Antiviral Drug Resistance in Herpesviruses

  • Jocelyne Piret
  • Emilien Drouot
  • Guy BoivinEmail author
Reference work entry


The discovery of acyclovir (ACV), a nucleoside analogue, more than 30 years ago, represents a milestone in the management of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. The modest activity of ACV against human cytomegalovirus (HCMV) has prompted the development of another nucleoside analogue, ganciclovir (GCV), for the management of systemic and organ-specific HCMV diseases. Second-line agents such as the pyrophosphate analogue foscarnet (FOS) and the nucleotide analogue cidofovir (CDV) have been approved subsequently. In contrast to ACV and GCV, the latter drugs do not require an initial phosphorylation step by viral protein kinases to be converted into their active forms. Since the introduction of these antivirals, the emergence of drug-resistant mutants has been constantly reported particularly in severely immunocompromised patients such as bone marrow and solid organ transplant recipients as well as human immunodeficiency virus (HIV)-infected individuals. In this chapter, we review the characteristics of the antiviral agents currently approved for the management of HSV, VZV, and HCMV diseases, the laboratory methods for assessing drug susceptibilities, and the clinical significance of drug-resistant infections and their management.


Herpesvirus Herpes simplex virus Varicella-zoster virus Human cytomegalovirus Antiviral drug Resistance Mutations Phenotypic testing Genotypic testing Clinical significance Management Immunocompromised patient 



G. B. is the holder of the Canada Research Chair on emerging viruses and antiviral resistance.


  1. Ahmed AM, Brantley JS, Madkan V et al (2007) Managing herpes zoster in immunocompromised patients. Herpes 14:32–36PubMedGoogle Scholar
  2. Allice T, Busca A, Locatelli F et al (2009) Valganciclovir as pre-emptive therapy for cytomegalovirus infection post-allogenic stem cell transplantation: implications for the emergence of drug-resistant cytomegalovirus. J Antimicrob Chemother 63:600–608PubMedCrossRefGoogle Scholar
  3. Alvarez-McLeod A, Havlik J, Drew KE (1999) Foscarnet treatment of genital infection due to acyclovir-resistant herpes simplex virus type 2 in a pregnant patient with AIDS: case report. Clin Infect Dis 29:937–938PubMedCrossRefGoogle Scholar
  4. Andrei G, Snoeck R (2013) Herpes simplex virus drug-resistance: new mutations and insights. Curr Opin Infect Dis 26:551–560PubMedCrossRefGoogle Scholar
  5. Andrei G, Fiten P, Froeyen M et al (2007) DNA polymerase mutations in drug-resistant herpes simplex virus mutants determine in vivo neurovirulence and drug-enzyme interactions. Antivir Ther 12:719–732PubMedGoogle Scholar
  6. Andrei G, de Clercq E, Snoeck R (2009) Viral genome replication. In: Cameron CE, Gotte M, Raney K (eds) Viral DNA polymerase inhibitors. Springer, New YorkCrossRefGoogle Scholar
  7. Andrei G, Topalis D, Fiten P et al (2012) In vitro-selected drug-resistant varicella-zoster virus mutants in the thymidine kinase and DNA polymerase genes yield novel phenotype-genotype associations and highlight differences between antiherpesvirus drugs. J Virol 86:2641–2652PubMedPubMedCentralCrossRefGoogle Scholar
  8. Asberg A, Humar A, Rollag H et al (2007) Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 7:2106–2113PubMedCrossRefGoogle Scholar
  9. Asberg A, Humar A, Jardine AG et al (2009) Long-term outcomes of CMV disease treatment with valganciclovir versus IV ganciclovir in solid organ transplant recipients. Am J Transplant 9:1205–1213PubMedCrossRefGoogle Scholar
  10. Avery RK, Bolwell BJ, Yen-Lieberman B et al (2004) Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection. Bone Marrow Transplant 34:1071–1075PubMedCrossRefGoogle Scholar
  11. Avery RK, Mossad SB, Poggio E et al (2010) Utility of leflunomide in the treatment of complex cytomegalovirus syndromes. Transplantation 90:419–426PubMedCrossRefGoogle Scholar
  12. Bacon TH, Boon RJ, Schultz M et al (2002) Surveillance for antiviral-agent-resistant herpes simplex virus in the general population with recurrent herpes labialis. Antimicrob Agents Chemother 46:3042–3044PubMedPubMedCentralCrossRefGoogle Scholar
  13. Bacon TH, Levin MJ, Leary JJ et al (2003) Herpes simplex virus resistance to acyclovir and penciclovir after two decades of antiviral therapy. Clin Microbiol Rev 16:114–128PubMedPubMedCentralCrossRefGoogle Scholar
  14. Balasubramaniam NK, Veerisetty V, Gentry GA (1990) Herpesviral deoxythymidine kinases contain a site analogous to the phosphoryl-binding arginine-rich region of porcine adenylate kinase; comparison of secondary structure predictions and conservation. J Gen Virol 71(Pt 12):2979–2987PubMedCrossRefGoogle Scholar
  15. Baldanti F, Underwood MR, Stanat SC et al (1996) Single amino acid changes in the DNA polymerase confer foscarnet resistance and slow-growth phenotype, while mutations in the UL97-encoded phosphotransferase confer ganciclovir resistance in three double-resistant human cytomegalovirus strains recovered from patients with AIDS. J Virol 70:1390–1395PubMedPubMedCentralGoogle Scholar
  16. Bernstein DI, Ireland J, Bourne N (2000) Pathogenesis of acyclovir-resistant herpes simplex type 2 isolates in animal models of genital herpes: models for antiviral evaluations. Antiviral Res 47:159–169PubMedCrossRefGoogle Scholar
  17. Besecker MI, Furness CL, Coen DM et al (2007) Expression of extremely low levels of thymidine kinase from an acyclovir-resistant herpes simplex virus mutant supports reactivation from latently infected mouse trigeminal ganglia. J Virol 81:8356–8360PubMedPubMedCentralCrossRefGoogle Scholar
  18. Bestman-Smith J, Boivin G (2002) Herpes simplex virus isolates with reduced adefovir susceptibility selected in vivo by foscarnet therapy. J Med Virol 67:88–91PubMedCrossRefGoogle Scholar
  19. Bestman-Smith J, Boivin G (2003) Drug resistance patterns of recombinant herpes simplex virus DNA polymerase mutants generated with a set of overlapping cosmids and plasmids. J Virol 77:7820–7829PubMedPubMedCentralCrossRefGoogle Scholar
  20. Bhorade SM, Lurain NS, Jordan A et al (2002) Emergence of ganciclovir-resistant cytomegalovirus in lung transplant recipients. J Heart Lung Transplant 21:1274–1282PubMedCrossRefGoogle Scholar
