Article

Selection of high-level resistance to human immunodeficiency virus type 1 protease inhibitors.

UNC Center for AIDS Research, Department of Biochemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA.
Antimicrobial Agents and Chemotherapy (impact factor: 4.84). 03/2003; 47(2):759-69. pp.759-69
Source: PubMed

ABSTRACT Protease inhibitors represent some of the most potent agents available for therapeutic strategies designed to inhibit human immunodeficiency virus type 1 (HIV-1) replication. Under certain circumstances the virus develops resistance to the inhibitor, thereby negating the benefits of this therapy. We have carried out selections for high-level resistance to each of three protease inhibitors (indinavir, ritonavir, and saquinavir) in cell culture. Mutations accumulated over most of the course of the increasing selective pressure. There was significant overlap in the identity of the mutations selected with the different inhibitors, and this gave rise to high levels of cross-resistance. Virus particles from the resistant variants all showed defects in processing at the NC/p1 protease cleavage site in Gag. Selections with pairs of inhibitors yielded similar patterns of resistance mutations. A virus that could replicate at near-toxic levels of the three protease inhibitors combined was selected. The pro sequence of this virus was similar to that of the viruses that had been selected for high-level resistance to each of the drugs singly. Finally, a molecular clone carrying the eight most common resistance mutations seen in these selections was characterized. The sequence of this virus was relatively stable during selection for revertants in spite of displaying poor processing at the NC/p1 site and having significantly reduced fitness. These results reveal patterns of drug resistance that extend to near the limits of attainable selective pressure with these inhibitors and confirm the patterns of cross-resistance for these three inhibitors and the attenuation of virion protein processing and fitness that accompanies high-level resistance.

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Keywords

accompanies high-level resistance
 
attainable selective pressure
 
cell culture
 
certain circumstances
 
common resistance mutations
 
different inhibitors
 
drug resistance
 
drugs singly
 
gave rise
 
high-level resistance
 
human immunodeficiency virus type 1
 
increasing selective pressure
 
NC/p1 site
 
potent agents available
 
Protease inhibitors
 
resistance mutations
 
three inhibitors
 
three protease inhibitors
 
virion protein processing
 
Virus particles