Inhibition of HIV by an anti-HIV protease synthetic peptide blocks an early step of viral replication.
The processing of the human immunodeficiency virus (HIV) gag and gag-pol precursor proteins by the virus-encoded protease is an essential step in maturation of infectious virus particles. Like most retroviral proteases, the HIV protease belongs to the aspartyl-protease family and can be inhibited by specific inhibitors. Twenty-four synthetic peptides known to be inhibitors of human renin were tested for inhibition of HIV replication in tissue cultures. One of them, a synthetic peptide analogue, SR41476, which has been shown to be a specific inhibitor of purified recombinant HIV1 protease in vitro, totally blocked infection with different isolates including the HIV1 LAV prototype, the highly cytopathic Zairian isolate HIV1 NDK, and HIV2 ROD, both in primary blood lymphocytes (PBL) and in the lymphoid cell lines MT4 and CEM, for at least 3 weeks. It also significantly reduced virus replication in chronically infected CEM cells, without any effect on cell proliferation. Radioimmunoprecipitation assay revealed that the inhibitor blocked processing of polyprotein precursors p55 gag and p40 gag into a mature form of gag proteins, p25 and p18. Synthetic peptide analogue SR 41476, when added before infection, efficiently inhibited formation of HIV DNA provirus and successfully suppressed synthesis of HIV-specific proteins. These results imply that the HIV protease inhibitor not only inhibited virus maturation in the late phase of the HIV replication cycle, but also interfered in the early phase, before the provirus was formed. This mechanism of antiviral activity provides new possibilities and strategies for AIDS chemotherapy.
Venaud
S
S
Unité de Recherches INSERM sur les Rétrovirus et Maladies Associées (U322), Marseille, France.
Yahi
N
N
Fehrentz
J L
JL
Guettari
N
N
Nisato
D
D
Hirsch
I
I
Chermann
J C
JC
D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D004279:DNA, Viral / Q000096:biosynthesis; D015683:Gene Products, gag / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008214:Lymphocytes / Q000382:microbiology; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects
D004279:DNA, Viral; D015683:Gene Products, gag; D017320:HIV Protease Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C079075:SR 41476; D014764:Viral Proteins