and by examining the crystal structures used to rationalize and optimize drug binding. Structural details of interactions between drug moieties and protein have led to the synthesis of new compound with higher anti-HIV potency.