It has been demonstrated that prolonged treatment with nucleoside analogues, such as 3′-azido-3′-deoxythymi-dine (zidovudine), 2’,3′-dideoxycytidine (zalcitabine) and 9-(2-phosphonylmethoxyethyl) adenine (PMEA), may cause selection of cells that are resistant to their anti-HIV activity. A human T-lymphoblastoid cell line that is resistant to the antiviral and cytotoxic activity of 2’,3′-didehydro-3′-deoxythymidine (stavudine) has developed as a result of prolonged treatment. These cells, called CEMstavudine, are also less sensitive to zidovudine. The cellular/pharmacological resistance acquired by the CEMstavudine cells is relatively low and appears to correlate with a reduction in thymidine kinase (TK) activity, rather than with a decreased expression of TK mRNA.
References
1.
ZhangL., RamratnamB., Tenner-RaczK., HeY., VesanenM., LewinS., TalalA., RaczP., PerelsonA.S., KorberB.T., MarkowitzM., & HoD.D.Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. New England Journal of Medicine1999; 340: 1605–1613.
2.
Martinez-PicadoJ., De PasqualeM P., KartsonisN., HannaG.J., WongJ., FinziD., RosenbergE., GunthardH.F., SuttonL., SavaraA., PetropoulosC.J., HelmannN., WalzerB.D., RichmanD.D., SilicianoR., & D'AquilaR.T.Antiretroviral resistance during successful therapy of HIV type 1 infection. Proceedings of the National Academy of Sciences of the USA2000; 97: 10948–10953.
3.
GunthardH.F., WongJ.K., IgnacioC.C., GuatelliJ.C., RiggsN.L., HavlirD.V., & RichmanD.D.Human immunodeficiency virus replication and genotypic resistance in blood and lymph nodes after a year of potent antiretroviral therapy. Journal of Virology1998; 72: 2422–2428.
O'BrienW.A.Resistance against reverse transcriptase inhibitors. Clinical Infectious Diseases2000; 30: S185–S192.
6.
GrossmanZ., FeinbergM., KuznetsovV., DimitrovD., & PaulW.HIV infection: how effective is drug combination treatment. Immunology Today1998; 19: 528–532.
7.
GroschelB., CinatlJ., & CinatlJ.Jr.Viral and cellular factors for resistance against antiretroviral agents. Intervirology1997; 14: 400–407.
8.
Di GregorioP., IacobelliS., PerrinL., & TelentiA.HIV treatment failure: testing for HIV resistance in clinical practice. Science1998; 280: 1871–1872.
9.
FridlandA., ConnellyM.C., & RobbinsB.L.Cellular factors for resistance against antiretroviral agents. Antiviral Therapy2000; 5: 181–185.
10.
TurrizianiO., AntonelliG., & DianzaniF.Cellular factors involved in the induction of resistance of HIV to antiretroviral agents. International Journal of Antimicrobial Agents2000; 16: 353–356.
11.
AvramisV.I., KwockR., SolorzanoM.M., & GompertsE.Evidence of in vitro development of drug resistance to azidothymidine in T-lymphotropic leukemia cell line (Jurkat E6-1/AZT-100) and in pediatric patients with HIV infection. Journal of Acquired Immune Deficiency Syndrome1993; 6: 1287–1296.
12.
DianzaniF., AntonelliG., TurrizianiO., RivaE., SimeoniE., SignorettiC., StrosselliS., & CianfrigliaM.Zidovudine induces the expression of cellular resistance affecting its antiviral activities. AIDS Research and Human Retroviruses1994; 10: 1471–1478.
13.
MagnaniM., BrandiG., CasabiancaA., FraternaleA., SchiavanoF., RossiL., & ChiarantiniL.2’,3′-dideoxycytidine metabolism in a new drug-resistant cell line. Biochemical Journal1995; 312: 115–123.
14.
SchuetzJ.D., ConnellyM.C., SunD., PaibirS.G., FlynnP.M., SrinivasR.V., KumarA., & FridlandA.MRP4: a previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nature Medicine1999; 5: 1048–1051.
15.
AntonelliG., TurrizianiO., VerriA., NarcisoP., FerriF., D'OffiziG., & DianzaniF.Long-term exposure to zidovudine affects in vitro and in vivo the efficiency of phosphorylation of thymidine kinase. AIDS Research and Human Retroviruses1996; 12: 223–228.
16.
TurrizianiO., AntonelliG., FocherF., BambacioniF., & DianzaniF.Further study of the mechanism underlying the cellular resistance to AZT. Biochemical and Biophysical Research Communications1996; 228: 797–801.
17.
HoH-T, & HitchcockM.J.M.Cellular pharmacology of 2’,3′-dideoxy-2’,3’ didehydrothymidine, a nucleoside analog active against human immunodeficiency virus. Antimicrobial Agents & Chemotherapy1989; 33: 844–849.
18.
