Human immunodeficiency virus type 1 Vif-derived peptides inhibit the viral protease and arrest virus production.
Human immunodeficiency virus type 1 (HIV-1) Vif protein is required for productive HIV-1 infection of peripheral blood lymphocytes and macrophages in cell culture and for pathogenesis in the SCID-hu mouse model of HIV-1 infection. Vif inhibits the viral protease (PR)-dependent autoprocessing of truncated HIV-1 Gag-Pol precursors expressed in bacterial cells and efficiently inhibits the PR-mediated hydrolysis of peptides in cell-free systems. The obstructive activity of Vif has been assigned to the 92 amino acids residing at its N'-terminus (N-Vif). To determine the minimal Vif sequence required to inhibit PR, we synthesized overlapping peptides derived from N-Vif. These peptides were then assessed, using two in vitro and two in vivo systems: (i) inhibition of purified PR, (ii) binding of PR, (iii) inhibition of the autoprocessing of the Gag-Pol polyprotein expressed by a vaccinia virus vector, and (iv) inhibition of mature virus production in human cells. The peptides derived from two regions of N-Vif encompassing residues Tyr-30-Val-65 and Asp-78-Val-98, inhibited PR activity in both the in vitro and the in vivo assays. Thus, these peptides can be used as lead compounds to design new PR inhibitors.
Baraz
L
L
Department of Molecular Genetics, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Friedler
A
A
Blumenzweig
I
I
Nussinuv
O
O
Chen
N
N
Steinitz
M
M
Gilon
C
C
Kotler
M
M
D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D002460:Cell Line; D015685:Fusion Proteins, gag-pol / Q000378:metabolism; D016346:Gene Products, vif / Q000737:chemistry*; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism* / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*; D054320:vif Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D015685:Fusion Proteins, gag-pol; D016346:Gene Products, vif; D017320:HIV Protease Inhibitors; D010446:Peptide Fragments; D054320:vif Gene Products, Human Immunodeficiency Virus; D016333:HIV Protease