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

 Previous Article  |  Next Article 

J. Virol., Oct 1996, 7171-7181, Vol 70, No. 10
Copyright © 1996, American Society for Microbiology

Zidovudine resistance is suppressed by mutations conferring resistance of human immunodeficiency virus type 1 to foscarnet

G Tachedjian, J Mellors, H Bazmi, C Birch and J Mills
National Centre in HIV Virology Research, Macfarlane Burnet Centre for Medical Research, Fairfield, Australia.

Both foscarnet (PFA) and zidovudine (AZT) select for drug-resistant variants of human immunodeficiency virus type 1 (HIV-1), but the interactions between the mutations causing such resistance are unknown. The introduction of the previously identified PFA resistance mutation W to G at codon 88 (W88G), E89K, L92I, or Q161L into an HIV-1 strain having the four known AZT resistance mutations completely reversed high- level AZT resistance. Two additional PFA resistance mutations, W88S and S156A, partially suppressed AZT resistance. Phenotypic reversion of AZT resistance by W88S, W88G, E89K, L921, and S156A was associated with a concomitant suppression of PFA resistance. The degree to which PFA resistance mutations reversed AZT resistance was directly correlated with each mutation's ability to confer high-level PFA resistance (> or = 5.0-fold) and AZT hypersusceptibility in a wild-type genetic background. Highly PFA-resistant HIV- 1 strains were hypersusceptible to AZT; conversely, AZT-resistant strains with M41L and T215Y; M41L, L210W, and T215Y; or M41L, D67N, K70R, and T215Y mutations were 2.2- to 2.5-fold hypersusceptible to PFA. Prolonged in vitro selection of wild- type or AZT-resistant HIV-1 strains with the combination AZT and PFA failed to generate coresistant virus, indicating that dual resistance was relatively difficult to achieve. Strains selected by passage in PFA plus AZT were phenotypically PFA resistant and AZT susceptible despite multiple reverse transcriptase mutations known to confer AZT resistance. These data show that PFA resistance mutations can phenotypically reverse AZT resistance and that AZT and PFA resistance might be mutually exclusive. The reciprocal interactions between AZT and PFA resistance-conferring mutations have implications for structure- function studies of the HIV-1 reverse transcriptase.

This article has been cited by other articles:

• 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]  
• 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]  
• Selmi, B., Deval, J., Alvarez, K., Boretto, J., Sarfati, S., Guerreiro, C., Canard, B. (2003). The Y181C Substitution in 3'-Azido-3'-deoxythymidine-resistant Human Immunodeficiency Virus, Type 1, Reverse Transcriptase Suppresses the ATP-mediated Repair of the 3'-Azido-3'-deoxythymidine 5'-Monophosphate-terminated Primer. J. Biol. Chem. 278: 40464-40472 [Abstract] [Full Text]  
• Meyer, P. R., Matsuura, S. E., Zonarich, D., Chopra, R. R., Pendarvis, E., Bazmi, H. Z., Mellors, J. W., Scott, W. A. (2003). Relationship between 3'-Azido-3'-Deoxythymidine Resistance and Primer Unblocking Activity in Foscarnet-Resistant Mutants of Human Immunodeficiency Virus Type 1 Reverse Transcriptase. J. Virol. 77: 6127-6137 [Abstract] [Full Text]  
• Murry, J. P., Higgins, J., Matthews, T. B., Huang, V. Y., Van Rompay, K. K. A., Pedersen, N. C., North, T. W. (2002). Reversion of the M184V Mutation in Simian Immunodeficiency Virus Reverse Transcriptase Is Selected by Tenofovir, Even in the Presence of Lamivudine. J. Virol. 77: 1120-1130 [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]  
• Hammond, J. L., Koontz, D. L., Bazmi, H. Z., Beadle, J. R., Hostetler, S. E., Kini, G. D., Aldern, K. A., Richman, D. D., Hostetler, K. Y., Mellors, J. W. (2001). Alkylglycerol Prodrugs of Phosphonoformate Are Potent In Vitro Inhibitors of Nucleoside-Resistant Human Immunodeficiency Virus Type 1 and Select for Resistance Mutations That Suppress Zidovudine Resistance. Antimicrob. Agents Chemother. 45: 1621-1628 [Abstract] [Full Text]  
• Bazmi, H. Z., Hammond, J. L., Cavalcanti, S. C. H., Chu, C. K., Schinazi, R. F., Mellors, J. W. (2000). In Vitro Selection of Mutations in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase That Decrease Susceptibility to (-)-beta -D-Dioxolane-Guanosine and Suppress Resistance to 3'-Azido-3'-Deoxythymidine. Antimicrob. Agents Chemother. 44: 1783-1788 [Abstract] [Full Text]  
• Arion, D., Sluis-Cremer, N., Parniak, M. A. (2000). Mechanism by Which Phosphonoformic Acid Resistance Mutations Restore 3'-Azido-3'-deoxythymidine (AZT) Sensitivity to AZT-resistant HIV-1 Reverse Transcriptase. J. Biol. Chem. 275: 9251-9255 [Abstract] [Full Text]  
• Smith, R. A., Klarmann, G. J., Stray, K. M., von Schwedler, U. K., Schinazi, R. F., Preston, B. D., North, T. W. (1999). A New Point Mutation (P157S) in the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 Confers Low-Level Resistance to (-)-beta -2',3'-Dideoxy-3'-Thiacytidine. Antimicrob. Agents Chemother. 43: 2077-2080 [Abstract] [Full Text]  
• Tachedjian, G., French, M., Mills, J. (1998). Coresistance to Zidovudine and Foscarnet Is Associated with Multiple Mutations in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase. Antimicrob. Agents Chemother. 42: 3038-3043 [Abstract] [Full Text]  
• Hirsch, M. S., Conway, B., D'Aquila, R. T., Johnson, V. A., Brun-Vezinet, F., Clotet, B., Demeter, L. M., Hammer, S. M., Jacobsen, D. M., Kuritzkes, D. R., Loveday, C., Mellors, J. W., Vella, S., Richman, D. D., for the International AIDS Society-USA Panel, (1998). Antiretroviral Drug Resistance Testing in Adults With HIV Infection: Implications for Clinical Management. JAMA 279: 1984-1991 [Abstract] [Full Text]  
• Canard, B., Sarfati, S. R., Richardson, C. C. (1998). Enhanced Binding of Azidothymidine-resistant Human Immunodeficiency Virus 1 Reverse Transcriptase to the 3'-Azido-3'-deoxythymidine 5'-Monophosphate-terminated Primer. J. Biol. Chem. 273: 14596-14604 [Abstract] [Full Text]  
• (1997). Foscarnet and AZT Resistance. AIDS Clin Care 1997: 5-5 [Full Text]  
• Rigourd, M., Lanchy, J.-M., Le Grice, S. F. J., Ehresmann, B., Ehresmann, C., Marquet, R. (2000). Inhibition of the Initiation of HIV-1 Reverse Transcription by 3'-Azido-3'-deoxythymidine. COMPARISON WITH ELONGATION. J. Biol. Chem. 275: 26944-26951 [Abstract] [Full Text]