Peptide Inhibitors of HIV-1 Protease and Viral Infection of Peripheral Blood Lymphocytes Based on HIV-1 Vif

• Published in: Proceedings of the National Academy of Sciences - PNAS 1998-11, Vol.95 (23), p.13865-13868
• Main Authors: Potash, Mary Jane, Bentsman, Galina, Muir, Tom, Krachmarov, Chavdar, Sova, Pavel, Volsky, David J.
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Biological Sciences; Cells, Cultured; Cultured cells; Drug therapy; Gene Products, vif - chemistry; Gene Products, vif - pharmacology; Gene Products, vif - therapeutic use; Genetics; HIV; HIV 1; HIV Infections - prevention & control; HIV Protease Inhibitors - pharmacology; HIV Protease Inhibitors - therapeutic use; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Infections; Lymphocytes; Lymphocytes - virology; Peptides; Polyproteins; Potash; Protease inhibitors; Proteins; Recombinant Proteins - chemistry; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; Sendai virus; vif Gene Products, Human Immunodeficiency Virus; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.23.13865

We recently reported that HIV-1 Vif (virion infectivity factor) inhibits HIV-1 protease in vitro and in bacteria, suggesting that it may serve as the basis for the design of new protease inhibitors and treatment for HIV-1 infection. To evaluate this possibility, we synthesized peptide 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-length recombinant Vif, and a peptide consisting of residues 21-65 of Vif, but not a control peptide or BSA, inhibited protease activity. Vif21-65blocked protease at a molar ratio of two to one. We then tested this peptide and a smaller peptide, Vif41-65, for their effects on HIV-1 infection of peripheral blood lymphocytes. Both Vif peptides inhibited virus expression below the limit of detection, but control peptides had no effect. To investigate its site of action, Vif21-65was tested for its effect on Gag cleavage by protease during HIV-1 infection. We found that commensurate with its reduction of virus expression, Vif21-65inhibited the cleavage of the polyprotein p55 to mature p24. These results are similar to those obtained by using Ro 31-8959, a protease inhibitor in clinical use. We conclude that Vif-derived peptides inhibit protease during HIV-1 infection and may be useful for the development of new protease inhibitors.