  21. Biron KK, Stanat SC, Sorrell JB et al (1985) Metabolic activation of the nucleoside analog 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine in human diploid fibroblasts infected with human cytomegalovirus. Proc Natl Acad Sci U S A 82:2473–2477PubMedPubMedCentralCrossRefGoogle Scholar
  22. Biron KK, Harvey RJ, Chamberlain SC et al (2002) Potent and selective inhibition of human cytomegalovirus replication by 1263 W94, a benzimidazole L-riboside with a unique mode of action. Antimicrob Agents Chemother 46:2365–2372PubMedPubMedCentralCrossRefGoogle Scholar
  23. Boeckh M, Huang M, Ferrenberg J et al (2004) Optimization of quantitative detection of cytomegalovirus DNA in plasma by real-time PCR. J Clin Microbiol 42:1142–1148PubMedPubMedCentralCrossRefGoogle Scholar
  24. Bohn K, Zell R, Schacke M et al (2011) Gene polymorphism of thymidine kinase and DNA polymerase in clinical strains of herpes simplex virus. Antivir Ther 16:989–997PubMedCrossRefGoogle Scholar
  25. Boivin G, Edelman CK, Pedneault L et al (1994) Phenotypic and genotypic characterization of acyclovir-resistant varicella-zoster viruses isolated from persons with AIDS. J Infect Dis 170:68–75PubMedCrossRefGoogle Scholar
  26. Boivin G, Gilbert C, Gaudreau A et al (2001) Rate of emergence of cytomegalovirus (CMV) mutations in leukocytes of patients with acquired immunodeficiency syndrome who are receiving valganciclovir as induction and maintenance therapy for CMV retinitis. J Infect Dis 184:1598–1602PubMedCrossRefGoogle Scholar
  27. Boivin G, Goyette N, Gilbert C et al (2004) Absence of cytomegalovirus-resistance mutations after valganciclovir prophylaxis, in a prospective multicenter study of solid-organ transplant recipients. J Infect Dis 189:1615–1618PubMedCrossRefGoogle Scholar
  28. Boivin G, Goyette N, Gilbert C et al (2005a) Analysis of cytomegalovirus DNA polymerase (UL54) mutations in solid organ transplant patients receiving valganciclovir or ganciclovir prophylaxis. J Med Virol 77:425–429PubMedCrossRefGoogle Scholar
  29. Boivin G, Goyette N, Gilbert C et al (2005b) Clinical impact of ganciclovir-resistant cytomegalovirus infections in solid organ transplant patients. Transpl Infect Dis 7:166–170PubMedCrossRefGoogle Scholar
  30. Boivin G, Goyette N, Rollag H et al (2009) Cytomegalovirus resistance in solid organ transplant recipients treated with intravenous ganciclovir or oral valganciclovir. Antivir Ther 14:697–704PubMedGoogle Scholar
  31. Boivin G, Goyette N, Farhan M et al (2012) Incidence of cytomegalovirus UL97 and UL54 amino acid substitutions detected after 100 or 200 days of valganciclovir prophylaxis. J Clin Virol 53:208–213PubMedCrossRefGoogle Scholar
  32. Boon RJ, Bacon TH, Robey HL et al (2000) Antiviral susceptibilities of herpes simplex virus from immunocompetent subjects with recurrent herpes labialis: a UK-based survey. J Antimicrob Chemother 46:324–325PubMedCrossRefGoogle Scholar
  33. Boutolleau D, Burrel S, Agut H (2011) Genotypic characterization of human cytomegalovirus UL97 phosphotransferase natural polymorphism in the era of ganciclovir and maribavir. Antiviral Res 91:32–35PubMedCrossRefGoogle Scholar
  34. Breton G, Fillet AM, Katlama C et al (1998) Acyclovir-resistant herpes zoster in human immunodeficiency virus-infected patients: results of foscarnet therapy. Clin Infect Dis 27:1525–1527PubMedCrossRefGoogle Scholar
  35. Brink AA, van Gelder M, Wolffs PF et al (2011) Compartmentalization of acyclovir-resistant varicella zoster virus: implications for sampling in molecular diagnostics. Clin Infect Dis 52:982–987PubMedCrossRefGoogle Scholar
  36. Bryan CJ, Prichard MN, Daily S et al (2008) Acyclovir-resistant chronic verrucous vaccine strain varicella in a patient with neuroblastoma. Pediatr Infect Dis J 27:946–948PubMedCrossRefGoogle Scholar
  37. Burrel S, Deback C, Agut H et al (2010) Genotypic characterization of UL23 thymidine kinase and UL30 DNA polymerase of clinical isolates of herpes simplex virus: natural polymorphism and mutations associated with resistance to antivirals. Antimicrob Agents Chemother 54:4833–4842PubMedPubMedCentralCrossRefGoogle Scholar
  38. Burrel S, Bonnafous P, Hubacek P et al (2012) Impact of novel mutations of herpes simplex virus 1 and 2 thymidine kinases on acyclovir phosphorylation activity. Antiviral Res 96:386–390PubMedCrossRefGoogle Scholar
  39. Burrel S, Aime C, Hermet L et al (2013a) Surveillance of herpes simplex virus resistance to antivirals: a 4-year survey. Antiviral Res 100:365–372PubMedCrossRefGoogle Scholar
  40. Burrel S, Boutolleau D, Azar G et al (2013b) Phenotypic and genotypic characterization of acyclovir-resistant corneal HSV-1 isolates from immunocompetent patients with recurrent herpetic keratitis. J Clin Virol 58:321–324PubMedCrossRefGoogle Scholar
  41. Castelo-Soccio L, Bernardin R, Stern J et al (2010) Successful treatment of acyclovir-resistant herpes simplex virus with intralesional cidofovir. Arch Dermatol 146:124–126PubMedPubMedCentralCrossRefGoogle Scholar
  42. Chakrabarti S, Pillay D, Ratcliffe D et al (2000) Resistance to antiviral drugs in herpes simplex virus infections among allogeneic stem cell transplant recipients: risk factors and prognostic significance. J Infect Dis 181:2055–2058PubMedCrossRefGoogle Scholar
  43. Chatis PA, Miller CH, Schrager LE et al (1989) Successful treatment with foscarnet of an acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with acquired immunodeficiency syndrome. N Engl J Med 320:297–300PubMedCrossRefGoogle Scholar
  44. Chen SH, Cook WJ, Grove KL et al (1998) Human thymidine kinase can functionally replace herpes simplex virus type 1 thymidine kinase for viral replication in mouse sensory ganglia and reactivation from latency upon explant. J Virol 72:6710–6715PubMedPubMedCentralGoogle Scholar
  45. Chen Y, Scieux C, Garrait V et al (2000) Resistant herpes simplex virus type 1 infection: an emerging concern after allogeneic stem cell transplantation. Clin Infect Dis 31:927–935PubMedCrossRefGoogle Scholar
  46. Chen SH, Pearson A, Coen DM et al (2004) Failure of thymidine kinase-negative herpes simplex virus to reactivate from latency following efficient establishment. J Virol 78:520–523PubMedPubMedCentralCrossRefGoogle Scholar
