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Science 31 March 1989:
Vol. 243. no. 4899, pp. 1731 - 1734
DOI: 10.1126/science.2467383
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Articles

Science, Vol 243, Issue 4899, 1731-1734
Copyright © 1989 by American Association for the Advancement of Science

articles

HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy

BA Larder, G Darby, and DD Richman

Molecular Sciences, Wellcome Research Laboratories, Beckenham, Kent BR3 3BS, United Kingdon.

The drug sensitivities of human immunodeficiency virus (HIV) isolates from a group of patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) who were receiving zidovudine (3'-azido-3'-deoythymidine, AZT) therapy were tested by means of a newly developed plaque assay in CD4+ HeLa cells. Fifty percent inhibitory dose (ID50) values of 18 isolates from untreated individuals ranged between 0.01 microM and 0.05 microM. In contrast, most isolates from patients who had received zidovudine for 6 months or more exhibited decreased sensitivity characterized by changes in ID50 or ID95 values (or both), with isolates from several patients (5/15) showing 100-fold increases in ID50. The latter isolates were also insensitive to 3'-azido-2',3'-dideoxyuridine; however, the isolates were still sensitive to 2',3'-dideoxycytidine, 2',3'-dideoxy-2',3'-didehydrothymidine, or phosphonoformate. It cannot be determined from this small sample of patients whether development of a less sensitive virus phenotype results in clinical resistance. Appearance of such variants was not associated with a consistent increase in viral p24 concentrations in patient plasma and did not herald any sudden deterioration in clinical status. More extensive studies are required to determine the clinical significance. Thus, it would be premature to alter any treatment protocols for HIV-infected individuals at present.


