• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jvirolPermissionsJournals.ASM.orgJournalJV ArticleJournal InfoAuthorsReviewers
J Virol. Mar 1994; 68(3): 1660–1666.
PMCID: PMC236624

Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy.

Abstract

Drug susceptibility and mutations in the reverse transcriptase (RT) gene were analyzed with 167 virus isolates from 38 patients treated with nevirapine, a potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) RT. Resistant isolates emerged quickly and uniformly in all patients administered nevirapine either as monotherapy or in combination with zidovudine (AZT). Resistance developed as early as 1 week, indicating rapid turnover of the virus population. The development of resistance was associated with the loss of antiviral drug activity as measured by CD4 lymphocyte counts and levels of HIV p24 antigen and RNA in serum. In addition to mutations at amino acid residues 103, 106, and 181 that had been identified by selection in cell culture, mutations at residues 108, 188, and 190 were also found in the patient isolates. Sequences from patient clones documented cocirculating mixtures of populations of different mutants. The most common mutation with monotherapy, tyrosine to cysteine at residue 181, was prevented from emerging by coadministration of AZT, which resulted in the selection of alternative mutations. The observations documented that, under selective drug pressure, the circulating virus population can change rapidly, and many alternative mutants can emerge, often in complex mixtures. The addition of a second RT inhibitor, AZT, significantly altered the pattern of mutations in the circulating population of HIV.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Bacolla A, Shih CK, Rose JM, Piras G, Warren TC, Grygon CA, Ingraham RH, Cousins RC, Greenwood DJ, Richman D, et al. 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]
  • Balzarini J, Karlsson A, Pérez-Pérez MJ, Camarasa MJ, Tarpley WG, 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. [PMC free article] [PubMed]
  • Byrnes VW, Sardana VV, Schleif WA, Condra JH, Waterbury JA, Wolfgang JA, Long WJ, Schneider CL, Schlabach AJ, Wolanski BS, et al. 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. [PMC free article] [PubMed]
  • Cheeseman SH, Hattox SE, McLaughlin MM, Koup RA, Andrews C, Bova CA, Pav JW, Roy T, Sullivan JL, Keirns JJ. Pharmacokinetics of nevirapine: initial single-rising-dose study in humans. Antimicrob Agents Chemother. 1993 Feb;37(2):178–182. [PMC free article] [PubMed]
  • Coffin JM. Genetic diversity and evolution of retroviruses. Curr Top Microbiol Immunol. 1992;176:143–164. [PubMed]
  • Corpet F. Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res. 1988 Nov 25;16(22):10881–10890. [PMC free article] [PubMed]
  • Daar ES, Moudgil T, Meyer RD, Ho DD. Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. N Engl J Med. 1991 Apr 4;324(14):961–964. [PubMed]
  • Dueweke TJ, Pushkarskaya T, Poppe SM, Swaney SM, Zhao JQ, Chen IS, Stevenson M, Tarpley WG. A mutation in reverse transcriptase of bis(heteroaryl)piperazine-resistant human immunodeficiency virus type 1 that confers increased sensitivity to other nonnucleoside inhibitors. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4713–4717. [PMC free article] [PubMed]
  • Embretson J, Zupancic M, Ribas JL, Burke A, Racz P, Tenner-Racz K, Haase AT. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature. 1993 Mar 25;362(6418):359–362. [PubMed]
  • Emini EA, Graham DJ, Gotlib L, Condra JH, Byrnes VW, Schleif WA. HIV and multidrug resistance. Nature. 1993 Aug 19;364(6439):679–679. [PubMed]
  • Eron JJ, Jr, Johnson VA, Merrill DP, Chou TC, Hirsch MS. Synergistic inhibition of replication of human immunodeficiency virus type 1, including that of a zidovudine-resistant isolate, by zidovudine and 2',3'-dideoxycytidine in vitro. Antimicrob Agents Chemother. 1992 Jul;36(7):1559–1562. [PMC free article] [PubMed]