  47. Chevillotte M, von Einem J, Meier BM et al (2010) A new tool linking human cytomegalovirus drug resistance mutations to resistance phenotypes. Antiviral Res 85:318–327PubMedCrossRefGoogle Scholar
  48. Chibo D, Druce J, Sasadeusz J et al (2004) Molecular analysis of clinical isolates of acyclovir resistant herpes simplex virus. Antiviral Res 61:83–91PubMedCrossRefGoogle Scholar
  49. Chilukuri S, Rosen T (2003) Management of acyclovir-resistant herpes simplex virus. Dermatol Clin 21:311–320PubMedCrossRefGoogle Scholar
  50. Chong AS, Zeng H, Knight DA et al (2006) Concurrent antiviral and immunosuppressive activities of leflunomide in vivo. Am J Transplant 6:69–75PubMedCrossRefGoogle Scholar
  51. Chou S (2008) Cytomegalovirus UL97 mutations in the era of ganciclovir and maribavir. Rev Med Virol 18:233–246PubMedCrossRefGoogle Scholar
  52. Chou S (2010) Recombinant phenotyping of cytomegalovirus UL97 kinase sequence variants for ganciclovir resistance. Antimicrob Agents Chemother 54:2371–2378PubMedPubMedCentralCrossRefGoogle Scholar
  53. Chou S, Meichsner CL (2000) A nine-codon deletion mutation in the cytomegalovirus UL97 phosphotransferase gene confers resistance to ganciclovir. Antimicrob Agents Chemother 44:183–185PubMedPubMedCentralCrossRefGoogle Scholar
  54. Chou S, Erice A, Jordan MC et al (1995a) Analysis of the UL97 phosphotransferase coding sequence in clinical cytomegalovirus isolates and identification of mutations conferring ganciclovir resistance. J Infect Dis 171:576–583PubMedCrossRefGoogle Scholar
  55. Chou S, Guentzel S, Michels KR et al (1995b) Frequency of UL97 phosphotransferase mutations related to ganciclovir resistance in clinical cytomegalovirus isolates. J Infect Dis 172:239–242PubMedCrossRefGoogle Scholar
  56. Chou S, Marousek G, Guentzel S et al (1997) Evolution of mutations conferring multidrug resistance during prophylaxis and therapy for cytomegalovirus disease. J Infect Dis 176:786–789PubMedCrossRefGoogle Scholar
  57. Chou S, Lurain NS, Weinberg A et al (1999) Interstrain variation in the human cytomegalovirus DNA polymerase sequence and its effect on genotypic diagnosis of antiviral drug resistance. Adult AIDS Clinical Trials Group CMV Laboratories. Antimicrob Agents Chemother 43:1500–1502PubMedPubMedCentralGoogle Scholar
  58. Chou S, Miner RC, Drew WL (2000) A deletion mutation in region V of the cytomegalovirus DNA polymerase sequence confers multidrug resistance. J Infect Dis 182:1765–1768PubMedCrossRefGoogle Scholar
  59. Chou S, Waldemer RH, Senters AE et al (2002) Cytomegalovirus UL97 phosphotransferase mutations that affect susceptibility to ganciclovir. J Infect Dis 185:162–169PubMedCrossRefGoogle Scholar
  60. Chou S, Lurain NS, Thompson KD et al (2003) Viral DNA polymerase mutations associated with drug resistance in human cytomegalovirus. J Infect Dis 188:32–39PubMedCrossRefGoogle Scholar
  61. Chou S, Marousek GI, Van Wechel LC et al (2007a) Growth and drug resistance phenotypes resulting from cytomegalovirus DNA polymerase region III mutations observed in clinical specimens. Antimicrob Agents Chemother 51:4160–4162PubMedPubMedCentralCrossRefGoogle Scholar
  62. Chou S, Wechel LC, Marousek GI (2007b) Cytomegalovirus UL97 kinase mutations that confer maribavir resistance. J Infect Dis 196:91–94PubMedCrossRefGoogle Scholar
  63. Chou S, Marousek G, Li S et al (2008) Contrasting drug resistance phenotypes resulting from cytomegalovirus DNA polymerase mutations at the same exonuclease locus. J Clin Virol 43:107–109PubMedPubMedCentralCrossRefGoogle Scholar
  64. Chou S, Hakki M, Villano S (2012) Effects on maribavir susceptibility of cytomegalovirus UL97 kinase ATP binding region mutations detected after drug exposure in vitro and in vivo. Antiviral Res 95:88–92PubMedPubMedCentralCrossRefGoogle Scholar
  65. Christophers J, Clayton J, Craske J et al (1998) Survey of resistance of herpes simplex virus to acyclovir in northwest England. Antimicrob Agents Chemother 42:868–872PubMedPubMedCentralGoogle Scholar
  66. Cihlar T, Fuller MD, Cherrington JM (1998a) Characterization of drug resistance-associated mutations in the human cytomegalovirus DNA polymerase gene by using recombinant mutant viruses generated from overlapping DNA fragments. J Virol 72:5927–5936PubMedPubMedCentralGoogle Scholar
  67. Cihlar T, Fuller MD, Mulato AS et al (1998b) A point mutation in the human cytomegalovirus DNA polymerase gene selected in vitro by cidofovir confers a slow replication phenotype in cell culture. Virology 248:382–393PubMedCrossRefGoogle Scholar
  68. Coen DM (1994) Acyclovir-resistant, pathogenic herpesviruses. Trends Microbiol 2:481–485PubMedCrossRefGoogle Scholar
  69. Coen DM, Kosz-Vnenchak M, Jacobson JG et al (1989) Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate. Proc Natl Acad Sci U S A 86:4736–4740PubMedPubMedCentralCrossRefGoogle Scholar
  70. Collins P, Ellis MN (1993) Sensitivity monitoring of clinical isolates of herpes simplex virus to acyclovir. J Med Virol Suppl 1:58–66CrossRefGoogle Scholar
  71. Couzi L, Helou S, Bachelet T et al (2012) High incidence of anticytomegalovirus drug resistance among D + R- kidney transplant recipients receiving preemptive therapy. Am J Transplant 12:202–209PubMedCrossRefGoogle Scholar
  72. Crassard N, Souillet AL, Morfin F et al (2000) Acyclovir-resistant varicella infection with atypical lesions in a non-HIV leukemic infant. Acta Paediatr 89:1497–1499PubMedCrossRefGoogle Scholar
  73. Dambrosi S, Martin M, Yim K et al (2010) Neurovirulence and latency of drug-resistant clinical herpes simplex viruses in animal models. J Med Virol 82:1000–1006PubMedCrossRefGoogle Scholar
  74. Danve-Szatanek C, Aymard M, Thouvenot D et al (2004) Surveillance network for herpes simplex virus resistance to antiviral drugs: 3-year follow-up. J Clin Microbiol 42:242–249PubMedPubMedCentralCrossRefGoogle Scholar
  75. Drew WL (2006) Is combination antiviral therapy for CMV superior to monotherapy? J Clin Virol 35:485–488PubMedCrossRefGoogle Scholar
  76. Drew WL, Miner RC, Busch DF et al (1991) Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection. J Infect Dis 163:716–719PubMedCrossRefGoogle Scholar
  77. Drew WL, Miner R, Saleh E (1993) Antiviral susceptibility testing of cytomegalovirus: criteria for detecting resistance to antivirals. Clin Diagn Virol 1:179–185PubMedCrossRefGoogle Scholar
