1887

Abstract

High level resistance to 3′-azido-3′-deoxythymidine (AZT, zidovudine or Retrovir) is conferred by the presence of four or five mutations (Met-41→ Leu; Asp- 67→Asn; Lys-70→ Arg; Thr-215→Tyr or Phe; Lys- 219→Gin) in the human immunodeficiency virus (HIV) reverse transcriptase. The order of appearance of these five mutations in asymptomatic patients during therapy has been studied. This has enabled us to propose a model for the acquisition of zidovudine resistance mutations during the treatment of high-risk asymptomatic HIV-infected individuals. A consistent acquisition pattern of mutations at codons 41, 70 and 215 was observed in 17 individuals. Complex mixtures of HIV species containing different combinations of single and linked double resistance mutations were present early in zidovudine therapy in isolates from two patients studied in detail. From these mixtures the linked Leu-41/Tyr- 215 genotype outgrew all others initially. The development of each new virus population is likely to be mediated primarily by the increase in the level of drug resistance rather than changes in the growth kinetics of the virus. This leads us to conclude that one major driving force in the outgrowth of different mutant viruses is the selective advantage conferred by higher levels of drug resistance.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-75-2-341
1994-02-01
2024-12-03
Loading full text...

Full text loading...

/deliver/fulltext/jgv/75/2/JV0750020341.html?itemId=/content/journal/jgv/10.1099/0022-1317-75-2-341&mimeType=html&fmt=ahah

