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Science 1 December 1989:
Vol. 246. no. 4934, pp. 1155 - 1158
DOI: 10.1126/science.2479983
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Articles

Science, Vol 246, Issue 4934, 1155-1158
Copyright © 1989 by American Association for the Advancement of Science

articles

Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT)

BA Larder and SD Kemp

Molecular Sciences Department, Wellcome Research Laboratories, Beckenham, Kent, United Kingdom.

Human immunodeficiency virus (HIV) isolates with reduced sensitivity to zidovudine (3'-azido-3'-deoxythymidine, AZT) from individuals with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex were studied to determine the genetic basis of their resistance. Most were sequential isolates obtained at the initiation of and during therapy. Comparative nucleotide sequence analysis of the reverse transcriptase (RT) coding region from five pairs of sensitive and resistant isolates identified three predicted amino acid substitutions common to all the resistant strains (Asp67----Asn, Lys70----Arg, Thr215----Phe or Tyr) plus a fourth in three isolates (Lys219----Gln). Partially resistant isolates had combinations of these four changes. An infectious molecular clone constructed with these four mutations in RT yielded highly resistant HIV after transfection of T cells. The reproducible nature of these mutations should make it possible to develop rapid assays to predict zidovudine resistance by performing polymerase chain reaction amplification of nucleic acid from peripheral blood lymphocytes, thereby circumventing current lengthy HIV isolation and sensitivity testing.