VealG.J., & BackD.J.Metabolism of zidovudine. General Pharmacology1995; 26: 1469–1475.
19.
BalzariniJ., HeredewijnP., & De ClerqE.Differential patterns of intracellular metabolism of 2’,3′-dideoxy-2’,3′-didehydrothymidine and 3′-azido-2’,3′-dideoxythymidine, two potent anti-human immunodeficiency virus compounds. Journal of Biological Chemistry1989; 284: 6127–6133.
20.
MartinJ.C., HitchcockM. J., FridlandA., GhazzouliI., KaulS., DunkleL.M., SterzyckiR.Z., & MansuriM.M.Comparative studies of 2’,3′-didehydro-2’,3′-dideoxythymidine (d4T) with other nucleoside analogs. Annals of the New York Academy of Sciences1990; 616: 22–28.
21.
Muench-PetersenB., CloosL., TyrstedG., & ErikssonS.Diverging substrate specificity of human thymidine kinase 1 and 2 against antiviral dideoxynucleosides. Journal of Biological Chemistry1991; 266: 9032–9038.
22.
TurrizianiO., SimeoniE., DianzaniF., & AntonelliG.Anti-HIV antiviral activity of stavudine in a thymidine kinase-deficient cellular line. Antiviral Therapy1998; 3: 191–194.
23.
AnkelH., TurrizianiO., & AntonelliG.Prostaglandin A inhibits replication of human immunodeficiency virus during acute infection. Journal of General Virology1991; 72: 2797–2800.
24.
DenizotF., & LangR.Rapid colorimetric assay for cell growth and survival. Journal of Immunological Methods1986; 89: 271–277.
25.
HuJ.M., & HsiungG.D.Evaluation of new antiviral agents: in vitro perspectives. Antiviral Research1989; 11: 217–232.
26.
MagaG., VerriA., BonizziL., PontiW., PoliG., GarbesiA., NiccolaiD., SpadariS., & FocherF.Lack of stereospecificity of suid pseudorabies virus with thymidine kinase. Biochemical Journal1993; 294: 381–385.
27.
LipsonK.E., & BasergaR.Transcriptional activity of the human thymidine kinase gene determined by a method using the polymerase chain reaction and an intron-specific probe. Proceedings of the National Academy of Sciences, USA1989; 86: 9774–9777.
28.
AntonelliG., SimeoniE., TurrizianiO., TesoroR., RedaelliA., RoffiL., AntonelliL., PistelloM., & DianzaniF.Correlation of interferon-induced expression of MxA mRNA in peripheral blood mononuclear cells with the response of patients with chronic active hepatitis C to IFN-α therapy. Journal of Interferon and Cytokine Research1999; 19: 243–251.
29.
VerriA., PrioriG., SpadariS., TondelliL., & FocherF.Relaxed enantioselectivity of human mitochondrial thymidine kinase and chemotherapeutic uses of L-nucleoside analogues. Biochemical Journal1997; 328: 317–320.
30.
KenionG.L.AZT monophosphate knocks thymidilate kinase for a loop. Nature Structural Biology1997; 4: 595–597.
31.
TornevikY., UllmanB., BalzariniJ., WahrenB., & ErikssonS.Cytotoxicity of 3′-azido-3′-deoxythymidine correlates with 3′-azidothymidine-5′-monophasphate (AZTMP) levels, whereas anti-human immunodeficiency virus (HIV) activity correlates with 3′-azidothymidine-5′-triphosphate (AZTTP) levels in cultured CEM T lymphoblastoid cells. Biochemical Pharmacology1995; 49: 829–837.
32.
GaoW., AgbariaR., DriscollJ.S., & MitsuyaH.Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2’,3′-dideoxynucleoside analogs in resting and activated human cells. Journal of Biological Chemistry1994; 269: 12633–12638.
33.
VillalbaN., SorianoV., Gomez-CanoM., CastillaJ., MasA., & Gonzales-LahozJ.Short- term efficacy and safety of stavudine in pretreated HIV-infected patients. Antiviral Therapy1997; 2: 185–189.
34.
HoggardP.G., SalesS.D., PhiboonbanakitD., LloydJ., MaherB.A., KhooS.H., CareyP., HartC.A., & BackD.J.Influence of prior exposure to zidovudine on stavudine phosphorylation in vivo and ex vivo. Antimicrobial Agents and Chemotherapy2001; 45: 577–582.
35.
JacobssonB., BrittonS., TornevikY., & ErikssonS.Decrease in thymidilate kinase activity in peripheral blood mononu-clear cells from HIV-infected individuals. Biochemical Pharmacology1998; 56: 389–395.
36.
HoetelmansR.M., BurgerD.M., MeenhorstP.L., & BeijnenJ.H.Pharmacokinetic individualization of zidovudine therapy. Current state of pharmacokinetic-pharmacodynamic relationship. Clinical Pharmacokinetics1996; 30: 314–327.