  78. Drouot E, Piret J, Boivin G (2013) Novel method based on “en passant” mutagenesis coupled with a Gaussia luciferase reporter assay for studying the combined effects of human cytomegalovirus mutations. J Clin Microbiol 51:3216–3224PubMedPubMedCentralCrossRefGoogle Scholar
  79. Duan R, de Vries RD, Osterhaus AD et al (2008) Acyclovir-resistant corneal HSV-1 isolates from patients with herpetic keratitis. J Infect Dis 198:659–663PubMedCrossRefGoogle Scholar
  80. Duan R, de Vries RD, van Dun JM et al (2009) Acyclovir susceptibility and genetic characteristics of sequential herpes simplex virus type 1 corneal isolates from patients with recurrent herpetic keratitis. J Infect Dis 200:1402–1414PubMedCrossRefGoogle Scholar
  81. Dunn JH, Weinberg A, Chan LK et al (2013) Long-term suppression of multidrug-resistant cytomegalovirus retinitis with systemically administered leflunomide. JAMA Ophthalmol 131:958–960PubMedCrossRefGoogle Scholar
  82. Efstathiou S, Kemp S, Darby G et al (1989) The role of herpes simplex virus type 1 thymidine kinase in pathogenesis. J Gen Virol 70(Pt 4):869–879PubMedCrossRefGoogle Scholar
  83. Eid AJ, Arthurs SK, Deziel PJ et al (2008) Emergence of drug-resistant cytomegalovirus in the era of valganciclovir prophylaxis: therapeutic implications and outcomes. Clin Transplant 22:162–170PubMedCrossRefGoogle Scholar
  84. Emery VC, Cope AV, Bowen EF et al (1999) The dynamics of human cytomegalovirus replication in vivo. J Exp Med 190:177–182PubMedPubMedCentralCrossRefGoogle Scholar
  85. Engel JP, Englund JA, Fletcher CV et al (1990) Treatment of resistant herpes simplex virus with continuous-infusion acyclovir. JAMA 263:1662–1664PubMedCrossRefGoogle Scholar
  86. Englund JA, Zimmerman ME, Swierkosz EM et al (1990) Herpes simplex virus resistant to acyclovir. A study in a tertiary care center. Ann Intern Med 112:416–422PubMedCrossRefGoogle Scholar
  87. Erard V, Wald A, Corey L et al (2007) Use of long-term suppressive acyclovir after hematopoietic stem-cell transplantation: impact on herpes simplex virus (HSV) disease and drug-resistant HSV disease. J Infect Dis 196:266–270PubMedCrossRefGoogle Scholar
  88. Erice A (1999) Resistance of human cytomegalovirus to antiviral drugs. Clin Microbiol Rev 12:286–297PubMedPubMedCentralGoogle Scholar
  89. Erlich KS, Jacobson MA, Koehler JE et al (1989) Foscarnet therapy for severe acyclovir-resistant herpes simplex virus type-2 infections in patients with the acquired immunodeficiency syndrome (AIDS). An uncontrolled trial. Ann Intern Med 110:710–713PubMedCrossRefGoogle Scholar
  90. Evans JS, Lock KP, Levine BA et al (1998) Herpesviral thymidine kinases: laxity and resistance by design. J Gen Virol 79(Pt 9):2083–2092PubMedCrossRefGoogle Scholar
  91. Evans KG, Morrissey KA, Goldstein SC et al (2011) Chronic acyclovir-resistant HSV-2 ulcer in an immunosuppressed patient treated with topical cidofovir. Arch Dermatol 147:1462–1463PubMedCrossRefGoogle Scholar
  92. Field HJ, Coen DM (1986) Pathogenicity of herpes simplex virus mutants containing drug resistance mutations in the viral DNA polymerase gene. J Virol 60:286–289PubMedPubMedCentralGoogle Scholar
  93. Fillet AM, Visse B, Caumes E et al (1995) Foscarnet-resistant multidermatomal zoster in a patient with AIDS. Clin Infect Dis 21:1348–1349PubMedCrossRefGoogle Scholar
  94. Fillet AM, Dumont B, Caumes E et al (1998) Acyclovir-resistant varicella-zoster virus: phenotypic and genetic characterization. J Med Virol 55:250–254PubMedCrossRefGoogle Scholar
  95. Fillet AM, Auray L, Alain S et al (2004) Natural polymorphism of cytomegalovirus DNA polymerase lies in two nonconserved regions located between domains delta-C and II and between domains III and I. Antimicrob Agents Chemother 48:1865–1868PubMedPubMedCentralCrossRefGoogle Scholar
  96. Frangoul H, Wills M, Crossno C et al (2007) Acyclovir-resistant herpes simplex virus pneumonia post-unrelated stem cell transplantation: a word of caution. Pediatr Transplant 11:942–944PubMedCrossRefGoogle Scholar
  97. Frobert E, Thouvenot D, Lina B et al (2007) Genotyping diagnosis of acyclovir resistant herpes simplex virus. Pathol Biol (Paris) 55:504–511CrossRefGoogle Scholar
  98. Frobert E, Cortay JC, Ooka T et al (2008) Genotypic detection of acyclovir-resistant HSV-1: characterization of 67 ACV-sensitive and 14 ACV-resistant viruses. Antiviral Res 79:28–36PubMedCrossRefGoogle Scholar
  99. Gateley A, Gander RM, Johnson PC et al (1990) Herpes simplex virus type 2 meningoencephalitis resistant to acyclovir in a patient with AIDS. J Infect Dis 161:711–715PubMedCrossRefGoogle Scholar
  100. Gaudreau A, Hill E, Balfour HH Jr et al (1998) Phenotypic and genotypic characterization of acyclovir-resistant herpes simplex viruses from immunocompromised patients. J Infect Dis 178:297–303PubMedCrossRefGoogle Scholar
  101. Gilbert C, Boivin G (2005) Human cytomegalovirus resistance to antiviral drugs. Antimicrob Agents Chemother 49:873–883PubMedPubMedCentralCrossRefGoogle Scholar
  102. Gilbert C, Roy J, Belanger R et al (2001) Lack of emergence of cytomegalovirus UL97 mutations conferring ganciclovir (GCV) resistance following preemptive GCV therapy in allogeneic stem cell transplant recipients. Antimicrob Agents Chemother 45:3669–3671PubMedPubMedCentralCrossRefGoogle Scholar
  103. Gilbert C, Bestman-Smith J, Boivin G (2002) Resistance of herpesviruses to antiviral drugs: clinical impacts and molecular mechanisms. Drug Resist Updat 5:88–114PubMedCrossRefGoogle Scholar
  104. Gill RB, Frederick SL, Hartline CB et al (2009) Conserved retinoblastoma protein-binding motif in human cytomegalovirus UL97 kinase minimally impacts viral replication but affects susceptibility to maribavir. Virol J 6:9PubMedPubMedCentralCrossRefGoogle Scholar
  105. Gimeno C, Solano C, Latorre JC et al (2008) Quantification of DNA in plasma by an automated real-time PCR assay (cytomegalovirus PCR kit) for surveillance of active cytomegalovirus infection and guidance of preemptive therapy for allogeneic hematopoietic stem cell transplant recipients. J Clin Microbiol 46:3311–3318PubMedPubMedCentralCrossRefGoogle Scholar
  106. Goldner T, Hewlett G, Ettischer N et al (2011) The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase. J Virol 85:10884–10893PubMedPubMedCentralCrossRefGoogle Scholar
