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) 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. Vif21-65 blocked 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, Vif21-65 was tested for its effect on Gag cleavage by protease during HIV-1 infection. We found that commensurate with its reduction of virus expression, Vif21-65 inhibited 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.
Potash
M J
MJ
Molecular Virology Laboratory, St. Luke's-Roosevelt Hospital Center, Columbia University, New York, NY 10019, USA.
Bentsman
G
G
Muir
T
T
Krachmarov
C
C
Sova
P
P
Volsky
D J
DJ
D002478:Cells, Cultured; D016346:Gene Products, vif / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000517:prevention & control*; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1; D006801:Humans; D008214:Lymphocytes / Q000821:virology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D054320:vif Gene Products, Human Immunodeficiency Virus
D016346:Gene Products, vif; D017320:HIV Protease Inhibitors; D011994:Recombinant Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus