Sequential herpes simplex virus type 1 (HSV-1) isolates were obtained from a paediatric haematopoietic stem cell transplant (HSCT) patient who received prolonged therapy with acyclovir (ACV) followed by foscarnet (PFA) and topical cidofovir (HPMPC) for severe persistent mucocutaneous HSV-1 infection. The isolates were retrospectively studied for drug resistance. The first resistant isolate associated with clinical failure of antiviral therapy emerged 44 days post-ACV treatment initiation. Susceptibility testing revealed an ACV-resistant HSV strain that demonstrated cross resistance to PFA in the absence of any previous PFA treatment. The observed cross resistance was conferred by a single amino acid substitution, Ser724Asn, in the HSV DNA polymerase (DNA pol) gene. During the subsequent course of ACV therapy, the ACV/PFA-cross-resistant isolates were replaced by ACV-resistant, PFA-sensitive isolates. These isolates carried no DNA pol mutations, but had an Arg163His substitution in the thymidine kinase gene. Upon subsequent switching of antiviral therapy from ACV to PFA, the original ACV/PFA-cross-resistant DNA pol mutant re-appeared. Our study shows the emergence of different drug-resistant HSV variants during ongoing, unchanged ACV therapy. Furthermore, a rapid re-selection of the original resistant variant was observed after switch. For optimal antiviral management of HSV infections in HSCT recipients, therapeutic decisions should be guided by drug susceptibility results whenever therapeutic failure is observed and/or when changes in antiviral treatment are considered.
ChristophersJ., ClaytonJ., CraskeJ., WardR., CollinsP., TrowbridgeM., & DarbyG.Survey of resistance of herpes simplex virus to acyclovir in northwest England.Antimicrobial Agents & Chemotherapy1998; 42: 868–872.
3.
LinaB., ThouvenotD., DanveC., MorfinF., BoucherA., BerlinI., & AymardM.Implementation of surveillance network of the herpes simplex virus resistance to antiviral drugs.European Virology 2000. Glasgow, Scotland, 17–21 September 2000. Abstract O-086.
4.
EnglundJ.A., ZimmermanM.E., SwierkoszE.M., GoodmanJ.L., SchollD.R., & BalfourH.H.Herpes simplex virus resistant to acyclovir. A study in a tertiary care center.Annals of Internal Medicine1990; 112: 416–422.
van KraaijM.G., VerdonckL.F., Rozenberg-ArskaM., & DekkerA.W.Early infections in adults undergoing matched related and matched unrelated/mismatched donor stem cell transplantation: a comparison of incidence.Bone Marrow Transplantation2002; 30: 303–309.
7.
MorfinF., ThouvenotD., SouilletG., MichalletM., & AymardM.Acyclovir-resistant (ACV-R) herpes viruses (HSV, VZV) in bone marrow transplantation patients.Progress in Clinical Virology V. Budapest, Hungary, 1–5 September 1999. Abstract 429.
8.
ArnulfB., ChebbiF., LefrereF., AitA.Z., VaretB., & FilletA.M.Multiple herpes simplex virus infections with various resistance patterns in a matched unrelated donor transplant recipient.Bone Marrow Transplantation2001; 28: 799–801.
9.
Bestman-SmithJ., SchmitI., PapadopoulouB., & BoivinG.Highly reliable heterologous system for evaluating resistance of clinical herpes simplex virus isolates to nucleoside analogues.Journal of Virology2001; 75: 3105–3110.
10.
GaudreauA., HillE., BalfourH.H.Jr., EriceA., & BoivinG.Phenotypic and genotypic characterization of acyclovirresistant herpes simplex viruses from immunocompromised patients.Journal of Infectious Diseases1998; 178: 297–303.
11.
MorfinF., SouilletG., BilgerK., OokaT., AymardM., & ThouvenotD.Genetic characterization of thymidine kinase from acyclovir-resistant and -susceptible herpes simplex virus type 1 isolated from bone marrow transplant recipients.Journal of Infectious Diseases2000; 182: 290–293.
12.