  107. Goldner T, Hempel C, Ruebsamen-Schaeff H et al (2014) Geno- and phenotypic characterization of human cytomegalovirus mutants selected in vitro after letermovir (AIC246) exposure. Antimicrob Agents Chemother 58:610–613PubMedPubMedCentralCrossRefGoogle Scholar
  108. Gorzer I, Guelly C, Trajanoski S et al (2010) Deep sequencing reveals highly complex dynamics of human cytomegalovirus genotypes in transplant patients over time. J Virol 84:7195–7203PubMedPubMedCentralCrossRefGoogle Scholar
  109. Greco A, Diaz JJ, Thouvenot D et al (2007) Novel targets for the development of anti-herpes compounds. Infect Disord Drug Targets 7:11–18PubMedCrossRefGoogle Scholar
  110. Hall JD, Orth KL, Sander KL et al (1995) Mutations within conserved motifs in the 3′–5′ exonuclease domain of herpes simplex virus DNA polymerase. J Gen Virol 76(Pt 12):2999–3008PubMedCrossRefGoogle Scholar
  111. Hamprecht K, Eckle T, Prix L et al (2003) Ganciclovir-resistant cytomegalovirus disease after allogeneic stem cell transplantation: pitfalls of phenotypic diagnosis by in vitro selection of an UL97 mutant strain. J Infect Dis 187:139–143PubMedCrossRefGoogle Scholar
  112. Hanks SK, Quinn AM, Hunter T (1988) The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241:42–52PubMedCrossRefGoogle Scholar
  113. Hantz S, Garnier-Geoffroy F, Mazeron MC et al (2010) Drug-resistant cytomegalovirus in transplant recipients: a French cohort study. J Antimicrob Chemother 65:2628–2640PubMedCrossRefGoogle Scholar
  114. Hostetler KY (2010) Synthesis and early development of hexadecyloxypropylcidofovir: an oral antipoxvirus nucleoside phosphonate. Viruses 2:2213–2225PubMedPubMedCentralCrossRefGoogle Scholar
  115. Humar A, Kumar D, Preiksaitis J et al (2005) A trial of valganciclovir prophylaxis for cytomegalovirus prevention in lung transplant recipients. Am J Transplant 5:1462–1468PubMedCrossRefGoogle Scholar
  116. Hwang CB, Ruffner KL, Coen DM (1992) A point mutation within a distinct conserved region of the herpes simplex virus DNA polymerase gene confers drug resistance. J Virol 66:1774–1776PubMedPubMedCentralGoogle Scholar
  117. Jabs DA (1995) Ocular manifestations of HIV infection. Trans Am Ophthalmol Soc 93:623–683PubMedPubMedCentralGoogle Scholar
  118. Jabs DA, Enger C, Dunn JP et al (1998a) Cytomegalovirus retinitis and viral resistance: ganciclovir resistance. J Infect Dis 177:770–773PubMedCrossRefGoogle Scholar
  119. Jabs DA, Enger C, Forman M et al (1998b) Incidence of foscarnet resistance and cidofovir resistance in patients treated for cytomegalovirus retinitis. The Cytomegalovirus Retinitis and Viral Resistance Study Group. Antimicrob Agents Chemother 42:2240–2244PubMedPubMedCentralGoogle Scholar
  120. James SH, Prichard MN (2011) The genetic basis of human cytomegalovirus resistance and current trends in antiviral resistance analysis. Infect Disord Drug Targets 11:504–513PubMedPubMedCentralCrossRefGoogle Scholar
  121. James SH, Prichard MN (2013) A possible pitfall in acyclovir prophylaxis for recurrent herpetic keratitis? J Infect Dis 208:1353–1355PubMedCrossRefGoogle Scholar
  122. Javaly K, Wohlfeiler M, Kalayjian R et al (1999) Treatment of mucocutaneous herpes simplex virus infections unresponsive to acyclovir with topical foscarnet cream in AIDS patients: a phase I/II study. J Acquir Immune Defic Syndr 21:301–306PubMedCrossRefGoogle Scholar
  123. Jeong TD, Sung H, Choi SH et al (2012) Cytomegalovirus ventriculoencephalitis with compartmentalization of antiviral-resistant cytomegalovirus in a T cell-depleted haploidentical peripheral blood stem cell transplant recipient. Diagn Microbiol Infect Dis 74:307–310PubMedCrossRefGoogle Scholar
  124. Kamiyama T, Kurokawa M, Shiraki K (2001) Characterization of the DNA polymerase gene of varicella-zoster viruses resistant to acyclovir. J Gen Virol 82:2761–2765PubMedCrossRefGoogle Scholar
  125. Kampmann SE, Schindele B, Apelt L et al (2011) Pyrosequencing allows the detection of emergent ganciclovir resistance mutations after HCMV infection. Med Microbiol Immunol 200:109–113PubMedCrossRefGoogle Scholar
  126. Kaptein SJ, Efferth T, Leis M et al (2006) The anti-malaria drug artesunate inhibits replication of cytomegalovirus in vitro and in vivo. Antiviral Res 69:60–69PubMedCrossRefGoogle Scholar
  127. Kaul DR, Stoelben S, Cober E et al (2011) First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246. Am J Transplant 11:1079–1084PubMedCrossRefGoogle Scholar
  128. Kim JH, Schaenman JM, Ho DY et al (2011) Treatment of acyclovir-resistant herpes simplex virus with continuous infusion of high-dose acyclovir in hematopoietic cell transplant patients. Biol Blood Marrow Transplant 17:259–264PubMedCrossRefGoogle Scholar
  129. Komatsu TE, Pikis A, Naeger LK et al (2014) Resistance of human cytomegalovirus to ganciclovir/valganciclovir: a comprehensive review of putative resistance pathways. Antiviral Res 101:12–25PubMedCrossRefGoogle Scholar
  130. Kopp T, Geusau A, Rieger A et al (2002) Successful treatment of an aciclovir-resistant herpes simplex type 2 infection with cidofovir in an AIDS patient. Br J Dermatol 147:134–138PubMedCrossRefGoogle Scholar
  131. Kotton CN, Kumar D, Caliendo AM et al (2013) Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 96:333–360PubMedCrossRefGoogle Scholar
  132. Lalezari J, Schacker T, Feinberg J et al (1997) A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. J Infect Dis 176:892–898PubMedCrossRefGoogle Scholar
  133. Landry ML, Stanat S, Biron K et al (2000) A standardized plaque reduction assay for determination of drug susceptibilities of cytomegalovirus clinical isolates. Antimicrob Agents Chemother 44:688–692PubMedPubMedCentralCrossRefGoogle Scholar
  134. Langston AA, Redei I, Caliendo AM et al (2002) Development of drug-resistant herpes simplex virus infection after haploidentical hematopoietic progenitor cell transplantation. Blood 99:1085–1088PubMedCrossRefGoogle Scholar
  135. Lascaux AS, Caumes E, Deback C et al (2012) Successful treatment of aciclovir and foscarnet resistant Herpes simplex virus lesions with topical imiquimod in patients infected with human immunodeficiency virus type 1. J Med Virol 84:194–197PubMedCrossRefGoogle Scholar
  136. Le Page AK, Jager MM, Iwasenko JM et al (2013) Clinical aspects of cytomegalovirus antiviral resistance in solid organ transplant recipients. Clin Infect Dis 56:1018–1029PubMedCrossRefGoogle Scholar
