Human Immunodeficiency Virus Type 1 Viral Background Plays a Major Role in Development of Resistance to Protease Inhibitors

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 4; pp. 1648 - 1653
• Main Authors: Rose, Ronald E., Gong, Yi-Fei, Greytok, Jill A., Bechtold, Clifford M., Terry, Brian J., Robinson, Brett S., Alam, Masud, Colonno, Richard J., Lin, Pin-Fang
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 20.02.1996; National Acad Sciences; National Academy of Sciences
• Subjects: Amino Acid Sequence; Antivirals; Carbamates - pharmacology; Clone Cells; Cross resistance; DNA Mutational Analysis; DNA, Recombinant - genetics; DNA, Viral - genetics; Drug Administration Schedule; Drug resistance; Drug Resistance, Microbial - genetics; Drug therapy; Drug Therapy, Combination; Enzymes; Ethanolamines - pharmacology; Genetic mutation; HeLa Cells; HIV; HIV 1; HIV Protease - genetics; HIV Protease Inhibitors - administration & dosage; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; Human immunodeficiency virus; human immunodeficiency virus 1; Humans; Indinavir; Infections; Isoquinolines - pharmacology; Medical research; Methylurea Compounds - pharmacology; Molecular Sequence Data; Point Mutation; Protease inhibitors; Proviruses - enzymology; Proviruses - genetics; Pyridines - pharmacology; Quinolines - pharmacology; Reassortant Viruses - drug effects; Reassortant Viruses - genetics; Recombinant Fusion Proteins - antagonists & inhibitors; Recombinant Fusion Proteins - metabolism; Saquinavir; T-Lymphocytes; Urea - analogs & derivatives; Urea - pharmacology; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.4.1648

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.