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K. Hertogs, S. Bloor, V. De Vroey, C. van den Eynde, P. Dehertogh, A. van Cauwenberge, M. Stürmer, T. Alcorn, S. Wegner, M. van Houtte, et al. (2000)
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Antimicrob. Agents Chemother. 43, 264-270
   Abstract »    Full Text »
Functional Analysis of Amino Acid Residues Constituting the dNTP Binding Pocket of HIV-1 Reverse Transcriptase.
D. Harris, N. Kaushik, P. K. Pandey, P. N. S. Yadav, and V. N. Pandey (1998)
J. Biol. Chem. 273, 33624-33634
   Abstract »    Full Text »    PDF »
Unblocking of chain-terminated primer by HIV-1 reverse transcriptase through a nucleotide-dependent mechanism.
P. R. Meyer, S. E. Matsuura, A. G. So, and W. A. Scott (1998)
PNAS 95, 13471-13476
   Abstract »    Full Text »    PDF »
Coresistance to Zidovudine and Foscarnet Is Associated with Multiple Mutations in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase.
G. Tachedjian, M. French, and J. Mills (1998)
Antimicrob. Agents Chemother. 42, 3038-3043
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Deoxyribonucleoside Triphosphate Pool Imbalances In Vivo Are Associated with an Increased Retroviral Mutation Rate.
J. G. Julias and V. K. Pathak (1998)
J. Virol. 72, 7941-7949
   Abstract »    Full Text »    PDF »
Dominance of the E89G Substitution in HIV-1 Reverse Transcriptase in Regard to Increased Polymerase Processivity and Patterns of Pausing.
Y. Quan, P. Inouye, C. Liang, L. Rong, M. Gotte, and M. A. Wainberg (1998)
J. Biol. Chem. 273, 21918-21925
   Abstract »    Full Text »    PDF »
3'-Azido-3'-deoxythymidine drug resistance mutations in HIV-1 reverse transcriptase can induce long range conformational changes.
J. Ren, R. M. Esnouf, A. L. Hopkins, E. Y. Jones, I. Kirby, J. Keeling, C. K. Ross, B. A. Larder, D. I. Stuart, and D. K. Stammers (1998)
PNAS 95, 9518-9523
   Abstract »    Full Text »    PDF »
Genotypic and Phenotypic Characterization of Human Immunodeficiency Virus Type 1 Variants Isolated from AIDS Patients after Prolonged Adefovir Dipivoxil Therapy.
A. S. Mulato, P. D. Lamy, M. D. Miller, W.-X. Li, K. E. Anton, N. S. Hellmann, and J. M. Cherrington (1998)
Antimicrob. Agents Chemother. 42, 1620-1628
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Simultaneous vs Sequential Initiation of Therapy With Indinavir, Zidovudine, and Lamivudine for HIV-1 Infection: 100-Week Follow-up.
R. M. Gulick, J. W. Mellors, D. Havlir, J. J. Eron, C. Gonzalez, D. McMahon, L. Jonas, A. Meibohm, D. Holder, W. A. Schleif, et al. (1998)
JAMA 280, 35-41
   Abstract »    Full Text »    PDF »
Public Health Implications of Antiretroviral Therapy and HIV Drug Resistance.
M. A. Wainberg and G. Friedland (1998)
JAMA 279, 1977-1983
   Abstract »    Full Text »    PDF »
Antiretroviral Drug Resistance Testing in Adults With HIV Infection: Implications for Clinical Management.
M. S. Hirsch, B. Conway, R. T. D'Aquila, V. A. Johnson, F. Brun-Vezinet, B. Clotet, L. M. Demeter, S. M. Hammer, D. M. Jacobsen, D. R. Kuritzkes, et al. (1998)
JAMA 279, 1984-1991
   Abstract »    Full Text »    PDF »
Enhanced Binding of Azidothymidine-resistant Human Immunodeficiency Virus 1 Reverse Transcriptase to the 3'-Azido-3'-deoxythymidine 5'-Monophosphate-terminated Primer.
B. Canard, S. R. Sarfati, and C. C. Richardson (1998)
J. Biol. Chem. 273, 14596-14604
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Antiviral Activities of 9-R-2-Phosphonomethoxypropyl Adenine (PMPA) and Bis(isopropyloxymethylcarbonyl)PMPA against Various Drug-Resistant Human Immunodeficiency Virus Strains.
R. V. Srinivas and A. Fridland (1998)
Antimicrob. Agents Chemother. 42, 1484-1487
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3'-Azido-3'-Deoxythymidine (AZT) Mediates Cross-Resistance to Nucleoside Analogs in the Case of AZT-Resistant Human Immunodeficiency Virus Type 1 Variants.
E. J. Arts, M. E. Quinones-Mateu, J. L. Albright, J.-P. Marois, C. Hough, Z. Gu, and M. A. Wainberg (1998)
J. Virol. 72, 4858-4865
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A Novel Polymorphism at Codon 333 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Can Facilitate Dual Resistance to Zidovudine and L-2',3'-Dideoxy-3'-Thiacytidine.
S. D. Kemp, C. Shi, S. Bloor, P. R. Harrigan, J. W. Mellors, and B. A. Larder (1998)
J. Virol. 72, 5093-5098
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Genotypic Changes in Human Immunodeficiency Virus Type 1 Associated with Loss of Suppression of Plasma Viral RNA Levels in Subjects Treated with Ritonavir (Norvir) Monotherapy.
P. S. Eastman, J. Mittler, R. Kelso, C. Gee, E. Boyer, J. Kolberg, M. Urdea, J. M. Leonard, D. W. Norbeck, H. Mo, et al. (1998)
J. Virol. 72, 5154-5164
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Switch to Unusual Amino Acids at Codon 215 of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Gene in Seroconvertors Infected with Zidovudine-Resistant Variants.
S. Yerly, A. Rakik, S. Kinloch De Loes, B. Hirschel, D. Descamps, F. Brun-Vezinet, and L. Perrin (1998)
J. Virol. 72, 3520-3523
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Relative Replicative Fitness of Zidovudine-Resistant Human Immunodeficiency Virus Type 1 Isolates In Vitro.
P. R. Harrigan, S. Bloor, and B. A. Larder (1998)
J. Virol. 72, 3773-3778
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Comparison of Culture- and Non-Culture-Based Methods for Quantification of Viral Load and Resistance to Antiretroviral Drugs in Patients Given Zidovudine Monotherapy.
R. S. Tedder, S. Kaye, C. Loveday, I. V. D. Weller, D. Jeffries, J. Norman, J. Weber, M. Bourelly, R. Foxall, A. Babiker, et al. (1998)
J. Clin. Microbiol. 36, 1056-1063
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1,1,3-Trioxo-2H,4H-Thieno[3,4-e][1,2,4]Thiadiazine (TTD) Derivatives: a New Class of Nonnucleoside Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase Inhibitors with Anti-HIV-1 Activity.
M. Witvrouw, M. E. Arranz, C. Pannecouque, R. Declercq, H. Jonckheere, J.-C. Schmit, A.-M. Vandamme, J. A. Diaz, S. T. Ingate, J. Desmyter, et al. (1998)
Antimicrob. Agents Chemother. 42, 618-623
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A Novel Point Mutation at Position 156 of Reverse Transcriptase from Feline Immunodeficiency Virus Confers Resistance to the Combination of (-)-beta -2',3'-Dideoxy-3'-Thiacytidine and 3'-Azido-3'-Deoxythymidine.
R. A. Smith, K. M. Remington, B. D. Preston, R. F. Schinazi, and T. W. North (1998)
J. Virol. 72, 2335-2340
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A Rapid Method for Simultaneous Detection of Phenotypic Resistance to Inhibitors of Protease and Reverse Transcriptase in Recombinant Human Immunodeficiency Virus Type 1 Isolates from Patients Treated with Antiretroviral Drugs.
K. Hertogs, M.-P. de Béthune, V. Miller, T. Ivens, P. Schel, A. Van Cauwenberge, C. Van den Eynde, V. van Gerwen, H. Azijn, M. van Houtte, et al. (1998)
Antimicrob. Agents Chemother. 42, 269-276
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Correlated Template-Switching Events during Minus-Strand DNA Synthesis: a Mechanism for High Negative Interference during Retroviral Recombination.
J. A. Anderson, R. J. Teufel II, P. D. Yin, and W.-S. Hu (1998)
J. Virol. 72, 1186-1194
   Abstract »    Full Text »    PDF »
Tracking Members of the Simian Immunodeficiency Virus deltaB670 Quasispecies Population In Vivo at Single-Cell Resolution.
T. A. Reinhart, M. J. Rogan, A. M. Amedee, M. Murphey-Corb, D. M. Rausch, L. E. Eiden, and A. T. Haase (1998)
J. Virol. 72, 113-120
   Abstract »    Full Text »    PDF »
Posttranscriptional modification of retroviral primers is required for late stages of DNA replication.
B. P. Burnett and C. S. McHenry (1997)
PNAS 94, 7210-7215
   Abstract »    Full Text »    PDF »


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