  137. Levin MJ, Dahl KM, Weinberg A et al (2003) Development of resistance to acyclovir during chronic infection with the Oka vaccine strain of varicella-zoster virus, in an immunosuppressed child. J Infect Dis 188:954–959PubMedCrossRefGoogle Scholar
  138. Levin MJ, Bacon TH, Leary JJ (2004) Resistance of herpes simplex virus infections to nucleoside analogues in HIV-infected patients. Clin Infect Dis 39(Suppl 5):S248–S257PubMedCrossRefGoogle Scholar
  139. Limaye AP (2002) Ganciclovir-resistant cytomegalovirus in organ transplant recipients. Clin Infect Dis 35:866–872PubMedCrossRefGoogle Scholar
  140. Limaye AP, Corey L, Koelle DM et al (2000) Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet 356:645–649PubMedCrossRefGoogle Scholar
  141. Limaye AP, Raghu G, Koelle DM et al (2002) High incidence of ganciclovir-resistant cytomegalovirus infection among lung transplant recipients receiving preemptive therapy. J Infect Dis 185:20–27PubMedCrossRefGoogle Scholar
  142. Lisboa LF, Asberg A, Kumar D et al (2011) The clinical utility of whole blood versus plasma cytomegalovirus viral load assays for monitoring therapeutic response. Transplantation 91:231–236PubMedCrossRefGoogle Scholar
  143. Lischka P, Hewlett G, Wunberg T et al (2010) In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. Antimicrob Agents Chemother 54:1290–1297PubMedPubMedCentralCrossRefGoogle Scholar
  144. Liu S, Homa FL (2009) Viral genome replication. In: Cameron CE, Gotte M, Raney K (eds) Atomic structure of the herpes simplex virus 1 DNA polymerase. Springer, New YorkCrossRefGoogle Scholar
  145. Ljungman P, Ellis MN, Hackman RC et al (1990) Acyclovir-resistant herpes simplex virus causing pneumonia after marrow transplantation. J Infect Dis 162:244–248PubMedCrossRefGoogle Scholar
  146. Lolis MS, Gonzalez L, Cohen PJ et al (2008) Drug-resistant herpes simplex virus in HIV infected patients. Acta Dermatovenerol Croat 16:204–208PubMedGoogle Scholar
  147. LoPresti AE, Levine JF, Munk GB et al (1998) Successful treatment of an acyclovir- and foscarnet-resistant herpes simplex virus type 1 lesion with intravenous cidofovir. Clin Infect Dis 26:512–513PubMedCrossRefGoogle Scholar
  148. Lurain NS, Chou S (2010) Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev 23:689–712PubMedPubMedCentralCrossRefGoogle Scholar
  149. Lurain NS, Spafford LE, Thompson KD (1994) Mutation in the UL97 open reading frame of human cytomegalovirus strains resistant to ganciclovir. J Virol 68:4427–4431PubMedPubMedCentralGoogle Scholar
  150. Lurain NS, Bhorade SM, Pursell KJ et al (2002) Analysis and characterization of antiviral drug-resistant cytomegalovirus isolates from solid organ transplant recipients. J Infect Dis 186:760–768PubMedCrossRefGoogle Scholar
  151. Malartre N, Boulieu R, Falah N et al (2012) Effects of mutations on herpes simplex virus 1 thymidine kinase functionality: an in vitro assay based on detection of monophosphate forms of acyclovir and thymidine using HPLC/DAD. Antiviral Res 95:224–228PubMedCrossRefGoogle Scholar
  152. Malvy D, Treilhaud M, Bouee S et al (2005) A retrospective, case–control study of acyclovir resistance in herpes simplex virus. Clin Infect Dis 41:320–326PubMedCrossRefGoogle Scholar
  153. Marfori JE, Exner MM, Marousek GI et al (2007) Development of new cytomegalovirus UL97 and DNA polymerase mutations conferring drug resistance after valganciclovir therapy in allogeneic stem cell recipients. J Clin Virol 38:120–125PubMedCrossRefGoogle Scholar
  154. Martin BK, Ricks MO, Forman MS et al (2007) Change over time in incidence of ganciclovir resistance in patients with cytomegalovirus retinitis. Clin Infect Dis 44:1001–1008PubMedCrossRefGoogle Scholar
  155. Martin M, Goyette N, Boivin G (2010a) Contrasting effects on ganciclovir susceptibility and replicative capacity of two mutations at codon 466 of the human cytomegalovirus UL97 gene. J Clin Virol 49:296–298PubMedCrossRefGoogle Scholar
  156. Martin M, Goyette N, Ives J et al (2010b) Incidence and characterization of cytomegalovirus resistance mutations among pediatric solid organ transplant patients who received valganciclovir prophylaxis. J Clin Virol 47:321–324PubMedCrossRefGoogle Scholar
  157. Marty FM, Ljungman P, Papanicolaou GA et al (2011) Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Infect Dis 11:284–292PubMedCrossRefGoogle Scholar
  158. Marty FM, Winston DJ, Rowley SD et al (2013) CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med 369:1227–1236PubMedCrossRefGoogle Scholar
  159. Morfin F, Thouvenot D (2003) Herpes simplex virus resistance to antiviral drugs. J Clin Virol 26:29–37PubMedCrossRefGoogle Scholar
  160. Morfin F, Thouvenot D, De Turenne-Tessier M et al (1999) Phenotypic and genetic characterization of thymidine kinase from clinical strains of varicella-zoster virus resistant to acyclovir. Antimicrob Agents Chemother 43:2412–2416PubMedPubMedCentralGoogle Scholar
  161. Morfin F, Souillet G, Bilger K et al (2000) Genetic characterization of thymidine kinase from acyclovir-resistant and -susceptible herpes simplex virus type 1 isolated from bone marrow transplant recipients. J Infect Dis 182:290–293PubMedCrossRefGoogle Scholar
  162. Morfin F, Bilger K, Boucher A et al (2004) HSV excretion after bone marrow transplantation: a 4-year survey. J Clin Virol 30:341–345PubMedCrossRefGoogle Scholar
  163. Myhre HA, Haug Dorenberg D, Kristiansen KI et al (2011) Incidence and outcomes of ganciclovir-resistant cytomegalovirus infections in 1244 kidney transplant recipients. Transplantation 92:217–223PubMedCrossRefGoogle Scholar
  164. Nichols WG, Corey L, Gooley T et al (2001) Rising pp 65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: risk factors, correlation with DNA load, and outcomes. Blood 97:867–874PubMedCrossRefGoogle Scholar
  165. Nichols WG, Boeckh M, Carter RA et al (2003) Transferred herpes simplex virus immunity after stem-cell transplantation: clinical implications. J Infect Dis 187:801–808PubMedCrossRefGoogle Scholar
  166. Nugier F, Colin JN, Aymard M et al (1992) Occurrence and characterization of acyclovir-resistant herpes simplex virus isolates: report on a two-year sensitivity screening survey. J Med Virol 36:1–12PubMedCrossRefGoogle Scholar
