Human immunodeficiency virus type 1 viral background plays a major role in development of resistance to protease inhibitors.
The observed in vitro and in vivo benefit of combination treatment with anti-human immunodeficiency virus (HIV) agents prompted us to examine the potential of resistance development when two protease inhibitors are used concurrently. Recombinant HIV-1 (NL4-3) proteases containing combined resistance mutations associated with BMS-186318 and A-77003 (or saquinavir) were either inactive or had impaired enzyme activity. Subsequent construction of HIV-1 (NL4-3) proviral clones containing the same mutations yielded viruses that were severely impaired in growth or nonviable, confirming that combination therapy may be advantageous. However, passage of BMS-186318-resistant HIV-1 (RF) in the presence of either saquinavir or SC52151, which represented sequential drug treatment, produced viable viruses resistant to both BMS-186318 and the second compound. The predominant breakthrough virus contained the G48V/A71T/V82A protease mutations. The clone-purified RF (G48V/A71T/V82A) virus, unlike the corresponding defective NL4-3 triple mutant, grew well and displayed cross-resistance to four distinct protease inhibitors. Chimeric virus and in vitro mutagenesis studies indicated that the RF-specific protease sequence, specifically the Ile at residue 10, enabled the NL4-3 strain with the triple mutant to grow. Our results clearly indicate that viral genetic background will play a key role in determining whether cross-resistance variants will arise.
Rose
R E
RE
Department of Virology, Bristol-Myers Squibb Company, Wallingford, CT 06492, USA.
Gong
Y F
YF
Greytok
J A
JA
Bechtold
C M
CM
Terry
B J
BJ
Robinson
B S
BS
Alam
M
M
Colonno
R J
RJ
Lin
P F
PF
D000595:Amino Acid Sequence; D002219:Carbamates / Q000494:pharmacology; D002999:Clone Cells; D004252:DNA Mutational Analysis; D004274:DNA, Recombinant / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D004334:Drug Administration Schedule; D004352:Drug Resistance, Microbial / Q000235:genetics; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000494:pharmacology; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D019469:Indinavir; D007546:Isoquinolines / Q000494:pharmacology; D008782:Methylurea Compounds / Q000494:pharmacology; D008969:Molecular Sequence Data; D017354:Point Mutation; D011533:Proviruses / Q000201:enzymology / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D016865:Reassortant Viruses / Q000187:drug effects / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019258:Saquinavir; D013601:T-Lymphocytes; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives
C092415:BMS 186318; D002219:Carbamates; D004274:DNA, Recombinant; D004279:DNA, Viral; D004983:Ethanolamines; D017320:HIV Protease Inhibitors; D007546:Isoquinolines; D008782:Methylurea Compounds; D011725:Pyridines; D011804:Quinolines; D011993:Recombinant Fusion Proteins; D019469:Indinavir; D014508:Urea; C079555:Abbott 77003; D016333:HIV Protease; D014633:Valine; C079293:SC 52151; D019258:Saquinavir