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 Meyer, P. R.
Right arrow Articles by Scott, W. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Meyer, P. R.
Right arrow Articles by Scott, W. A.

 Previous Article  |  Next Article 

Journal of Virology, June 2003, p. 6127-6137, Vol. 77, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.11.6127-6137.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Relationship between 3'-Azido-3'-Deoxythymidine Resistance and Primer Unblocking Activity in Foscarnet-Resistant Mutants of Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Peter R. Meyer,1 Suzanne E. Matsuura,1 Dianna Zonarich,2 Rahul R. Chopra,1 Eric Pendarvis,1 Holly Z. Bazmi,2 John W. Mellors,2 and Walter A. Scott1*

Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, Florida,1 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania2

Received 28 October 2002/ Accepted 2 March 2003

Phosphonoformate (foscarnet) is a pyrophosphate (PPi) analogue and a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), acting through the PPi binding site on the enzyme. HIV-1 RT can unblock a chain-terminated DNA primer by phosphorolytic transfer of the terminal residue to an acceptor substrate (PPi or a nucleotide such as ATP) which also interacts with the PPi binding site. Primer-unblocking activity is increased in mutants of HIV-1 that are resistant to the chain-terminating nucleoside inhibitor 3'-azido-3'-deoxythymidine (AZT). We have compared the primer-unblocking activity for HIV-1 RT containing various foscarnet resistance mutations (K65R, W88G, W88S, E89K, S117T, Q161L, M164I, and the double mutant Q161L/H208Y) alone or in combination with AZT resistance mutations. The level of primer-unblocking activity varied over a 150-fold range for these enzymes and was inversely correlated with foscarnet resistance and directly correlated with AZT resistance. Based on published crystal structures of HIV-1 RT, many of the foscarnet resistance mutations affect residues that do not make direct contact with the catalytic residues of RT, the incoming deoxynucleoside triphosphate (dNTP), or the primer-template. These mutations may confer foscarnet resistance and reduce primer unblocking by indirectly decreasing the binding and retention of foscarnet, PPi, and ATP. Alternatively, the binding position or orientation of PPi, ATP, or the primer-template may be changed in the mutant enzyme complex so that molecular interactions required for the unblocking reaction are impaired while dNTP binding and incorporation are not.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, P.O. Box 016129, Miami, FL 33101-6129. Phone: (305) 243-6359. Fax: (305) 243-3065. E-mail: wscott{at}med.miami.edu.