  • Gao WY, Shirasaka T, Johns DG, Broder S, Mitsuya H. Differential phosphorylation of azidothymidine, dideoxycytidine, and dideoxyinosine in resting and activated peripheral blood mononuclear cells. J Clin Invest. 1993 May;91(5):2326–2333. [PMC free article] [PubMed]
  • Holland JJ, De La Torre JC, Steinhauer DA. RNA virus populations as quasispecies. Curr Top Microbiol Immunol. 1992;176:1–20. [PubMed]
  • Johnson VA, Merrill DP, Videler JA, Chou TC, Byington RE, Eron JJ, D'Aquila RT, Hirsch MS. Two-drug combinations of zidovudine, didanosine, and recombinant interferon-alpha A inhibit replication of zidovudine-resistant human immunodeficiency virus type 1 synergistically in vitro. J Infect Dis. 1991 Oct;164(4):646–655. [PubMed]
  • Kellam P, Boucher CA, Larder BA. 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. [PMC free article] [PubMed]
  • Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA. Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science. 1992 Jun 26;256(5065):1783–1790. [PubMed]
  • Larder BA. 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. [PMC free article] [PubMed]
  • Larder BA, Kellam P, Kemp SD. Convergent combination therapy can select viable multidrug-resistant HIV-1 in vitro. Nature. 1993 Sep 30;365(6445):451–453. [PubMed]
  • Larder BA, Kemp SD. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science. 1989 Dec 1;246(4934):1155–1158. [PubMed]
  • Merluzzi VJ, Hargrave KD, Labadia M, Grozinger K, Skoog M, Wu JC, Shih CK, Eckner K, Hattox S, Adams J, et al. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science. 1990 Dec 7;250(4986):1411–1413. [PubMed]
  • Nunberg JH, Schleif WA, Boots EJ, O'Brien JA, Quintero JC, Hoffman JM, Emini EA, Goldman ME. Viral resistance to human immunodeficiency virus type 1-specific pyridinone reverse transcriptase inhibitors. J Virol. 1991 Sep;65(9):4887–4892. [PMC free article] [PubMed]
  • Pantaleo G, Graziosi C, Demarest JF, Butini L, Montroni M, Fox CH, Orenstein JM, Kotler DP, Fauci AS. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993 Mar 25;362(6418):355–358. [PubMed]
  • Piatak M, Jr, Saag MS, Yang LC, Clark SJ, Kappes JC, Luk KC, Hahn BH, Shaw GM, Lifson JD. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science. 1993 Mar 19;259(5102):1749–1754. [PubMed]
  • Richman D, Rosenthal AS, Skoog M, Eckner RJ, Chou TC, Sabo JP, Merluzzi VJ. BI-RG-587 is active against zidovudine-resistant human immunodeficiency virus type 1 and synergistic with zidovudine. Antimicrob Agents Chemother. 1991 Feb;35(2):305–308. [PMC free article] [PubMed]
  • Richman D, Shih CK, 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. [PMC free article] [PubMed]
  • Saag MS, Emini EA, Laskin OL, Douglas J, Lapidus WI, Schleif WA, Whitley RJ, Hildebrand C, Byrnes VW, Kappes JC, et al. 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. [PubMed]
  • Sardana VV, Emini EA, Gotlib L, Graham DJ, Lineberger DW, Long WJ, Schlabach AJ, Wolfgang JA, Condra JH. 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]
  • Shih CK, Rose JM, Hansen GL, Wu JC, Bacolla A, Griffin JA. 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. [PMC free article] [PubMed]
  • Spector SA, Kennedy C, McCutchan JA, Bozzette SA, Straube RG, Connor JD, Richman DD. The antiviral effect of zidovudine and ribavirin in clinical trials and the use of p24 antigen levels as a virologic marker. J Infect Dis. 1989 May;159(5):822–828. [PubMed]
  • St Clair MH, Martin JL, Tudor-Williams G, Bach MC, Vavro CL, King DM, Kellam P, Kemp SD, Larder BA. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science. 1991 Sep 27;253(5027):1557–1559. [PubMed]
  • Wu JC, Warren TC, Adams J, Proudfoot J, Skiles J, Raghavan P, Perry C, Potocki I, Farina PR, Grob PM. A novel dipyridodiazepinone inhibitor of HIV-1 reverse transcriptase acts through a nonsubstrate binding site. Biochemistry. 1991 Feb 26;30(8):2022–2026. [PubMed]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...