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. 1993 Jun;37(6):1390–1392. doi: 10.1128/aac.37.6.1390

The same mutation that encodes low-level human immunodeficiency virus type 1 resistance to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine confers high-level resistance to the (-) enantiomer of 2',3'-dideoxy-3'-thiacytidine.

Q Gao 1, Z Gu 1, M A Parniak 1, J Cameron 1, N Cammack 1, C Boucher 1, M A Wainberg 1
PMCID: PMC187976  PMID: 8392313

Abstract

Variants of human immunodeficiency virus type 1 that display 500- to 1,000-fold resistance to the (-) enantiomer of 2'-deoxy-3'-thiacytidine and approximately 4- to 8-fold resistance to 2',3'-dideoxycytidine and 2',3'-dideoxyinosine have been generated through in vitro selection with the former compound. The polymerase regions of several of these resistant viruses shared a codon alteration at site 184 (ATG-->GTG; methionine-->valine), a mutation previously associated with low-level resistance to 2',3'-dideoxycytidine. The biological relevance of this mutation for the (-) enantiomer of 2'-deoxy-3'-thiacytidine was confirmed by site-directed mutagenesis with the HXB2-D clone of human immunodeficiency virus type 1.

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Selected References

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  1. Coates J. A., Cammack N., Jenkinson H. J., Mutton I. M., Pearson B. A., Storer R., Cameron J. M., Penn C. R. The separated enantiomers of 2'-deoxy-3'-thiacytidine (BCH 189) both inhibit human immunodeficiency virus replication in vitro. Antimicrob Agents Chemother. 1992 Jan;36(1):202–205. doi: 10.1128/aac.36.1.202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Fisher A. G., Collalti E., Ratner L., Gallo R. C., Wong-Staal F. A molecular clone of HTLV-III with biological activity. Nature. 1985 Jul 18;316(6025):262–265. doi: 10.1038/316262a0. [DOI] [PubMed] [Google Scholar]
  3. Gao Q., Gu Z. X., Parniak M. A., Li X. G., Wainberg M. A. In vitro selection of variants of human immunodeficiency virus type 1 resistant to 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine. J Virol. 1992 Jan;66(1):12–19. doi: 10.1128/jvi.66.1.12-19.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gao Q., Gu Z., Hiscott J., Dionne G., Wainberg M. A. Generation of drug-resistant variants of human immunodeficiency virus type 1 by in vitro passage in increasing concentrations of 2',3'-dideoxycytidine and 2',3'-dideoxy-3'-thiacytidine. Antimicrob Agents Chemother. 1993 Jan;37(1):130–133. doi: 10.1128/aac.37.1.130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gu Z., Gao Q., Li X., Parniak M. A., Wainberg M. A. Novel mutation in the human immunodeficiency virus type 1 reverse transcriptase gene that encodes cross-resistance to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine. J Virol. 1992 Dec;66(12):7128–7135. doi: 10.1128/jvi.66.12.7128-7135.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Kellam P., Boucher C. A., Larder B. A. Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1934–1938. doi: 10.1073/pnas.89.5.1934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Larder B. A., Darby G., Richman D. D. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989 Mar 31;243(4899):1731–1734. doi: 10.1126/science.2467383. [DOI] [PubMed] [Google Scholar]
  8. Larder B. A., Kemp S. D. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science. 1989 Dec 1;246(4934):1155–1158. doi: 10.1126/science.2479983. [DOI] [PubMed] [Google Scholar]
  9. Larder B. A., Kemp S. D., Purifoy D. J. Infectious potential of human immunodeficiency virus type 1 reverse transcriptase mutants with altered inhibitor sensitivity. Proc Natl Acad Sci U S A. 1989 Jul;86(13):4803–4807. doi: 10.1073/pnas.86.13.4803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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. Viral resistance to human immunodeficiency virus type 1-specific pyridinone reverse transcriptase inhibitors. J Virol. 1991 Sep;65(9):4887–4892. doi: 10.1128/jvi.65.9.4887-4892.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Prasad V. R., Lowy I., de los Santos T., Chiang L., Goff S. P. Isolation and characterization of a dideoxyguanosine triphosphate-resistant mutant of human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11363–11367. doi: 10.1073/pnas.88.24.11363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Preston B. D., Poiesz B. J., Loeb L. A. Fidelity of HIV-1 reverse transcriptase. Science. 1988 Nov 25;242(4882):1168–1171. doi: 10.1126/science.2460924. [DOI] [PubMed] [Google Scholar]
  13. Rooke R., Tremblay M., Soudeyns H., DeStephano L., Yao X. J., Fanning M., Montaner J. S., O'Shaughnessy M., Gelmon K., Tsoukas C. Isolation of drug-resistant variants of HIV-1 from patients on long-term zidovudine therapy. Canadian Zidovudine Multi-Centre Study Group. AIDS. 1989 Jul;3(7):411–415. doi: 10.1097/00002030-198907000-00001. [DOI] [PubMed] [Google Scholar]
  14. Sardana V. V., Emini E. A., Gotlib L., Graham D. J., Lineberger D. W., Long W. J., Schlabach A. J., Wolfgang J. A., Condra J. H. Functional analysis of HIV-1 reverse transcriptase amino acids involved in resistance to multiple nonnucleoside inhibitors. J Biol Chem. 1992 Sep 5;267(25):17526–17530. [PubMed] [Google Scholar]
  15. Schinazi R. F., Chu C. K., Peck A., McMillan A., Mathis R., Cannon D., Jeong L. S., Beach J. W., Choi W. B., Yeola S. Activities of the four optical isomers of 2',3'-dideoxy-3'-thiacytidine (BCH-189) against human immunodeficiency virus type 1 in human lymphocytes. Antimicrob Agents Chemother. 1992 Mar;36(3):672–676. doi: 10.1128/aac.36.3.672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Schinazi R. F., Lloyd R. M., Jr, Nguyen M. H., Cannon D. L., McMillan A., Ilksoy N., Chu C. K., Liotta D. C., Bazmi H. Z., Mellors J. W. Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. Antimicrob Agents Chemother. 1993 Apr;37(4):875–881. doi: 10.1128/aac.37.4.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Soudeyns H., Yao X. I., Gao Q., Belleau B., Kraus J. L., Nguyen-Ba N., Spira B., Wainberg M. A. Anti-human immunodeficiency virus type 1 activity and in vitro toxicity of 2'-deoxy-3'-thiacytidine (BCH-189), a novel heterocyclic nucleoside analog. Antimicrob Agents Chemother. 1991 Jul;35(7):1386–1390. doi: 10.1128/aac.35.7.1386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. St Clair M. H., Martin J. L., Tudor-Williams G., Bach M. C., Vavro C. L., King D. M., Kellam P., Kemp S. D., Larder B. A. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science. 1991 Sep 27;253(5027):1557–1559. doi: 10.1126/science.1716788. [DOI] [PubMed] [Google Scholar]

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