We examined the in vitro phenotypic and genotypic profiles of an extensively passaged human immunodeficiency virus type 1 clinical isolate which has been selected for lamivudine resistance, with an M184V mutation in a zidovudine-resistant genetic background, and then cultured with zidovudine alone. Our passaging strategy led to a decrease in lamivudine IC50 values, which were comparable to those prior to lamivudine exposure, and the genotypic restoration of the wild-type sequence at codon 184 of reverse transcriptase.
Get full access to this article
View all access options for this article.
References
1.
CoatesJ.A.V., CammackN., JenkinsonH.J., JowettA.J., JowettM.I., PearsonB.A., PennC.R., RouseP.L., VinerK.C., & CameronJ.M.(-)-2′-deoxy-3′-thiacytidine (lamivudine) is a potent, highly selective inhibitor of human immunodeficiency virus type 1 and type 2 replication in vitro. Antimicrobial Agents and Chemotherapy1992; 36: 733–739
2.
HartG.J., OrrD.C., PennC.R., FigueiredoH.T., GrayN.M., BoehmeR.E., & CameronJ.M.Effect of (-)-2′-deoxy-3′-thiacytidine (lamivudine) 5′-triphosphate on human immunodeficiency virus reverse transcriptase and mammalian DNA polymerases alpha, beta, and gamma. Antimicrobial Agents and Chemotherapy1992; 36: 1688–1694
3.
BartlettJ.A., BenoitS.L., JohnsonV.A., QuinnJ.B., SepulvedaG.E., EhmannW.C., TsoukasC., FallonM.A., SelfP.L., & RubinM.Lamivudine plus zidovudine compared with zalcitabine plus zidovudine in patients with HIV infection. Annals of Internal Medicine1996; 125: 161–172
4.
EronJ.J., BenoitS.H., JemsekJ., MacArthurR.D., SantanaJ., QuinnJ.B., KuritzkesD.R., FallonM.A., & RubinM for the North American HIV Working Party. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. New England Journal of Medicine1995; 333: 1662–1669
5.
KatlamaC., IngrandD., LovedayC., ClumeckN., MallolasJ., StaszewskiS., JohnsonM., HillA.M., PearceG., McDadeH. & Lamivudine European HIV Working Group. Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine-naive patients. A randomized controlled comparison with zidovudine monotherapy. Journal of the American Medical Association1996; 276: 118–125
6.
KuritzkesD.R., QuinnJ.B., BenoitS.L., ShugartsD.L., GriffinA., BakhtiariM., PotichaD., EronJ.J., FallonM.A., & RubinM.Drug resistance and virologic response in NUCA 3001, a randomized trial of lamivudine (3TC) versus zidovudine (ZDV) versus ZDV plus 3TC in previously untreated patients. AIDS1996; 10: 975–981
7.
StaszewskiS., LovedayC., PicazoJ.J., DellamonicaP., SkinhøjP., JohnsonM.A., DannerS.A., HarriganP.R., HillA.M., VerityL., McDadeH. & Lamivudine European HIV Working Group. Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine-experienced patients. A randomized controlled comparison with zidovudine monotherapy. Journal of the American Medical Association1996; 276: 111–117
8.
CAESAR Coordinator Committee.Randomized trial of addition of lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial. Lancet1997; 349: 1413–1421
9.
TisdaleM., KempS.D., ParryN.R., & LarderB.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. Proceedings of the National Academy of Sciences, USA1993; 90: 5653–5656.
10.
BoucherC.A.B., CammackN., SchipperP., SchuurmanR., RouseP.L., & CameronJ.M.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. Antimicrobial Agents and Chemotherapy1993; 37: 2231–2234
11.
GouldenM.G., CammackN., HopewellP.L., PennC.R., & CameronJ.M.Selection in vitro of an HIV-1 variant resistant to both lamivudine (3TC) and zidovudine. AIDS1996; 10: 101–102
12.
RusconiS., De PasqualeM.P., MilazzoL., BulgheroniE., CitterioP., KurtagicS., d'Arminio-MonforteA., & GalliM.In vitro effects of a continuous pressure with zidovudine (zidovudine) and lamivudine (3TC) on a zidovudine-resistant HIV-1 isolate. AIDS1997; 11: 1406–1410
13.
