Both 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-dideoxynosine (ddl) strongly inhibit the replication of human immunodeficiency virus type 1 (HIV-1). Here, it is shown that combination of AZT and ddl at concentrations that are readily achievable in vivo synergistically inhibit HIV-1 replication in C8166 cells and peripheral blood mononuclear cells. The synergism is significant even when the effect of AZT and ddl alone was negligible.
Our findings show that AZT-resistance is less likely to occur when a combination of AZT and ddl is used. Particularly, generation of AZT-resistant strains by in vitro selection is prevented, or delayed, by the combination of AZT plus ddl.
Taken together these observations provide a rationale for combination of AZT and ddl in the therapy of AIDS patients.
References
1.
AntonelliG.TurrizianiO.CianfrigliaM.RivaE.DongG.FattorossiA., and DianzaniF. (1992) Resistance of HIV-1 to AZT might also involve the cellular expression of multidrug resistance P-glycoprotein. 1992. AIDS Res Hum Retroviruses8: 1851–1856.
2.
ChouT., and TalalayP. (1984) Quantitative analysis of dose effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul22: 27–55.
3.
ClaphamP.R.WeissR.A.DalgleishA.G.ExleyM.WhitbyD., and HoggN. (1987) Human immunodeficiency virus infection of monocytic and T-lymphocyte cells: receptor modulation and differentiation induced by phorbol ester. Virology158: 44–51.
4.
CoxS.AlbertJ.WahlbergJ.VhlenM., and WahrenB. (1992) Loss of synergistic response to combinations containing AZT in AZT-resistant-HIV-1. AIDS Res Hum Retroviruses8: 1229–1234.
5.
De ClercqE. (1989) New acquisitions in the development of anti-HIV agents. Antiviral Res12: 1–20.
6.
DenizotF., and LangR. (1986) Rapid colorimetric assay for cell growth and survival. J Immunol Methods89: 271–277.
7.
DianzaniF.AntonelliG.CapobianchiM.R.De MarcoF. (1988) Replication of human immunodeficiency virus: yield of infectious virus under single growth cycle conditions. Arch Virol103: 127–131.
8.
DianzaniF.CapobianchiM.R.AntonelliG.AmicucciP., and De MarcoF. (1989) Susceptibility of human immunodeficiency virus to antiviral agents measured by infectious virus yield reduction. Antiviral Res11: 299–306.
9.
DianzaniF.AntonelliG.TurrizianiO.DongG.CapobianchiM.R., and RivaE. (1992) In vitro selection of human immunodeficiency virus type 1 resistant to 3′-azido-3′-deoxythymidine. Antiviral Res18: 39–52.
10.
DornisifeR.E.St ClairM.H.HuangA.T.PanellaT.J.Kos-ZalkaG.W.BurnsC.L., and AverettD.R. (1991) Anti-human immunodeficiency virus synergism by zidovudine (3′-azidothymidine) and didanosine (dideoxyinosine) contrasts with their additive inhibition of normal human marrow progenitor cells. Antimicrob Agents Chemother35: 322–328.
11.
DournonE.MatheronS.RozenbaumW.GharakhanianS.MichonC.GirardP.M.PerronneC.SalmonD.De TruchisP.LeportC.BouvetE.DazzaM.C.LevacherM., and RegnierB. (1988) Effects of zidovudine in 365 consecutive patients with AIDS or AIDS-related complex. Lancet2: 1297–1302.
12.
FischlM.A.RichmanD.D.GriccoM.H.GottlichM.S.VolberdingP.A.LaskinO.L.LeedomJ.M.GroopmanJ.E.MildvanD.SchooleyR.T.JacksonG.G.DurakD.T., King, D., and the ZDV Collaborative Working Group (1987) The efficacy of azidothymidine (ZDV) in the treatment of patients with AIDS and AIDS-related complex. A double-blind placebo-controlled trial. N Engl J Med317: 185–191.
13.
FischlM.A.RichmanD.D.HansenN.CollierA.C.CareyJ.T.ParaM.F.HardyW.D.DolinR.PowderlyW.G.AllanJ.D.WongB.MeriganT.C.McAullifeV.J.HyslopN.E.RhameF.S.BalfourH.H.SpectorS.A.VolberdingP.A.PettinelliC., Anderson, J., and the AIDS Clinical Trials Group (1990) The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection. Ann Intern Med112: 727–737.
14.
GaoQ.GuZ.ParniakM.A.LiX., and WainbergM.A. (1992a) In vitro selection of variants of human immunodeficiency virus type 1 resistant to 3′-azido-3′ deoxythymidine and 2′,3′-dideoxyinosine. J Virol66: 12–19.
15.
GaoQ.ParniakM.A.GuZ., and WainbergM.A. (1992b) Generation of nucleoside-resistant variants of HIV-1 by in vitro selection in the presence of AZT or DDI but not by combinations. Leukemia6: 192S–195S.
16.
HartshornK.L.VogtM.W.ChouT.C.BlumbergR.S.ByingtonR.SchooleyR.T., and HirschM.S. (1987) Synergistic inhibition of human immunodeficiency virus in vitro by azidothymidine and recombinant alpha A interferon. Antimicrob Agents Chemother31: 168–172.