References

  1. Albert J., Wahlberg J., Lundeberg J., Cox S., Sandstrom E., Wahren B., Uhlen M. 1992; Persistence of azidothymidine- resistant human immunodeficiency virus type 1 RNA genotypes in posttreatment sera. Journal of Virology 66:5627–5630
    [Google Scholar]
  2. Beemon K., Duesberg P., Vogt P. 1974; Evidence for crossing-over between avian tumor viruses based on analysis of viral RNAs. Proceedings of the National Academy of Sciences, U.S.A 714254–4258
    [Google Scholar]
  3. Blair D. G. 1977; Genetic recombination between avian leukosis and sarcoma viruses. Experimental variables and the frequencies of recombination. Virology 77:534–544
    [Google Scholar]
  4. Boucher C. A. B., Tersmette M., Lange J. M. A., Kellam P., Degoede R. E. Y., Mulder J. W., Darby G., Goudsmit J., Larder B. A. 1990; Zidovudine sensitivity of human immuno-deficiency virus from high-risk, symptom free individuals during therapy. Lancet 336:585–589
    [Google Scholar]
  5. Boucher C. A. B., O’Sullivan E., Mulder J. W., Ramautarsing C., Kellam P., Darby G., Lange J. M. A., Goudsmit J., Larder B. A. 1992a; Ordered appearance of zidovudine resistant mutations during treatment of 18 human immunodeficiency virus positive subjects. Journal of Infectious Diseases 165:105–110
    [Google Scholar]
  6. Boucher C. A. B., Lange J. M. A., Miedema F. F., Weverling G. J., Koot M., Mulder J. W., Goudsmit J., Kellam P., Larder B. A., Tersmette M. 1992b; HIV-1 biological phenotype and the development of zidovudine resistance in relation to disease progression in asymptomatic individuals during treatment. AIDS 6:1259–1264
    [Google Scholar]
  7. Boucher C. A. B., Van Leeuwen R., Kellam P., Schipper P., Tijnagel J., Lange J. M. A., Larder B. A. 1993; Effects of discontinuation of zidovudine treatment on the zidovudine sensitivity of human immunodeficiency virus type 1 isolates. Antimicrobial Agents and Chemotherapy 37:1525–1530
    [Google Scholar]
  8. Chesebro B., Wehrly K. 1988; Development of a sensitive quantitative focal assay for human immunodeficiency virus in- fectivity. Journal of Virology 62:3779–3788
    [Google Scholar]
  9. Delassus S., Cheyneir R., Wain Hobson S. 1991; Evolution of human immunodeficiency virus type 1 nef and long terminal repeat sequences over 4 years in vitro and in vivo. Journal of Virologv 65:225–231
    [Google Scholar]
  10. Fitzgibbon J. E., Howell R. M., Haberzettl C. A., Sperber S. J., Gocke D. J., Dubin D. T. 1992; Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2′-,3′-dideoxycytidine. Antimicrobial Agents and Chemotherapy 36:153–157
    [Google Scholar]
  11. Gingeras T. R., Prodanovich P., Latimer T., Guatelli S. C., Richman D. D., Barringer K. J. 1991; Use of the selfsustained sequence replication amplification reaction to analyse and detect mutations in zidovudine-resistant human immunodeficiency virus. Journal of Infectious Diseases 164:1066–1074
    [Google Scholar]
  12. Goodenow M., Huet T., Saurin W., Kwok S., Sninsky J., Wainhobson S. 1989; HIV-1 isolates are rapidly evolving quasispecies: evidence for viral mixtures and preferred nucleotide substitutions. Journal of Acquired Immune Deficiency Syndromes 2:344–352
    [Google Scholar]
  13. Harada S., Kovanaoi Y., Yamamoto N. 1985; Infection of HTLV-III/LAV in HTLV-I carrying cells MT-2 and MT-4 and application in a plaque assay. Science 229:563–566
    [Google Scholar]
  14. Hu W. S., Temin H. M. 1990; Genetic consequences of packaging two RNA genomes in one retroviral particle: pseudodiploidy and high rate of genetic recombination. Proceedings of the National Academy of Sciences, U.S.A 871556–1560
    [Google Scholar]
  15. Japour A. J., Chatis P. A., Eigenrauch H. A., Crumpacker C. S. 1991; Detection of human immunodeficiency virus type 1 clinical isolates with reduced sensitivity to zidovudine and dideoxy-inosine by RNA:RNA hybridization. Proceedings of the National Academy of Sciences, U.S.A 883092–3096
    [Google Scholar]
  16. Kellam P., Boucher C. A. B., Larder B. A. 1992; Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. Proceedings of the National Academy of Sciences, U.S.A 891934–1938
    [Google Scholar]
  17. Koot M., Vos A. H. V., Keet R. P. M., Degoede R. E. Y., Dercksen M. W., Terpstra F. G., Coutinho R. A., Miedema F., Tersmette M. 1992; HIV-1 biological phenotype in long term infected individuals evaluated with an MT-2 cocultivation assay. AIDS 6:49–54
    [Google Scholar]
  18. Land S., Treloaer G., Mcphee D., Birch C., Dohert R., Cooper D., Gust I. 1990; Decreased in vitro susceptibility to zidovudine of HIV isolates obtained from patients with AIDS. Journal of Infectious Diseases 161:326–329
    [Google Scholar]
  19. Land S, Mcgavin K., Birch C., Lucas R. 1991; Reversion from zidovudine resistance to sensitivity on cessation of treatment. Lancet 338:830–831
    [Google Scholar]
  20. Larder B. A. 1992; 3′-Azido-3′-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors. Antimicrobial Agents and Chemotherapy 36:2664–2669
    [Google Scholar]
  21. Larder B. A., Kemp S. D. 1989; Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science 246:1155–1158
    [Google Scholar]
  22. Larder B. A., Darby G., Richman D. D. 1989; HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243:1731–1734
    [Google Scholar]
  23. Larder B. A., Chesebro B., Richman D. D. 1990; Susceptibilities of zidovudine-susceptible and -resistant human immunodeficiency virus isolates to antiviral agents determined by using a quantitative plaque reduction assay. Antimicrobial Agents and Chemotherapy 34:436–441
    [Google Scholar]
  24. Larder B. A., Kellam P., Kemp S. D. 1991; Zidovudine resistance predicted by direct detection of mutations in DNA from HIV-infected lymphocytes. AIDS 5:137–144