RusconiS., De PasqualeM.P., MilazzoL., MoscatelliG., BulgheroniE., CitterioP., d'Arminio-MonforteA., MoroniM., & GalliM.Loss of antiviral effect owing to zidovudine and lamivudine double resistance in HIV-1-infected patients in an ongoing open label trial. Antiviral Therapy1997; 2: 41–48
14.
GassR.J.A., ShugartsD., YoungR., AllenM., RosandichM., & KuritzkesD.R.Emergence of dual resistance to zidovudine and lamivudine in clinical HIV-1 isolates from patients receiving zidovudine/lamivudine combination therapy. Antiviral Therapy1998; 3: 97–102
15.
MillerV., PhillipsA., RottmannC., StaszewskiS., PauwelsR., HertogsK., de BethuneM-P, KempS.D., BloorS., HarriganP.R., & LarderB.A.Dual resistance to zidovudine and lamivudine in patients treated with zidovudine-lamivudine combination therapy: association with therapy failure. Journal of Infectious Diseases1998; 177: 1521–1532
16.
LarderB., KempS., & HarriganP.Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science1995; 269: 696–699
17.
JohnsonV.A., MerrillD.P., VidelerJ.A., ChouT-C, ByingtonR.E., EronJ.J., D'AquilaR.T., & HirschM.S.Two-drug combinations of zidovudine, didanosine, and recombinant interferon-α A inhibit replication of zidovudine resistant human immunodeficiency virus type 1 synergistically in vitro. Journal of Infectious Diseases1991; 164: 646–655
18.
JapourA.J., FiscusS.A., ArduinoJ-M, MayersD.L., ReichelderferP.S., & KuritzkesD.R.Standardized microtiter assay for determination of syncytium-inducing phenotypes of clinical human immunodeficiency virus type 1 isolates. Journal of Clinical Microbiology1994; 32: 2291–2294
19.
StuyverL., WyseurA., RomboutA., LouwagieJ., ScarcezT., VerhofstedeC., RimlandD., SchinaziR.F., & RossauR.Line probe assay for rapid detection of drug-selected mutations in the human immunodeficiency virus type 1 reverse transcriptase gene. Antimicrobial Agents and Chemotherapy1997; 41: 284–291
20.
DulbeccoR.Endpoint methods - measurements of the infectious titer of a viral sample. In Virology, 1988, pp. 22–25. Edited by DulbeccoR., & GinsbergH.S.Philadelphia: JP Lippincott
21.
OlmstedR.A., SladeD.E., KoptaL.A., PoppeS.M., PoelT.J., NewportS.W., RankK.B., BilesC., MorgeR.A., DuewekeT.J., YagiY., RomeroD.L., ThomasR.C., SharmaS.K., & TarpleyW.G.(Alkylamino)piperidine bis(heteroaryl)piperazine analogs are potent, broad-spectrum nonnucleoside reverse transcriptase inhibitors of drug-resistant isolates of human immunodeficiency virus type 1 (HIV-1) and select for drug-resistant variants of HIV-1 IIIB with reduced replication phenotypes. Journal of Virology1996; 70: 3698–3705
22.
HarriganP.R., BloorS., & LarderB.A.Relative replicative fitness of zidovudine-resistant human immunodeficiency virus type 1 isolates in vitro. Journal of Virology1998; 72: 3773–3778
23.
NguyenB-Y.T., ShayL.E., WyvillK.M., PludaJ.M., BrawleyO., CohenR.B., WhitcupS.M., VenzonD.J., BroderS., & YarchoanR.A pilot study of sequential therapy with zidovudine plus acyclovir, dideoxyinosine, and dideoxycytidine in patients with severe human immunodeficiency infection. Journal of Infectious Diseases1993; 168: 810–817
24.
YachoanR., LietzauJ.A., NguyenB-Y, BrawleyO.W., PludaJ.M., SavilleM.W., WyvillK.M., SteinbergS.M., AgbariaR., MitsuyaH., & BroderS.A randomized pilot study of alternating or simultaneous zidovudine and didanosine therapy in patients with symptomatic human immunodeficiency virus infection. Journal of Infectious Diseases1994; 169: 9–17