17.
JapourA.J.ChatisP.A.EigenrauchH.A., and CrumpackerC.S. (1991) Detection of human immunodeficiency virus type 1 clinical isolates with reduced sensitivity to zidovudine and dideoxyinosine by RNA.RNA hybridization. Proc Natl Acad Sci USA88: 3092–3096.
18.
JohnsonV.A.BarlowM.A.MerrillD.P.ChouT.C.HirschM.S. (1990) Drug synergistic inhibition of HIV-1 replication in vitro by zidovudine, recombinant soluble CD4, and recombinant interferon-alpha A. J Infect Dis161: 1059–1067.
19.
JohnsonV.A.MerrillD.P.VidelerJ.A.ChouT.C.ByingtonR.E.EronJ.J.D'AquilaR.T., and HirschM.S. (1991) Two-drug combinations of zidovudine, didanosine, and recombinant interferon-a A inhibit replication of zidovudine-resistant human immunodeficiency virus type 1 synergistically in vitro. J Infect Dis164: 646–655.
20.
KevanL.H.VogtM.W.ChouT.C.BlumbergR.S.ByingtonR.SchooleyR.T., and HirschM.S. (1987) Synergistic inhibition of human immunodeficiency virus in vitro by azidothymidine and recombinant alpha A interferon. Antimicrob Agents Chemother31: 168–172.
21.
LandS.TreloarG.McPheeD.BirchC.DohertyR.CooperD., and GustI. (1990) Decreased in vitro susceptibility to zidovudine of HIV isolates obtained from patients with AIDS. J Infect Dis161: 326–329.
22.
LarderB.A., and KempS.D. (1989) Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science246: 1155–1158.
23.
LarderB.A.DarbyG., and RichmanD.D. (1989) HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science243: 1731–1734.
24.
LarderB.A.CoatesK.E., and SharonD.K. (1991) Zidovudine-resistant human immunodeficiency virus selected by passage in cell culture. J Virol65: 5232–5236.
25.
MeriganT.C. (1991) Treatment of AIDS with combinations of antiretroviral agents. Am J Med90: 4A–8S/175.
26.
NielsenC.GotzscheP.C.NielsenC.M.GerstoftJ., and VestergaardB.F. (1992) Development of resistance to zidovudine in HIV strains isolated from CD4+ lymphocytes and plasma during therapy. Antiviral Res18: 303–316.
27.
O'MarroS.D.ArmstrongJ.A.AsuncionC.GueverraL., and HoM. (1992) The effect of combinations of ampligen and zidovudine or dideoxyinosine against human immunodeficiency viruses in vitro. Antiviral Res17: 169–177.
28.
RichmanD.D.FischlM.A.GriecoM.H.GottliebM.S.VolberdingP.A.LaskinO.L.LeedomJ.M.GroopmanJ.E.MildvanD.HirschM.S.JacksonG.G.DurackD.T., Nusinoff-Lehrman, S., and the AZT Collaborative Working Group (1987) The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo-controlled trial. N Engl J Med317: 192–197.
29.
RookeR.ParniakM.A.TremblayM.SoudeynsH.XuguangL.LiX.GaoQ.YaoX.-J., and WainbergM.A. (1991) Biological comparison of wild-type and zidovudine-resistant isolates of human immunodeficiency virus type 1 from the same subjects: susceptibility and resistance to other drugs. Antimicrob Agents Chemother35: 988–991.
30.
RookeR.TremblayM.SoudeynsH.DeStephanoL.YaoX.-J.FammingM.MontanerJ.S.G.O'ShaughnessyM.GelmonK.TsoukasC.GillJ.RuedyJ., Wainberg, M.A., and the Canadian Zidovudine Multi-Centre Study Group (1989) Isolation of drug-resistant variants of HIV-1 from patients on long-term zidovudine (AZT) therapy. AIDS3: 411–415.
31.
St ClairM.H.MartinJ.L.Tudor-WilliamsG.BachM.C.VavroC.L.KingD.M.KellamP.KempS.D.LarderB.A. (1991) Resistance to ddl and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science253: 1557–1559.
32.
Volberding, P.A., Lagakos, S.W., Koch, M.A., Pettinelli, C., Myers, M.W., Booth, D.K., Balfour, Jr. H.H., Reichman, R.C., Bartlett, J.A., Hirsch, M.S., Murphy, R.L., Hardy, W.D., Sociro, R., Fisch, M.A., Bartlett, J.G., Merigan, T.C., Hyslop, N.E., Richman, D.D., Valentine, F.T., Corey, L., and the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Disease (1990) Zidovudine in asymptomatic human immunodeficiency virus infection. N Engl J Med322: 941–949.
33.
YarchoanR.PludaJ.M.ThomasR.V.MitsuyaH.BrouwersP.WyvillK.M.HartmanN.JohnsD.G., and BroderS. (1990) Long-term toxicity/activity profile of 2′-3′-dideoxyinosine in AIDS or AIDS-related complex. Lancet336: 526–529.