  167. Oberg B (1989) Antiviral effects of phosphonoformate (PFA, foscarnet sodium). Pharmacol Ther 40:213–285PubMedCrossRefGoogle Scholar
  168. Ozaki KS, Camara NO, Nogueira E et al (2007) The use of sirolimus in ganciclovir-resistant cytomegalovirus infections in renal transplant recipients. Clin Transplant 21:675–680PubMedCrossRefGoogle Scholar
  169. Pan D, Kaye SB, Hopkins M et al (2014) Common and new acyclovir resistant herpes simplex virus-1 mutants causing bilateral recurrent herpetic keratitis in an immunocompetent patient. J Infect Dis 209:345–349PubMedCrossRefGoogle Scholar
  170. Paya C, Humar A, Dominguez E et al (2004) Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 4:611–620PubMedCrossRefGoogle Scholar
  171. Pechere M, Wunderli W, Trellu-Toutous L et al (1998) Treatment of acyclovir-resistant herpetic ulceration with topical foscarnet and antiviral sensitivity analysis. Dermatology 197:278–280PubMedCrossRefGoogle Scholar
  172. Pelosi E, Rozenberg F, Coen DM et al (1998) A herpes simplex virus DNA polymerase mutation that specifically attenuates neurovirulence in mice. Virology 252:364–372PubMedCrossRefGoogle Scholar
  173. Pescovitz MD, Rabkin J, Merion RM et al (2000) Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents Chemother 44:2811–2815PubMedPubMedCentralCrossRefGoogle Scholar
  174. Piiparinen H, Hockerstedt K, Gronhagen-Riska C et al (2004) Comparison of two quantitative CMV PCR tests, Cobas Amplicor CMV Monitor and TaqMan assay, and pp 65-antigenemia assay in the determination of viral loads from peripheral blood of organ transplant patients. J Clin Virol 30:258–266PubMedCrossRefGoogle Scholar
  175. Piret J, Boivin G (2011) Resistance of herpes simplex viruses to nucleoside analogues: mechanisms, prevalence, and management. Antimicrob Agents Chemother 55:459–472PubMedCrossRefGoogle Scholar
  176. Piret J, Boivin G (2014) Antiviral drug resistance in herpesviruses other than cytomegalovirus. Rev Med Virol 24:186–218PubMedCrossRefGoogle Scholar
  177. Pottage JC, Kessler HA (1995) Herpes simplex virus resistance to acyclovir: clinical relevance. Infect Agents Dis 4:115–124PubMedGoogle Scholar
  178. Prichard MN, Gao N, Jairath S et al (1999) A recombinant human cytomegalovirus with a large deletion in UL97 has a severe replication deficiency. J Virol 73:5663–5670PubMedPubMedCentralGoogle Scholar
  179. Reardon JE, Spector T (1989) Herpes simplex virus type 1 DNA polymerase. Mechanism of inhibition by acyclovir triphosphate. J Biol Chem 264:7405–7411PubMedGoogle Scholar
  180. Reusser P, Cordonnier C, Einsele H et al (1996) European survey of herpesvirus resistance to antiviral drugs in bone marrow transplant recipients. Infectious diseases working party of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 17:813–817PubMedGoogle Scholar
  181. Reyes M, Shaik NS, Graber JM et al (2003) Acyclovir-resistant genital herpes among persons attending sexually transmitted disease and human immunodeficiency virus clinics. Arch Intern Med 163:76–80PubMedCrossRefGoogle Scholar
  182. Roberts GB, Fyfe JA, Gaillard RK et al (1991) Mutant varicella-zoster virus thymidine kinase: correlation of clinical resistance and enzyme impairment. J Virol 65:6407–6413PubMedPubMedCentralGoogle Scholar
  183. Sacks SL, Shafran SD, Diaz-Mitoma F et al (1998) A multicenter phase I/II dose escalation study of single-dose cidofovir gel for treatment of recurrent genital herpes. Antimicrob Agents Chemother 42:2996–2999PubMedPubMedCentralGoogle Scholar
  184. Safrin S, Assaykeen T, Follansbee S et al (1990) Foscarnet therapy for acyclovir-resistant mucocutaneous herpes simplex virus infection in 26 AIDS patients: preliminary data. J Infect Dis 161:1078–1084PubMedCrossRefGoogle Scholar
  185. Safrin S, Berger TG, Gilson I et al (1991) Foscarnet therapy in five patients with AIDS and acyclovir-resistant varicella-zoster virus infection. Ann Intern Med 115:19–21PubMedCrossRefGoogle Scholar
  186. Safrin S, Elbeik T, Phan L et al (1994a) Correlation between response to acyclovir and foscarnet therapy and in vitro susceptibility result for isolates of herpes simplex virus from human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 38:1246–1250PubMedPubMedCentralCrossRefGoogle Scholar
  187. Safrin S, Kemmerly S, Plotkin B et al (1994b) Foscarnet-resistant herpes simplex virus infection in patients with AIDS. J Infect Dis 169:193–196PubMedCrossRefGoogle Scholar
  188. Sahoo MK, Lefterova MI, Yamamoto F et al (2013) Detection of cytomegalovirus drug resistance mutations by next-generation sequencing. J Clin Microbiol 51:3700–3710PubMedPubMedCentralCrossRefGoogle Scholar
  189. Saijo M, Yasuda Y, Yabe H et al (2002) Bone marrow transplantation in a child with Wiskott-Aldrich syndrome latently infected with acyclovir-resistant (ACV(r)) herpes simplex virus type 1: emergence of foscarnet-resistant virus originating from the ACV(r) virus. J Med Virol 68:99–104PubMedCrossRefGoogle Scholar
  190. Saint-Leger E, Caumes E, Breton G et al (2001) Clinical and virologic characterization of acyclovir-resistant varicella-zoster viruses isolated from 11 patients with acquired immunodeficiency syndrome. Clin Infect Dis 33:2061–2067PubMedCrossRefGoogle Scholar
  191. Sarisky RT, Bacon T, Boon R et al (2002) Penciclovir susceptibilities of herpes simplex virus isolates from patients using penciclovir cream for treatment of recurrent herpes labialis. Antimicrob Agents Chemother 46:2848–2853PubMedPubMedCentralCrossRefGoogle Scholar
  192. Sarisky RT, Bacon TH, Boon RJ et al (2003) Profiling penciclovir susceptibility and prevalence of resistance of herpes simplex virus isolates across eleven clinical trials. Arch Virol 148:1757–1769PubMedCrossRefGoogle Scholar
  193. Sasadeusz JJ, Tufaro F, Safrin S et al (1997) Homopolymer mutational hot spots mediate herpes simplex virus resistance to acyclovir. J Virol 71:3872–3878PubMedPubMedCentralGoogle Scholar
  194. Sauerbrei A, Eichhorn U, Schacke M et al (1999) Laboratory diagnosis of herpes zoster. J Clin Virol 14:31–36PubMedCrossRefGoogle Scholar
  195. Sauerbrei A, Deinhardt S, Zell R et al (2010) Phenotypic and genotypic characterization of acyclovir-resistant clinical isolates of herpes simplex virus. Antiviral Res 86:246–252PubMedCrossRefGoogle Scholar