Journal of Virology, June 2003, p. 6127-6137, Vol. 77, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.11.6127-6137.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Matamoros, T., Nevot, M., Martinez, M. A., Menendez-Arias, L. (2009). Thymidine Analogue Resistance Suppression by V75I of HIV-1 Reverse Transcriptase: EFFECTS OF SUBSTITUTING VALINE 75 ON STAVUDINE EXCISION AND DISCRIMINATION. J. Biol. Chem. 284: 32792-32802 [Abstract] [Full Text]  
  • Nebbia, G., Sabin, C. A., Dunn, D. T., Geretti, A. M., on behalf of the UK Collaborative Group on HIV Dru, (2007). Emergence of the H208Y mutation in the reverse transcriptase (RT) of HIV-1 in association with nucleoside RT inhibitor therapy. J Antimicrob Chemother 59: 1013-1016 [Abstract] [Full Text]  
  • Marchand, B., Tchesnokov, E. P., Gotte, M. (2007). The Pyrophosphate Analogue Foscarnet Traps the Pre-translocational State of HIV-1 Reverse Transcriptase in a Brownian Ratchet Model of Polymerase Translocation. J. Biol. Chem. 282: 3337-3346 [Abstract] [Full Text]  
  • Margot, N. A., Waters, J. M., Miller, M. D. (2006). In Vitro Human Immunodeficiency Virus Type 1 Resistance Selections with Combinations of Tenofovir and Emtricitabine or Abacavir and Lamivudine. Antimicrob. Agents Chemother. 50: 4087-4095 [Abstract] [Full Text]  
  • Meyer, P. R., Smith, A. J., Matsuura, S. E., Scott, W. A. (2006). Chain-Terminating Dinucleoside Tetraphosphates Are Substrates for DNA Polymerization by Human Immunodeficiency Virus Type 1 Reverse Transcriptase with Increased Activity against Thymidine Analogue-Resistant Mutants. Antimicrob. Agents Chemother. 50: 3607-3614 [Abstract] [Full Text]  
  • Cruchaga, C., Anso, E., Rouzaut, A., Martinez-Irujo, J. J. (2006). Selective Excision of Chain-terminating Nucleotides by HIV-1 Reverse Transcriptase with Phosphonoformate as Substrate. J. Biol. Chem. 281: 27744-27752 [Abstract] [Full Text]  
  • Smith, R. A., Anderson, D. J., Preston, B. D. (2006). Hypersusceptibility to Substrate Analogs Conferred by Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase. J. Virol. 80: 7169-7178 [Abstract] [Full Text]  
  • Svicher, V., Sing, T., Santoro, M. M., Forbici, F., Rodriguez-Barrios, F., Bertoli, A., Beerenwinkel, N., Bellocchi, M. C., Gago, F., d'Arminio Monforte, A., Antinori, A., Lengauer, T., Ceccherini-Silberstein, F., Perno, C. F. (2006). Involvement of Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutations in the Regulation of Resistance to Nucleoside Inhibitors. J. Virol. 80: 7186-7198 [Abstract] [Full Text]  
  • Parikh, U. M., Bacheler, L., Koontz, D., Mellors, J. W. (2006). The K65R Mutation in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Exhibits Bidirectional Phenotypic Antagonism with Thymidine Analog Mutations.. J. Virol. 80: 4971-4977 [Abstract] [Full Text]  
  • Tchesnokov, E. P., Gilbert, C., Boivin, G., Gotte, M. (2006). Role of Helix P of the Human Cytomegalovirus DNA Polymerase in Resistance and Hypersusceptibility to the Antiviral Drug Foscarnet. J. Virol. 80: 1440-1450 [Abstract] [Full Text]  
  • Parikh, U. M., Koontz, D. L., Chu, C. K., Schinazi, R. F., Mellors, J. W. (2005). In Vitro Activity of Structurally Diverse Nucleoside Analogs against Human Immunodeficiency Virus Type 1 with the K65R Mutation in Reverse Transcriptase. Antimicrob. Agents Chemother. 49: 1139-1144 [Abstract] [Full Text]  
  • Meyer, P. R., Smith, A. J., Matsuura, S. E., Scott, W. A. (2004). Effects of Primer-Template Sequence on ATP-dependent Removal of Chain-terminating Nucleotide Analogues by HIV-1 Reverse Transcriptase. J. Biol. Chem. 279: 45389-45398 [Abstract] [Full Text]  
  • Boyer, P. L., Imamichi, T., Sarafianos, S. G., Arnold, E., Hughes, S. H. (2004). Effects of the {Delta}67 Complex of Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase on Nucleoside Analog Excision. J. Virol. 78: 9987-9997 [Abstract] [Full Text]  
  • Smith, R. A., Anderson, D. J., Preston, B. D. (2004). Purifying Selection Masks the Mutational Flexibility of HIV-1 Reverse Transcriptase. J. Biol. Chem. 279: 26726-26734 [Abstract] [Full Text]  
  • Boyer, P. L., Stenbak, C. R., Clark, P. K., Linial, M. L., Hughes, S. H. (2004). Characterization of the Polymerase and RNase H Activities of Human Foamy Virus Reverse Transcriptase. J. Virol. 78: 6112-6121 [Abstract] [Full Text]  
  • Matamoros, T., Franco, S., Vazquez-Alvarez, B. M., Mas, A., Martinez, M. A., Menendez-Arias, L. (2004). Molecular Determinants of Multi-nucleoside Analogue Resistance in HIV-1 Reverse Transcriptases Containing a Dipeptide Insertion in the Fingers Subdomain: EFFECT OF MUTATIONS D67N AND T215Y ON REMOVAL OF THYMIDINE NUCLEOTIDE ANALOGUES FROM BLOCKED DNA PRIMERS. J. Biol. Chem. 279: 24569-24577 [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»