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. 1994 Jun;38(6):1404–1407. doi: 10.1128/aac.38.6.1404

Susceptibilities of human immunodeficiency virus type 1 enzyme and viral variants expressing multiple resistance-engendering amino acid substitutions to reserve transcriptase inhibitors.

V W Byrnes 1, E A Emini 1, W A Schleif 1, J H Condra 1, C L Schneider 1, W J Long 1, J A Wolfgang 1, D J Graham 1, L Gotlib 1, A J Schlabach 1, et al.
PMCID: PMC188219  PMID: 7522428

Abstract

To evaluate the potential that multiply resistant human immunodeficiency virus type 1 variants may arise during combination nucleoside and nonnucleoside reverse transcriptase inhibitor therapy, we constructed a series of mutant reverse transcriptase enzymes and viruses that coexpressed various combinations of resistance-associated amino acid substitutions. Substitutions at residues 100 (Leu-->Ile) and 181 (Tyr-->Cys), which mediate resistance to the nonnucleosides, suppressed resistance to 3'-azido-3'-deoxythymidine (AZT) when coexpressed with AZT-specific substitutions. However, a number of viral variants that exhibited significantly reduced susceptibilities to both classes of inhibitors were constructed.

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Selected References

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  1. Bacolla A., Shih C. K., Rose J. M., Piras G., Warren T. C., Grygon C. A., Ingraham R. H., Cousins R. C., Greenwood D. J., Richman D. Amino acid substitutions in HIV-1 reverse transcriptase with corresponding residues from HIV-2. Effect on kinetic constants and inhibition by non-nucleoside analogs. J Biol Chem. 1993 Aug 5;268(22):16571–16577. [PubMed] [Google Scholar]
  2. Balzarini J., Karlsson A., Pérez-Pérez M. J., Camarasa M. J., Tarpley W. G., De Clercq E. Treatment of human immunodeficiency virus type 1 (HIV-1)-infected cells with combinations of HIV-1-specific inhibitors results in a different resistance pattern than does treatment with single-drug therapy. J Virol. 1993 Sep;67(9):5353–5359. doi: 10.1128/jvi.67.9.5353-5359.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Byrnes V. W., Sardana V. V., Schleif W. A., Condra J. H., Waterbury J. A., Wolfgang J. A., Long W. J., Schneider C. L., Schlabach A. J., Wolanski B. S. Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors. Antimicrob Agents Chemother. 1993 Aug;37(8):1576–1579. doi: 10.1128/aac.37.8.1576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Colonno R. J., Condra J. H., Mizutani S., Callahan P. L., Davies M. E., Murcko M. A. Evidence for the direct involvement of the rhinovirus canyon in receptor binding. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5449–5453. doi: 10.1073/pnas.85.15.5449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Condra J. H., Emini E. A., Gotlib L., Graham D. J., Schlabach A. J., Wolfgang J. A., Colonno R. J., Sardana V. V. Identification of the human immunodeficiency virus reverse transcriptase residues that contribute to the activity of diverse nonnucleoside inhibitors. Antimicrob Agents Chemother. 1992 Jul;36(7):1441–1446. doi: 10.1128/aac.36.7.1441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Davey R. T., Jr, Dewar R. L., Reed G. F., Vasudevachari M. B., Polis M. A., Kovacs J. A., Falloon J., Walker R. E., Masur H., Haneiwich S. E. Plasma viremia as a sensitive indicator of the antiretroviral activity of L-697,661. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5608–5612. doi: 10.1073/pnas.90.12.5608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Emini E. A., Graham D. J., Gotlib L., Condra J. H., Byrnes V. W., Schleif W. A. HIV and multidrug resistance. Nature. 1993 Aug 19;364(6439):679–679. doi: 10.1038/364679b0. [DOI] [PubMed] [Google Scholar]
  8. Goldman M. E., Nunberg J. H., O'Brien J. A., Quintero J. C., Schleif W. A., Freund K. F., Gaul S. L., Saari W. S., Wai J. S., Hoffman J. M. Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6863–6867. doi: 10.1073/pnas.88.15.6863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Higuchi R., Krummel B., Saiki R. K. A general method of in vitro preparation and specific mutagenesis of DNA fragments: study of protein and DNA interactions. Nucleic Acids Res. 1988 Aug 11;16(15):7351–7367. doi: 10.1093/nar/16.15.7351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Larder B. A. 3'-Azido-3'-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. 1992 Dec;36(12):2664–2669. doi: 10.1128/aac.36.12.2664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Larder B. A., Kellam P., Kemp S. D. Convergent combination therapy can select viable multidrug-resistant HIV-1 in vitro. Nature. 1993 Sep 30;365(6445):451–453. doi: 10.1038/365451a0. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Mellors J. W., Im G. J., Tramontano E., Winkler S. R., Medina D. J., Dutschman G. E., Bazmi H. Z., Piras G., Gonzalez C. J., Cheng Y. C. A single conservative amino acid substitution in the reverse transcriptase of human immunodeficiency virus-1 confers resistance to (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5, 1- jk][1,4]benzodiazepin-2(1H)-thione (TIBO R82150). Mol Pharmacol. 1993 Jan;43(1):11–16. [PubMed] [Google Scholar]
  16. Merluzzi V. J., Hargrave K. D., Labadia M., Grozinger K., Skoog M., Wu J. C., Shih C. K., Eckner K., Hattox S., Adams J. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science. 1990 Dec 7;250(4986):1411–1413. doi: 10.1126/science.1701568. [DOI] [PubMed] [Google Scholar]
  17. Mitsuya H., Broder S. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1911–1915. doi: 10.1073/pnas.83.6.1911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mitsuya H., Weinhold K. J., Furman P. A., St Clair M. H., Lehrman S. N., Gallo R. C., Bolognesi D., Barry D. W., Broder S. 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7096–7100. doi: 10.1073/pnas.82.20.7096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Richman D. D., Havlir D., Corbeil J., Looney D., Ignacio C., Spector S. A., Sullivan J., Cheeseman S., Barringer K., Pauletti D. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol. 1994 Mar;68(3):1660–1666. doi: 10.1128/jvi.68.3.1660-1666.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Richman D., Shih C. K., Lowy I., Rose J., Prodanovich P., Goff S., Griffin J. Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11241–11245. doi: 10.1073/pnas.88.24.11241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Saag M. S., Emini E. A., Laskin O. L., Douglas J., Lapidus W. I., Schleif W. A., Whitley R. J., Hildebrand C., Byrnes V. W., Kappes J. C. A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. L-697,661 Working Group. N Engl J Med. 1993 Oct 7;329(15):1065–1072. doi: 10.1056/NEJM199310073291502. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Shih C. K., Rose J. M., Hansen G. L., Wu J. C., Bacolla A., Griffin J. A. Chimeric human immunodeficiency virus type 1/type 2 reverse transcriptases display reversed sensitivity to nonnucleoside analog inhibitors. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9878–9882. doi: 10.1073/pnas.88.21.9878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Tisdale M., Kemp S. D., Parry N. R., Larder B. A. Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3'-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5653–5656. doi: 10.1073/pnas.90.12.5653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. White E. L., Buckheit R. W., Jr, Ross L. J., Germany J. M., Andries K., Pauwels R., Janssen P. A., Shannon W. M., Chirigos M. A. A TIBO derivative, R82913, is a potent inhibitor of HIV-1 reverse transcriptase with heteropolymer templates. Antiviral Res. 1991 Oct;16(3):257–266. doi: 10.1016/0166-3542(91)90005-c. [DOI] [PubMed] [Google Scholar]

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