CoenD.M., Kosz-VnenchakM., JacobsonJ.G., LeibD.A., BogardC.L., SchafferP.A., TylerK.L., & KnipeD.M.Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate.Proceedings of National Academy of Sciences, USA1989; 86: 4736–4740.
13.
EfstathiouS., KempS., DarbyG., & MinsonA.C.The role of herpes simplex virus type 1 thymidine kinase in pathogenesis.Journal of General Virology1989; 70: 869–879.
14.
LarderB.A., & DarbyG.Susceptibility to other antiherpes drugs of pathogenic variants of herpes simplex virus selected for resistance to acyclovir.Antimicrobial Agents & Chemotherapy1986; 29: 894–898.
15.
LarderB.A., & DarbyG.Selection and characterisation of acyclovir-resistant herpes simplex virus type 1 mutants inducing altered DNA polymerase activities.Virology1985; 146: 262–271.
16.
SchmitI., & BoivinG.Characterization of the DNA polymerase and thymidine kinase genes of herpes simplex virus isolates from AIDS patients in whom acyclovir and foscarnet therapy sequentially failed.Journal of Infectious Diseases1999; 180: 487–490.
17.
ChiboD., MijchA., DohertyR., & BirchC.Novel mutations in the thymidine kinase and DNA polymerase genes of acyclovir and foscarnet resistant herpes simplex viruses infecting an immunocompromised patient.Journal of Clinical Virology2002; 25: 165–170.
18.
SacksS.L., WanklinR.J., ReeceD.E., HicksK.A., TylerK.L., & CoenD.M.Progressive esophagitis from acyclovir-resistant herpes simplex. Clinical roles for DNA polymerase mutants and viral heterogeneity?Annals of Internal Medicine1989; 111: 893–899.
19.
HwangC.B., RuffnerK.L., & CoenD.M.A point mutation within a distinct conserved region of the herpes simplex virus DNA polymerase gene confers drug resistance.Journal of Virology1992; 66: 1774–1776.
20.
CollinsP., LarderB.A., OliverN.M., KempS., SmithI.W., & DarbyG.Characterization of a DNA polymerase mutant of herpes simplex virus from a severely immunocompromised patient receiving acyclovir.Journal of General Virology1989; 70: 375–382.
21.
FieldH.J., & CoenD.M.Pathogenicity of herpes simplex virus mutants containing drug resistance mutations in the viral DNA polymerase gene.Journal of Virology1986; 60: 286–289.
22.
LarderB.A., & DarbyG.Virus drug-resistance: mechanisms and consequences.Antiviral Research1984; 4: 1–42.
23.
CollinsP., & DarbyG.Laboratory Studies of Herpes simplex virus strains resistant to acyclovir.Reviews in Medical Virology1991; 1: 19–28.
24.
SchilhamM.W., ClaasE.C., van ZaaneW., HeemskerkB., VossenJ.M., LankesterA.C., ToesR.E., EchavarriaM., KroesA.C., & van TolM.J.High levels of adenovirus DNA in serum correlate with fatal outcome of adenovirus infection in children after allogeneic stem-cell transplantation.Clinical Infectious Diseases2002; 35: 526–532.
25.
SnoeckR., BossensM., ParentD., DelaereB., DegreefH., Van RanstM., NoelJ.C., WulfsohnM.S., RooneyJ.F., JaffeH.S., & De ClercqE.Phase II double-blind, placebo-controlled study of the safety and efficacy of cidofovir topical gel for the treatment of patients with human papillomavirus infection.Clinical Infectious Diseases2001; 33: 597–602.
26.
SchafferP.A., AronG.M., BiswalN., & Benyesh-MelnickM.Temperature-sensitive mutants of herpes simplex virus type 1: isolation, complementation and partial characterization.Virology1973; 52: 57–71.
27.
StranskaR., van LoonA.M., PolmanM., & SchuurmanR.Application of real-time PCR for determination of antiviral drug susceptibility of herpes simplex virus.Antimicrobial Agents & Chemotherapy2002; 46: 2943–2947.
28.