    [Google Scholar]
  25. Linial M., Blair D. 1982; Genetics of retroviruses. In RNA Tumor Viruses pp. 649–783 Weiss R., Teich N., Varmus H., Coffin J. Edited by New York: Cold Spring Harbor Laboratory;
    [Google Scholar]
  26. Meyerhans A., Cheynier R., Albert J., Seth M., Kwok S., Sninsky J., Morfeldt-Manson L., Asjo B., Wain Hobson S. 1989; Temporal fluctuations in HIV quasispecies in vivo are not reflected by sequential HIV isolates. Cell 58:901–910
    [Google Scholar]
  27. Meyerhans A., Vartanian J. -P., Wain Hobson S. 1990; DNA recombination during PCR. Nucleic Acids Research 18:1687–1691
    [Google Scholar]
  28. Nunberg J. H., Schleif W. A., Boots E. J., O’Brien J. A., Quintero J. C., Hoffman J. M., Emini E. A., Goldman M. E. 1991; Viral resistance to human immunodeficiency virus type-1 specific pyridinone reverse transcriptase inhibitors. Journal of Virology 65:4887–4892
    [Google Scholar]
  29. Pedroza Martins L., Chenciner N., Asjo B., Meyerhans A., Wain Hobson S. 1991; Independent fluctuation of human immunodeficiency virus type 1 rev and gp41 quasispecies in vivo. Journal of Virology 65:4502–4507
    [Google Scholar]
  30. Perno C. -F., Yarchoan R., Balzarini J., Bergamini A., Milanese G., Pauwels R., Declercq E., Rocchi G., Calio R. 1992; Different pattern of activity of inhibitors of human immuno-deficiency virus in lymphocytes and monocyte/macrophages. Antiviral Research 17:289–304
    [Google Scholar]
  31. Richman D. D., Grimes J. M., Lagakos S. W. 1990; Effect of stage of disease and drug dose on zidovudine susceptibilities of isolates of human immunodeficiency virus. Journal of Acquired Immune Deficiency Syndromes 3:743–746
    [Google Scholar]
  32. Richman D. D., Shih C. K., Lowy I., Rose J., Prodanovich P., Goff S., Griffin J. 1991a; Human immunodeficiency virus type 1 mutants resistant to non-nucleoside inhibitors of reverse transcriptase arise in tissue culture. Proceedings of the National Academy of Sciences, U.S.A 8811241–11243
    [Google Scholar]
  33. Richman D. D., Guatelli J. C., Grimes J., Tstat A., Gingeras T. 1991b; Detection of mutants associated with zidovudine resistance in human immunodeficiency virus by use of the polymerase chain reaction. Journal of Infectious Diseases 164:1075–1081
    [Google Scholar]
  34. Rocancourt D., Bonnerot C., Jouin H., Emerman M., Nicolas J. -F. 1990; Activation of a β-galactosidose recombinant provirus: application to titration of human immunodeficiency virus (HIV) and HIV-infected cells. Journal of Virology 64:2660–2668
    [Google Scholar]
  35. Rooke R., Tremblay M., Soudeynes H., Destephano L., Yao X. -J., Fanning M., Montaner J. S. G., O’Shaughnessy M., Gelman K., Tsoukas C., Gill J., Ruedy J., Wainberg M. A. 1989; Isolation of drug-resistant variants of HIV-1 from patients on long term zidovudine therapy. AIDS 3:411–415
    [Google Scholar]
  36. Salahuddin S. Z., Markham P. D., Wong-Staal F., Franchini G., Kalyanaraman V. S., Gallo R. C. 1983; Restricted expression of human T-cell leukemia-lymphoma virus (HTLV) in transformed human umbilical cord blood lymphocytes. Virology 129:51–64
    [Google Scholar]
  37. Sanger F., Nicklen S., Coulson A. R. 1977; DNA sequencing with chain-terminating inhibitors. Proceedings of the National Academy of Sciences, U.S.A 745463–5467
    [Google Scholar]
  38. Schuitemaker H., Kootstra N. A., De Goede F., De Wolf F., Miedema F., Tersmette M. 1990; Monocytotropic human immunodeficiency virus 1 (HIV-1) variants detectable in all stages of HIV infection are predominantly lacking T-cell line tropism and syncytium-inducing ability in primary T-cell culture. Journal of Virology 65:356–363
    [Google Scholar]
  39. Schuurman R., Keulen W. 1990; Modified protocol for DNA sequence analysis using Sequenase 2.0. Biotechniques 11:185
    [Google Scholar]
  40. Sheehy N., Desselberger U. 1993; Sequence analysis of reverse transcriptase genes of zidovudine (AZT)-resistant and -sensitive human immunodeficiency virus type 1 strains. Journal of General Virology 74:223–228
    [Google Scholar]
  41. Shenpang H., Akashi V., O’Brien W. A., Chen I. S. Y. 1991; HIV-1 env sequence variation in brain tissue of patients with AIDS related neurologic disease. Journal of Acquired Immune Deficiency Syndromes 4:1082–1092
    [Google Scholar]
  42. Simmonds P., Zhang L. Q., Mcomish F., Balfe P., Ludlam C. A., Leigh-Brown A. J. 1991; Discontinuous sequence change of human immunodeficiency virus (HIV) type 1 env sequences in the plasma viral and lymphocyte associated proviral populations in vivo: implications for models of HIV pathogenesis. Journal of Virology 65:6266–6276
    [Google Scholar]
  43. Stclair M. H., Martin J. L., Tudor-William G., Bach M. C., Vavro C. L., King D. M., Kellam P., Kemp S. D., Larder B. A. 1991; Resistance of ddl and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 253:1557–1559
    [Google Scholar]
  44. Tersmette M., Lange J. M. A., De Goede R. E. Y., De Wolf F., Beftink-Schattenkerk J. K. M., Schellekens P. T. W. A., Coutinho R. A., Huisman J. G., Goudsmit J., Miedema F. 1989; Association between biological properties of human immunodeficiency virus variants and risk for AIDS and AIDS mortality. Lancet i:983–985
    [Google Scholar]
  45. Zoller M. J., Smith M. 1984; Oligonucleotide-directed mutagenesis: a simple method using two oligonucleotide primers and a single-stranded DNA template. DNA 3:479–488
    [Google Scholar]
/content/journal/jgv/10.1099/0022-1317-75-2-341
Loading
/content/journal/jgv/10.1099/0022-1317-75-2-341
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error