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Antimicrob Agents Chemother. Aug 1995; 39(8): 1704–1710.
PMCID: PMC162812

Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors.

Abstract

Human immunodeficiency virus type 1 (HIV-1) protease inhibitor-resistant variants, isolated on passage of HIV-1HXB2 in MT-4 cells with five different protease inhibitors, have been examined for cross-resistance to five inhibitors. The protease inhibitors studied were Ro 31-8959, A-77003, XM323, L-735,524, and VX-478. Resistant variants with two to four mutations within their protease sequence and 9- to 40-fold-decreased susceptibility were selected for all five inhibitors within six to eight passes in cell culture. Passage of a zidovudine-resistant mutant in Ro 31-8959 generated a dual reverse transcriptase- and protease-resistant virus. Variants were cloned directly into a modified pHXB2-D infectious clone for cross-resistance analysis. Although the resistant variants selected possessed different combinations of protease mutations for each inhibitor, many showed cross-resistance to the other inhibitors, and one showed cross-resistance to all five inhibitors. Interestingly, some mutants showed increased susceptibility to some inhibitors. Further HIV passage studies in the combined presence of two protease inhibitors demonstrated that in vitro it was possible to delay significantly selection of mutations producing resistance to one or both inhibitors. These studies indicate that there may be some rationale for combining different protease inhibitors as well as protease and reverse transcriptase inhibitors in HIV combination therapy.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Boucher CA, Cammack N, Schipper P, Schuurman R, Rouse P, Wainberg MA, Cameron JM. High-level resistance to (-) enantiomeric 2'-deoxy-3'-thiacytidine in vitro is due to one amino acid substitution in the catalytic site of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother. 1993 Oct;37(10):2231–2234. [PMC free article] [PubMed]
  • Condra JH, Schleif WA, Blahy OM, Gabryelski LJ, Graham DJ, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature. 1995 Apr 6;374(6522):569–571. [PubMed]
  • el-Farrash MA, Kuroda MJ, Kitazaki T, Masuda T, Kato K, Hatanaka M, Harada S. Generation and characterization of a human immunodeficiency virus type 1 (HIV-1) mutant resistant to an HIV-1 protease inhibitor. J Virol. 1994 Jan;68(1):233–239. [PMC free article] [PubMed]
  • Erickson-Viitanen S, Klabe RM, Cawood PG, O'Neal PL, Meek JL. Potency and selectivity of inhibition of human immunodeficiency virus protease by a small nonpeptide cyclic urea, DMP 323. Antimicrob Agents Chemother. 1994 Jul;38(7):1628–1634. [PMC free article] [PubMed]
  • Fisher AG, Collalti E, Ratner L, Gallo RC, Wong-Staal F. A molecular clone of HTLV-III with biological activity. Nature. 1985 Jul 18;316(6025):262–265. [PubMed]
  • Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Schooley RT, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185–191. [PubMed]
  • Fitzgibbon JE, Howell RM, Haberzettl CA, Sperber SJ, Gocke DJ, Dubin DT. Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine. Antimicrob Agents Chemother. 1992 Jan;36(1):153–157. [PMC free article] [PubMed]
  • Gao Q, Gu ZX, Parniak MA, Li XG, Wainberg MA. 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. [PMC free article] [PubMed]
  • Hirsch MS, D'Aquila RT. Therapy for human immunodeficiency virus infection. N Engl J Med. 1993 Jun 10;328(23):1686–1695. [PubMed]
  • Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995 Jan 12;373(6510):123–126. [PubMed]
  • Ho DD, Toyoshima T, Mo H, Kempf DJ, Norbeck D, Chen CM, Wideburg NE, Burt SK, Erickson JW, Singh MK. Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor. J Virol. 1994 Mar;68(3):2016–2020. [PMC free article] [PubMed]
  • Jacobsen H, Yasargil K, Winslow DL, Craig JC, Kröhn A, Duncan IB, Mous J. Characterization of human immunodeficiency virus type 1 mutants with decreased sensitivity to proteinase inhibitor Ro 31-8959. Virology. 1995 Jan 10;206(1):527–534. [PubMed]
  • Kaplan AH, Michael SF, Wehbie RS, Knigge MF, Paul DA, Everitt L, Kempf DJ, Norbeck DW, Erickson JW, Swanstrom R. Selection of multiple human immunodeficiency virus type 1 variants that encode viral proteases with decreased sensitivity to an inhibitor of the viral protease. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5597–5601. [PMC free article] [PubMed]