AndreiG., SnoeckR., De ClercqE., EsnoufR., FitenP., & OpdenakkerG.Resistance of herpes simplex virus type 1 against different phosphonylmethoxyalkyl derivatives of purines and pyrimidines due to specific mutations in the viral DNA polymerase gene.Journal of General Virology2001; 81: 639–48.
ChakrabartiS., PillayD., RatcliffeD., CaneP.A., CollinghamK.E., & MilliganD.W.Resistance to antiviral drugs in herpes simplex virus infections among allogeneic stem cell transplant recipients: risk factors and prognostic significance.Journal of Infectious Diseases2000; 181: 2055–2058.
31.
SnoeckR., AndreiG., GerardM., SilvermanA., HeddermanA., BalzariniJ., Sadzot-DelvauxC., TricotG., ClumeckN., & De ClercqE.Successful treatment of progressive mucocutaneous infection due to acyclovir- and foscarnet-resistant herpes simplex virus with (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC).Clinical Infectious Diseases1994; 18: 570–578.
32.
LarderB.A., KempS.D., & DarbyG.Related functional domains in virus DNA polymerases.EMBO Journal1987; 6: 169–175.
33.
GibbsJ.S., ChiouH.C., BastowK.F., ChengY.C., & CoenD.M.Identification of amino acids in herpes simplex virus DNA polymerase involved in substrate and drug recognition.Proceedings of National Academy of Sciences, USA1988; 85: 6672–6676.
34.
Bestman-SmithJ., & BoivinG.Herpes simplex virus isolates with reduced adefovir susceptibility selected in vivo by foscarnet therapy.Journal of Medical Virology2002; 67: 88–91.
35.
Bestman-SmithJ., & BoivinG.Drug resistance patterns of recombinant herpes simplex virus DNA polymerase mutants generated with a set of overlapping cosmids and plasmids.Journal of Virology2003; 77: 7820–7829.
36.
EvansJ.S., LockK.P., LevineB.A., ChampnessJ.N., SandersonM.R., SummersW.C., McLeishP.J., & BuchanA.Herpesviral thymidine kinases: laxity and resistance by design.Journal of General Virology1998; 79: 2083–2092.
37.
ChampnessJ.N., BennettM.S., WienF., VisseR., SummersW.C., HerdewijnP., De ClerqE., OstrowskiT., JarvestR.L., & SandersonM.R.Exploring the active site of herpes simplex virus type-1 thymidine kinase by X-ray crystallography of complexes with acyclovir and other ligands.Proteins1998; 32: 350–361.
38.
BlackM.E., & LoebL.A.Identification of important residues within the putative nucleoside binding site of HSV-1 thymidine kinase by random sequence selection: analysis of selected mutants in vitro.Biochemistry1993; 32: 11618–11626.
39.
RobertsG.B., FyfeJ.A., GaillardR.K., & ShortS.A.Mutant varicella-zoster virus thymidine kinase: correlation of clinical resistance and enzyme impairment.Journal of Virology1991; 65: 6407–6413.
40.
SawyerM.H., InchauspeG., BironK.K., WatersD.J., StrausS.E., & OstroveJ.M.Molecular analysis of the pyrimidine deoxyribonucleoside kinase gene of wild-type and acyclovir-resistant strains of varicella-zoster virus.Journal of General Virology1988; 69: 2585–2593.
41.
ParrisD.S., & HarringtonJ.E.Herpes simplex virus variants resistant to high concentrations of acyclovir exist in clinical isolates.Antimicrobial Agents & Chemotherapy1982; 22: 71–77.
42.
HwangC.B., & ChenH.J.An altered spectrum of herpes simplex virus mutations mediated by an antimutator DNA polymerase.Gene1995; 152: 191–193.
43.
BlotN., SchneiderP., YoungP., JanvresseC., DehesdinD., TronP., & VannierJ.P.Treatment of an acyclovir and foscarnet-resistant herpes simplex virus infection with cidofovir in a child after an unrelated bone marrow transplant.Bone Marrow Transplantation2000; 26: 903–905.
