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 Peters, S.
Right arrow Articles by Telenti, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Peters, S.
Right arrow Articles by Telenti, A.

 Previous Article  |  Next Article 

Journal of Virology, October 2001, p. 9644-9653, Vol. 75, No. 20
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.20.9644-9653.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Resistance to Nucleoside Analog Reverse Transcriptase Inhibitors Mediated by Human Immunodeficiency Virus Type 1 p6 Protein

Solange Peters,1 Miguel Muñoz,2 Sabine Yerly,3 Victor Sanchez-Merino,4 Cecilio Lopez-Galindez,4 Luc Perrin,3 Brendan Larder,5 Dusan Cmarko,6 Stanislav Fakan,6 Pascal Meylan,2 and Amalio Telenti1,2,*

Division of Infectious Diseases1 and Institute of Microbiology,2 University Hospital, and Center of Electron Microscopy,6 Lausanne, and Division of Infectious Diseases, University Hospital, Geneva,3 Switzerland; Centro Nacional de Biologìa Fundamental, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain4; and Virco, Cambridge, United Kingdom5

Received 6 April 2001/Accepted 9 July 2001

Resistance of human immunodeficiency virus type 1 (HIV-1) to antiretroviral agents results from target gene mutation within the pol gene, which encodes the viral protease, reverse transcriptase (RT), and integrase. We speculated that mutations in genes other that the drug target could lead to drug resistance. For this purpose, the p1-p6gag-p6pol region of HIV-1, placed immediately upstream of pol, was analyzed. This region has the potential to alter Pol through frameshift regulation (p1), through improved packaging of viral enzymes (p6Gag), or by changes in activation of the viral protease (p6Pol). Duplication of the proline-rich p6Gag PTAP motif, necessary for late viral cycle activities, was identified in plasma virus from 47 of 222 (21.2%) patients treated with nucleoside analog RT inhibitor (NRTI) antiretroviral therapy but was identified very rarely from drug-naïve individuals. Molecular clones carrying a 3-amino-acid duplication, APPAPP (transframe duplication SPTSPT in p6Pol), displayed a delay in protein maturation; however, they packaged a 34% excess of RT and exhibited a marked competitive growth advantage in the presence of NRTIs. This phenotype is reminiscent of the inoculum effect described in bacteriology, where a larger input, or a greater infectivity of an organism with a wild-type antimicrobial target, leads to escape from drug pressure and a higher MIC in vitro. Though the mechanism by which the PTAP region participates in viral maturation is not known, duplication of this proline-rich motif could improve assembly and packaging at membrane locations, resulting in the observed phenotype of increased infectivity and drug resistance.


* Corresponding author. Mailing address: Division of Infectious Diseases, CHUV, 1011 Lausanne, Switzerland. Phone: 41 21 314 0550. Fax: 41 21 314 1008. E-mail: amalio.telenti{at}chuv.hospvd.ch.


Journal of Virology, October 2001, p. 9644-9653, Vol. 75, No. 20
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.20.9644-9653.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.



This article has been cited by other articles:

  • Leiherer, A., Ludwig, C., Wagner, R. (2009). Uncoupling Human Immunodeficiency Virus Type 1 gag and pol Reading Frames: Role of the Transframe Protein p6* in Viral Replication. J. Virol. 83: 7210-7220 [Abstract] [Full Text]  
  • 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]  
  • Cao, J., McNevin, J., McSweyn, M., Liu, Y., Mullins, J. I., McElrath, M. J. (2008). Novel Cytotoxic T-Lymphocyte Escape Mutation by a Three-Amino-Acid Insertion in the Human Immunodeficiency Virus Type 1 p6Pol and p6Gag Late Domain Associated with Drug Resistance. J. Virol. 82: 495-502 [Abstract] [Full Text]  
  • Dykes, C., Demeter, L. M. (2007). Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness. Clin. Microbiol. Rev. 20: 550-578 [Abstract] [Full Text]  
  • Girnary, R., King, L., Robinson, L., Elston, R., Brierley, I. (2007). Structure-function analysis of the ribosomal frameshifting signal of two human immunodeficiency virus type 1 isolates with increased resistance to viral protease inhibitors. J. Gen. Virol. 88: 226-235 [Abstract] [Full Text]  
  • Winters, M. A., Merigan, T. C. (2005). Insertions in the Human Immunodeficiency Virus Type 1 Protease and Reverse Transcriptase Genes: Clinical Impact and Molecular Mechanisms. Antimicrob. Agents Chemother. 49: 2575-2582 [Full Text]  
  • van der Hoek, L., Back, N., Jebbink, M. F., de Ronde, A., Bakker, M., Jurriaans, S., Reiss, P., Parkin, N., Berkhout, B. (2005). Increased Multinucleoside Drug Resistance and Decreased Replicative Capacity of a Human Immunodeficiency Virus Type 1 Variant with an 8-Amino-Acid Insert in the Reverse Transcriptase. J. Virol. 79: 3536-3543 [Abstract] [Full Text]  
  • Tamiya, S., Mardy, S., Kavlick, M. F., Yoshimura, K., Mistuya, H. (2004). Amino Acid Insertions near Gag Cleavage Sites Restore the Otherwise Compromised Replication of Human Immunodeficiency Virus Type 1 Variants Resistant to Protease Inhibitors. J. Virol. 78: 12030-12040 [Abstract] [Full Text]  
  • Gonzalez, L. M. F., Brindeiro, R. M., Aguiar, R. S., Pereira, H. S., Abreu, C. M., Soares, M. A., Tanuri, A. (2004). Impact of Nelfinavir Resistance Mutations on In Vitro Phenotype, Fitness, and Replication Capacity of Human Immunodeficiency Virus Type 1 with Subtype B and C Proteases. Antimicrob. Agents Chemother. 48: 3552-3555 [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]  
  • Bleiber, G., Peters, S., Martinez, R., Cmarko, D., Meylan, P., Telenti, A. (2004). The central region of human immunodeficiency virus type 1 p6 protein (Gag residues S14-I31) is dispensable for the virus in vitro. J. Gen. Virol. 85: 921-927 [Abstract] [Full Text]  
  • Simon, V., Padte, N., Murray, D., Vanderhoeven, J., Wrin, T., Parkin, N., Di Mascio, M., Markowitz, M. (2003). Infectivity and Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1 Variants Isolated during Primary Infection. J. Virol. 77: 7736-7745 [Abstract] [Full Text]  
  • Gallego, O., de Mendoza, C., Corral, A., Soriano, V. (2003). Changes in the Human Immunodeficiency Virus p7-p1-p6 gag Gene in Drug-Naive and Pretreated Patients. J. Clin. Microbiol. 41: 1245-1247 [Abstract] [Full Text]  
  • Diallo, K., Oliveira, M., Moisi, D., Brenner, B., Wainberg, M. A., Gotte, M. (2002). Pressure of Zidovudine Accelerates the Reversion of Lamivudine Resistance-Conferring M184V Mutation in the Reverse Transcriptase of Human Immunodeficiency Virus Type 1. Antimicrob. Agents Chemother. 46: 2254-2256 [Abstract] [Full Text]