  • Kellam P, Boucher CA, Tijnagel JM, Larder BA. Zidovudine treatment results in the selection of human immunodeficiency virus type 1 variants whose genotypes confer increasing levels of drug resistance. J Gen Virol. 1994 Feb;75(Pt 2):341–351. [PubMed]
  • Kempf DJ, Marsh KC, Paul DA, Knigge MF, Norbeck DW, Kohlbrenner WE, Codacovi L, Vasavanonda S, Bryant P, Wang XC, et al. Antiviral and pharmacokinetic properties of C2 symmetric inhibitors of the human immunodeficiency virus type 1 protease. Antimicrob Agents Chemother. 1991 Nov;35(11):2209–2214. [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, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989 Mar 31;243(4899):1731–1734. [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]
  • Larder BA, Kohli A, Kellam P, Kemp SD, Kronick M, Henfrey RD. Quantitative detection of HIV-1 drug resistance mutations by automated DNA sequencing. Nature. 1993 Oct 14;365(6447):671–673. [PubMed]
  • Markowitz M, Mo H, Kempf DJ, Norbeck DW, Bhat TN, Erickson JW, Ho DD. Selection and analysis of human immunodeficiency virus type 1 variants with increased resistance to ABT-538, a novel protease inhibitor. J Virol. 1995 Feb;69(2):701–706. [PMC free article] [PubMed]
  • McLeod GX, McGrath JM, Ladd EA, Hammer SM. Didanosine and zidovudine resistance patterns in clinical isolates of human immunodeficiency virus type 1 as determined by a replication endpoint concentration assay. Antimicrob Agents Chemother. 1992 May;36(5):920–925. [PMC free article] [PubMed]
  • Navia MA, Fitzgerald PM, McKeever BM, Leu CT, Heimbach JC, Herber WK, Sigal IS, Darke PL, Springer JP. Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature. 1989 Feb 16;337(6208):615–620. [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]
  • Otto MJ, Garber S, Winslow DL, Reid CD, Aldrich P, Jadhav PK, Patterson CE, Hodge CN, Cheng YS. In vitro isolation and identification of human immunodeficiency virus (HIV) variants with reduced sensitivity to C-2 symmetrical inhibitors of HIV type 1 protease. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7543–7547. [PMC free article] [PubMed]
  • Pauwels R, Balzarini J, Baba M, Snoeck R, Schols D, Herdewijn P, Desmyter J, De Clercq E. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods. 1988 Aug;20(4):309–321. [PubMed]
  • Richman DD, Havlir D, Corbeil J, Looney D, Ignacio C, Spector SA, Sullivan J, Cheeseman S, Barringer K, Pauletti D, et al. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol. 1994 Mar;68(3):1660–1666. [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]
  • Roberts NA, Martin JA, Kinchington D, Broadhurst AV, Craig JC, Duncan IB, Galpin SA, Handa BK, Kay J, Kröhn A, et al. Rational design of peptide-based HIV proteinase inhibitors. Science. 1990 Apr 20;248(4953):358–361. [PubMed]
  • Robins T, Plattner J. HIV protease inhibitors: their anti-HIV activity and potential role in treatment. J Acquir Immune Defic Syndr. 1993 Feb;6(2):162–170. [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]
  • Schinazi RF, Lloyd RM, Jr, Nguyen MH, Cannon DL, McMillan A, Ilksoy N, Chu CK, Liotta DC, Bazmi HZ, Mellors JW. Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. Antimicrob Agents Chemother. 1993 Apr;37(4):875–881. [PMC free article] [PubMed]
  • Smith MS, Brian EL, Pagano JS. Resumption of virus production after human immunodeficiency virus infection of T lymphocytes in the presence of azidothymidine. J Virol. 1987 Dec;61(12):3769–3773. [PMC free article] [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]
  • Tisdale M, Kemp SD, Parry NR, Larder BA. 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. [PMC free article] [PubMed]
  • Vacca JP, Dorsey BD, Schleif WA, Levin RB, McDaniel SL, Darke PL, Zugay J, Quintero JC, Blahy OM, Roth E, et al. L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):4096–4100. [PMC free article] [PubMed]
  • Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, Lifson JD, Bonhoeffer S, Nowak MA, Hahn BH, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995 Jan 12;373(6510):117–122. [PubMed]
  • Wlodawer A, Erickson JW. Structure-based inhibitors of HIV-1 protease. Annu Rev Biochem. 1993;62:543–585. [PubMed]
  • Wlodawer A, Miller M, Jaskólski M, Sathyanarayana BK, Baldwin E, Weber IT, Selk LM, Clawson L, Schneider J, Kent SB. Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science. 1989 Aug 11;245(4918):616–621. [PubMed]

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