Ordered accumulation of mutations in HIV protease confers resistance to ritonavir.
Analysis of the HIV protease gene from the plasma of HIV-infected patients revealed substitutions at nine different codons selected in response to monotherapy with the protease inhibitor ritonavir. Mutants at valine-82, although insufficient to confer resistance, appeared first in most patients. Significant phenotypic resistance required multiple mutations in HIV protease, which emerged subsequently in an ordered, stepwise fashion. The appearance of resistance mutations was delayed in patients with higher plasma levels of ritonavir. Early mutants retained susceptibility to structurally diverse protease inhibitors, suggesting that dual protease inhibitor therapy might increase the duration of viral suppression.
Molla
A
A
Department of Anti-Infective Research, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Korneyeva
M
M
Gao
Q
Q
Vasavanonda
S
S
Schipper
P J
PJ
Mo
H M
HM
Markowitz
M
M
Chernyavskiy
T
T
Niu
P
P
Lyons
N
N
Hsu
A
A
Granneman
G R
GR
Ho
D D
DD
Boucher
C A
CA
Leonard
J M
JM
Norbeck
D W
DW
Kempf
D J
DJ
D003062:Codon; D005838:Genotype; D006678:HIV / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D015658:HIV Infections / Q000097:blood; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D009154:Mutation; D010641:Phenotype; D019438:Ritonavir; D013844:Thiazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000235:genetics / Q000494:pharmacology
D003062:Codon; D017320:HIV Protease Inhibitors; D013844:Thiazoles; D016333:HIV Protease; D014633:Valine; D019438:Ritonavir