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JAMA 281, 2169-2170
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Structure of a Covalently Trapped Catalytic Complex of HIV-1 Reverse Transcriptase: Implications for Drug Resistance.
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Coresistance to Zidovudine and Foscarnet Is Associated with Multiple Mutations in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase.
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J. Virol. 72, 7941-7949
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D. Tewari, S. L. Goldstein, A. L. Notkins, and P. Zhou (1998)
J. Immunol. 161, 2642-2647
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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
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Human Immunodeficiency Virus Type 1 Reverse Transcriptase Expressing the K70E Mutation Exhibits a Decrease in Specific Activity and Processivity.
M. D. Miller, P. D. Lamy, M. D. Fuller, A. S. Mulato, N. A. Margot, T. Cihlar, and J. M. Cherrington (1998)
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Antimicrob. Agents Chemother. 42, 1620-1628
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Antimicrob. Agents Chemother. 42, 1788-1793
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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
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Public Health Implications of Antiretroviral Therapy and HIV Drug Resistance.
M. A. Wainberg and G. Friedland (1998)
JAMA 279, 1977-1983
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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
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Drug-Resistant HIV-1: The Virus Strikes Back.
D. L. Mayers (1998)
JAMA 279, 2000-2002
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Role of p38 mitogen-activated protein kinase in HIV type 1 production in vitro.
L. Shapiro, K. A. Heidenreich, M. K. Meintzer, and C. A. Dinarello (1998)
PNAS 95, 7422-7426
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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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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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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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Stability of Human Immunodeficiency Virus RNA in Blood Specimens as Measured by a Commercial PCR-Based Assay.
K. Sebire, K. McGavin, S. Land, T. Middleton, and C. Birch (1998)
J. Clin. Microbiol. 36, 493-498
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Cells Transfected with a Non-Neutralizing Antibody Gene Are Resistant to HIV Infection: Targeting the Endoplasmic Reticulum and Trans-Golgi Network.
P. Zhou, S. Goldstein, K. Devadas, D. Tewari, and A. L. Notkins (1998)
J. Immunol. 160, 1489-1496
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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
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Metabolism of the HIV-1 Reverse Transcriptase Inhibitor Delavirdine In Mice.
M. Chang, V. K. Sood, G. J. Wilson, D. A. Kloosterman, P. E. Sanders, M. J. Hauer, W. Zhang, and D. G. Branstetter (1997)
Drug Metab. Dispos. 25, 828-839
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Virus dynamics and drug therapy.
S. Bonhoeffer, R. M. May, G. M. Shaw, and M. A. Nowak (1997)
PNAS 94, 6971-6976
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Human Immunodeficiency Virus Type 1 Protease Inhibitors.
C. K. McDonald and D. R. Kuritzkes (1997)
Arch Intern Med 157, 951-959
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Metabolism of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitor Delavirdine in Rats.
M. Chang, V. K. Sood, G. J. Wilson, D. A. Kloosterman, P. E. Sanders, M. J. Hauer, and P. E. Fagerness (1997)
Drug Metab. Dispos. 25, 228-242
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Duration of the Survival Benefit of Zidovudine Therapy in HIV Infection.
R. D. Moore, J. C. Keruly, and R. E. Chaisson (1996)
Arch Intern Med 156, 1073-1077
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A. C. Collier, R. W. Coombs, D. A. Schoenfeld, R. L. Bassett, J. Timpone, A. Baruch, M. Jones, K. Facey, C. Whitacre, V. J. McAuliffe, et al. (1996)
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   Abstract »    PDF »
Treatment with Lamivudine, Zidovudine, or Both in HIV-Positive Patients with 200 to 500 CD4+ Cells per Cubic Millimeter.
J. J. Eron, S. L. Benoit, J. Jemsek, R. D. MacArthur, J. Santana, J. B. Quinn, D. R. Kuritzkes, M. A. Fallon, M. Rubin, and The North American HIV Working Party (1995)
N. Engl. J. Med. 333, 1662-1669
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A Quarter-Century of Antiviral Therapy.
T. C. Merigan (1995)
N. Engl. J. Med. 333, 1704-1705
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A Controlled Trial of Zidovudine in Primary Human Immunodeficiency Virus Infection.
S. Kinloch-de Loes, B. J. Hirschel, B. Hoen, D. A. Cooper, B. Tindall, A. Carr, J.-H. Saurat, N. Clumeck, A. Lazzarin, L. Mathiesen, et al. (1995)
N. Engl. J. Med. 333, 408-413
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Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy.
B. Larder, S. Kemp, and P. Harrigan (1995)
Science 269, 696-699
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Synthesis of a Photoaffinity Analog of 3`-Azidothymidine, 5-Azido-3`-azido-2`,3`-dideoxyuridine.
F. Mao, T. M. Rechtin, R. Jones, A. A. Cantu, L. S. Anderson, A. Radominska, M. P. Moyer, and R. R. Drake (1995)
J. Biol. Chem. 270, 13660-13664
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Zidovudine Compared With Didanosine in Patients With Advanced HIV Type I Infection and Little or No Previous Experience With Zidovudine.
R. Dolin, D. A. Amato, M. A. Fischl, C. Pettinelli, M. Beltangady, S.-h. Liou, M. J. Brown, A. P. Cross, M. S. Hirsch, W. D. Hardy, et al. (1995)
Arch Intern Med 155, 961-974
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Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors.
R. Spence, W. Kati, K. Anderson, and K. Johnson (1995)
Science 267, 988-993
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Structures of ternary complexes of rat DNA polymerase beta, a DNA template-primer, and ddCTP.
H Pelletier, M. Sawaya, A Kumar, S. Wilson, and J Kraut (1994)
Science 264, 1891-1903
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Evaluation of the Quality of Life Associated with Zidovudine Treatment in Asymptomatic Human Immunodeficiency Virus Infection.
W. R. Lenderking, R. D. Gelber, D. J. Cotton, B. F. Cole, A. Goldhirsch, P. A. Volberding, M. A. Testa, and The AIDS Clinical Trials Group (1994)
N. Engl. J. Med. 330, 738-743
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A Short-Term Clinical Evaluation of L-697,661, a Non-Nucleoside Inhibitor of HIV-1 Reverse Transcriptase.
M. S. Saag, E. A. Emini, O. L. Laskin, J. Douglas, W. I. Lapidus, W. A. Schleif, R. J. Whitley, C. Hildebrand, V. W. Byrnes, J. C. Kappes, et al. (1993)
N. Engl. J. Med. 329, 1065-1072
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Combination Ganciclovir and Foscarnet in the Treatment of Clinically Resistant Cytomegalovirus Retinitis in Patients With Acquired Immunodeficiency Syndrome.
B. D. Kuppermann, M. Flores-Aguilar, J. I. Quiceno, L. S. Rickman, and W. R. Freeman (1993)
Arch Ophthalmol 111, 1359-1366
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Preventive Services Guidelines for Primary Care Clinicians Caring for Adults and Adolescents Infected With the Human Immunodeficiency Virus.
A. R. Gerber, R. O. Valdiserri, D. R. Holtgrave, T. S. Jones, G. R. West, A. R. Hinman, and J. W. Curran (1993)
Arch Fam Med 2, 969-979
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Therapy for Human Immunodeficiency Virus Infection.
M. S. Hirsch and R. T. D'Aquila (1993)
N. Engl. J. Med. 328, 1686-1695
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Present status and future prospects for HIV therapies.
M. Johnston and D. Hoth (1993)
Science 260, 1286-1293
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Primary Infection with Zidovudine-Resistant Human Immunodeficiency Virus Type 1.
A. Erice, D. L. Mayers, D. G. Strike, K. J. Sannerud, F. E. McCutchan, K. Henry, and H. H. Balfour (1993)
N. Engl. J. Med. 328, 1163-1165
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In-Vitro Resistance to Zidovudine and Alpha-interferon in HIV-1 Isolates from Patients: Correlations with Treatment Duration and Response.
B. R. Edlin, M. H. St. Clair, P.M. Pitha, S. M. Whaling, D. M. King, J. D. Bitran, and R. A. Weinstein (1992)
Ann Intern Med 117, 457-460
   Abstract »    PDF »
Zidovudine: Five Years Later.
G. X. McLeod and S. M. Hammer (1992)
Ann Intern Med 117, 487-501
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Molecular Epidemiology of HIV Transmission in a Dental Practice.
C.-Y. Ou, C. A. Ciesielski, G. Myers, C. I. Bandea, C.-C. Luo, B. T. M. Korber, J. I. Mullins, G. Schochetman, R. L. Berkelman, A. N. Economou, et al. (1992)
Science 256, 1165-1171
   Abstract »    PDF »
Quantitative RNA and DNA gene amplification can rapidly monitor HIV infection and antiviral activity in cell cultures..
M A Winters, M Holodniy, D A Katzenstein, and T C Merigan (1992)
Genome Res. 1, 257-262
   Abstract »    PDF »
Relationship between Dideoxyinosine Exposure, CD4 Counts, and p24 Antigen Levels in Human Immunodeficiency Virus Infection: A Phase I Trial.
G. L. Drusano, G. J. Yuen, J. S. Lambert, M. Seidlin, R. Dolin, and F. T. Valentine (1992)
Ann Intern Med 116, 562-566
   Abstract »    PDF »
Antiretroviral Chemotherapy of Human Immunodeficiency Virus Infections Other Than With Azidothymidine.
M. K. Sachs (1992)
Arch Intern Med 152, 485-501
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