Generation and characterization of a human immunodeficiency virus type 1 (HIV-1) mutant resistant to an HIV-1 protease inhibitor.
A synthetic peptide, RPI 312, that specifically inhibits the protease of the human immunodeficiency virus type 1 (HIV-1) showed a potent inhibition on virus production, maturation, and infectivity. Treatment with this agent prevented the cleavage of Gag protein at the site between p17 and p24 in HIV-1 chronically infected MOLT-4 cells as well as in the released virus. Passage of HIV-1 in the presence of gradually increasing concentrations of this protease inhibitor resulted in emergence of a variant that could evade the drug effects. In the resistant variant the maturation of Gag proteins appeared normal, but its infectivity was reduced compared with that of the parent virus. The nucleotides coding the amino acids at and around the cleavage site between Gag proteins p17 and p24 were not changed. One point mutation (A-->G) at site 2082 of the pol gene that resulted in one amino acid change at site 84 of the protease from isoleucine to valine (I-84-->V) could be detected in the resistant variant. An HIV-1 infectious DNA clone with the I-84-->V mutation also showed reduced sensitivity to this protease inhibitor. The findings that the resistant variant had lower infectivity and was still affected by higher doses of the drug support the speculation that resistance to protease inhibitors may not be as problematic as other drug resistance.
el-Farrash
M A
MA
Department of Biodefence and Medical Virology, Kumamoto University School of Medicine, Japan.
Kuroda
M J
MJ
Kitazaki
T
T
Masuda
T
T
Kato
K
K
Hatanaka
M
M
Harada
S
S
D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004352:Drug Resistance, Microbial / Q000235:genetics*; D015683:Gene Products, gag / Q000096:biosynthesis / Q000235:genetics; D015751:Genes, pol / Q000235:genetics; D015488:HIV Antigens / Q000235:genetics; D016655:HIV Core Protein p24 / Q000235:genetics; D016333:HIV Protease / Q000187:drug effects / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D017354:Point Mutation / Q000235:genetics*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014633:Valine / Q000235:genetics; D014764:Viral Proteins; D014774:Virulence / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus
D015683:Gene Products, gag; D015488:HIV Antigens; D016655:HIV Core Protein p24; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1; D007532:Isoleucine; C073513:KNI 102; D016333:HIV Protease; D014633:Valine