HIV-1 Vif-derived peptide inhibits drug-resistant HIV proteases.
Vif, one of the six accessory genes expressed by HIV-1, is essential for the productive infection of natural target cells. Previously we suggested that Vif acts as a regulator of the viral protease (PR): It prevents the autoprocessing of Gag and Gag-Pol precursors until virus assembly, and it may control the PR activity in the preintegration complex at the early stage of infection. It was demonstrated before that Vif, and specifically the 98 amino acid stretch residing at the N'-terminal part of Vif (N'-Vif), inhibits both the autoprocessing of truncated Gag-Pol polyproteins in bacterial cells and the hydrolysis of synthetic peptides by PR in cell-free systems. Linear synthetic peptides derived from N'-Vif specifically inhibit and bind HIV-1 PR in vitro, and arrest virus production in tissue culture. Peptide mapping of N'-Vif revealed that Vif88-98 is the most potent PR inhibitor. Here we report that this peptide inhibits both HIV-1 and HIV-2, but not ASLV proteases in vitro. Vif88-98 retains its inhibitory effect against drug-resistant HIV-1 PR variants, isolated from patients undergoing long-term treatment with anti-PR drugs. Variants of HIV protease bearing the mutation G48V are resistant to inhibition by this Vif-derived peptide, as shown by in vitro assays. In agreement with the in vitro experiments, Vif88-98 has no effect on the production of infectious particles in cells infected with a G48V mutated virus.
Blumenzweig
Immanuel
I
Department of Pathology, Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel.
Baraz
Lea
L
Friedler
Assaf
A
Danielson
U Helena
UH
Gilon
Chaim
C
Steinitz
Michael
M
Kotler
Moshe
M
D019943:Amino Acid Substitution; D016282:Aspartic Acid Endopeptidases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D016346:Gene Products, vif / Q000737:chemistry; D006678:HIV / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D015658:HIV Infections / Q000201:enzymology; D016333:HIV Protease / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins; D009154:Mutation; D010446:Peptide Fragments / Q000494:pharmacology*; D013379:Substrate Specificity; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D054320:vif Gene Products, Human Immunodeficiency Virus
C028391:G protein, vesicular stomatitis virus; D016346:Gene Products, vif; D017320:HIV Protease Inhibitors; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D014759:Viral Envelope Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; D016282:Aspartic Acid Endopeptidases; D016333:HIV Protease; C065184:p16 protease, Human immunodeficiency virus 2