PEPTIDE INHIBITORS OF HIV-1 PROTEASE AND VIRAL-INFECTION OF PERIPHERAL-BLOOD LYMPHOCYTES BASED ON HIV-1 VIF

We recently reported that HIV-1 Vif (virion infectivity factor) inhibi ts HIV-1 protease in vitro and in bacteria, suggesting that it may ser ve as the basis for the design of new protease inhibitors and treatmen t for HIV-1 infection. To evaluate this possibility, we synthesized pe ptide derivatives from the region of Vif, which inhibits protease, and tested their activity on protease, In an assay of cleavage of virion- like particles composed of HIV-1 Gag precursor polyprotein, full-lengt h recombinant Vif, and a peptide consisting of residues 21-65 of Vif, but not a central peptide or BSA, inhibited protease activity. Vif(21- 65) blocked protease at a molar ratio of two to one. We then tested th is peptide and a smaller peptide, Vif(41-65), for their effects on HIV -1 infection of peripheral blood lymphocytes. Both Vif peptides inhibi ted virus expression below the limit of detection, but control peptide s had no effect. To investigate its site of action, Vif(21-65) was tes ted for its effect on Gag cleavage by protease during HIV-1 infection. We found that commensurate with its reduction of virus expression, Vi f(21-65) inhibited the cleavage of the polyprotein p55 to mature p24, These results are similar to those obtained by using Ro 31-8959, a pro tease inhibitor in clinical use. We conclude that Vif-derived peptides inhibit protease during HIV-1 infection and may be useful for the dev elopment of new protease inhibitors.