This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Watkins, T.
Right arrow Articles by Swanstrom, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Watkins, T.
Right arrow Articles by Swanstrom, R.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, February 2003, p. 759-769, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.759-769.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Selection of High-Level Resistance to Human Immunodeficiency Virus Type 1 Protease Inhibitors

Terri Watkins,1,{dagger} Wolfgang Resch,2,{ddagger} David Irlbeck,1,3 and Ronald Swanstrom1,2*

UNC Center for AIDS Research,1 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-72952

Received 21 May 2002/ Returned for modification 8 August 2002/ Accepted 17 October 2002

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.

* Corresponding author. Mailing address: CB7295 Lineberger Bldg., Rm. 22-006, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Phone: (919) 966-5710. Fax: (919) 966-8212. E-mail: risunc{at}med.unc.edu.

{dagger} Present address: Bayer Corporation, NAT Development, Raleigh, NC 27610.

{ddagger} Present address: NIAID, MSC 0445, NIH, Bethesda, MD 20892-0054.

§ Present address: MMV Clinical Virology, GlaxoSmithKline, Durham, NC 27713-1852.

Antimicrobial Agents and Chemotherapy, February 2003, p. 759-769, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.759-769.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Aoki, M., Venzon, D. J., Koh, Y., Aoki-Ogata, H., Miyakawa, T., Yoshimura, K., Maeda, K., Mitsuya, H. (2009). Non-Cleavage Site Gag Mutations in Amprenavir-Resistant Human Immunodeficiency Virus Type 1 (HIV-1) Predispose HIV-1 to Rapid Acquisition of Amprenavir Resistance but Delay Development of Resistance to Other Protease Inhibitors. J. Virol. 83: 3059-3068 [Abstract] [Full Text]  
  • Lin, Y.-C., Brik, A., de Parseval, A., Tam, K., Torbett, B. E., Wong, C.-H., Elder, J. H. (2006). Altered gag polyprotein cleavage specificity of feline immunodeficiency virus/human immunodeficiency virus mutant proteases as demonstrated in a cell-based expression system.. J. Virol. 80: 7832-7843 [Abstract] [Full Text]  
  • Weinheimer, S., Discotto, L., Friborg, J., Yang, H., Colonno, R. (2005). Atazanavir Signature I50L Resistance Substitution Accounts for Unique Phenotype of Increased Susceptibility to Other Protease Inhibitors in a Variety of Human Immunodeficiency Virus Type 1 Genetic Backbones. Antimicrob. Agents Chemother. 49: 3816-3824 [Abstract] [Full Text]  
  • Resch, W., Parkin, N., Watkins, T., Harris, J., Swanstrom, R. (2005). Evolution of Human Immunodeficiency Virus Type 1 Protease Genotypes and Phenotypes In Vivo under Selective Pressure of the Protease Inhibitor Ritonavir. J. Virol. 79: 10638-10649 [Abstract] [Full Text]  
  • Charpentier, C., Dwyer, D. E., Mammano, F., Lecossier, D., Clavel, F., Hance, A. J. (2004). Role of Minority Populations of Human Immunodeficiency Virus Type 1 in the Evolution of Viral Resistance to Protease Inhibitors. J. Virol. 78: 4234-4247 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»