  196. Sauerbrei A, Bohn K, Heim A et al (2011a) Novel resistance-associated mutations of thymidine kinase and DNA polymerase genes of herpes simplex virus type 1 and type 2. Antivir Ther 16:1297–1308PubMedCrossRefGoogle Scholar
  197. Sauerbrei A, Taut J, Zell R et al (2011b) Resistance testing of clinical varicella-zoster virus strains. Antiviral Res 90:242–247PubMedCrossRefGoogle Scholar
  198. Sauerbrei A, Liermann K, Bohn K et al (2012) Significance of amino acid substitutions in the thymidine kinase gene of herpes simplex virus type 1 for resistance. Antiviral Res 96:105–107PubMedCrossRefGoogle Scholar
  199. Sauerbrei A, Vodisch S, Bohn K et al (2013) Screening of herpes simplex virus type 1 isolates for acyclovir resistance using DiviTumR assay. J Virol Methods 188:70–72PubMedCrossRefGoogle Scholar
  200. Sawyer MH, Inchauspe G, Biron KK et al (1988) Molecular analysis of the pyrimidine deoxyribonucleoside kinase gene of wild-type and acyclovir-resistant strains of varicella-zoster virus. J Gen Virol 69(Pt 10):2585–2593PubMedCrossRefGoogle Scholar
  201. Schliefer K, Gumbel HO, Rockstroh JK et al (1999) Management of progressive outer retinal necrosis with cidofovir in a human immunodeficiency virus-infected patient. Clin Infect Dis 29:684–685PubMedCrossRefGoogle Scholar
  202. Schmit I, Boivin G (1999) 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. J Infect Dis 180:487–490PubMedCrossRefGoogle Scholar
  203. Schubert A, Ehlert K, Schuler-Luettmann S et al (2013) Fast selection of maribavir resistant cytomegalovirus in a bone marrow transplant recipient. BMC Infect Dis 13:330PubMedPubMedCentralCrossRefGoogle Scholar
  204. Schulte EC, Sauerbrei A, Hoffmann D et al (2010) Acyclovir resistance in herpes simplex encephalitis. Ann Neurol 67:830–833PubMedCrossRefGoogle Scholar
  205. Schuurman R, Demeter L, Reichelderfer P et al (1999) Worldwide evaluation of DNA sequencing approaches for identification of drug resistance mutations in the human immunodeficiency virus type 1 reverse transcriptase. J Clin Microbiol 37:2291–2296PubMedPubMedCentralGoogle Scholar
  206. Scott GM, Weinberg A, Rawlinson WD et al (2007) Multidrug resistance conferred by novel DNA polymerase mutations in human cytomegalovirus isolates. Antimicrob Agents Chemother 51:89–94PubMedCrossRefGoogle Scholar
  207. Sergerie Y, Boivin G (2006) Thymidine kinase mutations conferring acyclovir resistance in herpes simplex type 1 recombinant viruses. Antimicrob Agents Chemother 50:3889–3892PubMedPubMedCentralCrossRefGoogle Scholar
  208. Shapira MY, Resnick IB, Chou S et al (2008) Artesunate as a potent antiviral agent in a patient with late drug-resistant cytomegalovirus infection after hematopoietic stem cell transplantation. Clin Infect Dis 46:1455–1457PubMedCrossRefGoogle Scholar
  209. Shin YK, Weinberg A, Spruance S et al (2003) Susceptibility of herpes simplex virus isolates to nucleoside analogues and the proportion of nucleoside-resistant variants after repeated topical application of penciclovir to recurrent herpes labialis. J Infect Dis 187:1241–1245PubMedCrossRefGoogle Scholar
  210. Shmueli E, Or R, Shapira MY et al (2014) High rate of cytomegalovirus drug resistance among patients receiving preemptive antiviral treatment after haploidentical stem cell transplantation. J Infect Dis 209:557–561PubMedCrossRefGoogle Scholar
  211. Sims CR, Thompson K, Chemaly RF et al (2007) Oral topical cidofovir: novel route of drug delivery in a severely immunosuppressed patient with refractory multidrug-resistant herpes simplex virus infection. Transpl Infect Dis 9:256–259PubMedCrossRefGoogle Scholar
  212. Snoeck R, Andrei G, Gerard M et al (1994) Successful treatment of progressive mucocutaneous infection due to acyclovir- and foscarnet-resistant herpes simplex virus with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). Clin Infect Dis 18:570–578PubMedCrossRefGoogle Scholar
  213. Stoelben S, Arns W, Renders L et al (2014) Preemptive treatment of Cytomegalovirus infection in kidney transplant recipients with letermovir: results of a Phase 2a study. Transpl Int 27:77–86PubMedCrossRefGoogle Scholar
  214. Stranska R, van Loon AM, Bredius RG et al (2004a) Sequential switching of DNA polymerase and thymidine kinase-mediated HSV-1 drug resistance in an immunocompromised child. Antivir Ther 9:97–104PubMedGoogle Scholar
  215. Stranska R, van Loon AM, Polman M et al (2004b) Genotypic and phenotypic characterization of acyclovir-resistant herpes simplex viruses isolated from haematopoietic stem cell transplant recipients. Antivir Ther 9:565–575PubMedGoogle Scholar
  216. Stranska R, Schuurman R, Nienhuis E et al (2005) Survey of acyclovir-resistant herpes simplex virus in the Netherlands: prevalence and characterization. J Clin Virol 32:7–18PubMedCrossRefGoogle Scholar
  217. Strasfeld L, Lee I, Tatarowicz W et al (2010) Virologic characterization of multidrug-resistant cytomegalovirus infection in 2 transplant recipients treated with maribavir. J Infect Dis 202:104–108PubMedCrossRefGoogle Scholar
  218. Sugar EA, Jabs DA, Ahuja A et al (2012) Incidence of cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 153(1016–1024):e1015Google Scholar
  219. Sullivan V, Biron KK, Talarico C et al (1993) A point mutation in the human cytomegalovirus DNA polymerase gene confers resistance to ganciclovir and phosphonylmethoxyalkyl derivatives. Antimicrob Agents Chemother 37:19–25PubMedPubMedCentralCrossRefGoogle Scholar
  220. Suzutani T, Ishioka K, De Clercq E et al (2003) Differential mutation patterns in thymidine kinase and DNA polymerase genes of herpes simplex virus type 1 clones passaged in the presence of acyclovir or penciclovir. Antimicrob Agents Chemother 47:1707–1713PubMedPubMedCentralCrossRefGoogle Scholar
  221. Swierkosz EM, Hodinka RL, Moore BM et al (2004) Antiviral susceptibility testing: herpes simplex virus by plaque reduction assay; approved standard. Clinical and Laboratory Standards Institute, WayneGoogle Scholar
  222. Talarico CL, Phelps WC, Biron KK (1993) Analysis of the thymidine kinase genes from acyclovir-resistant mutants of varicella-zoster virus isolated from patients with AIDS. J Virol 67:1024–1033PubMedPubMedCentralGoogle Scholar
  223. van der Beek MT, Marijt EW, Vossen AC et al (2012) Failure of pre-emptive treatment of cytomegalovirus infections and antiviral resistance in stem cell transplant recipients. Antivir Ther 17:45–51PubMedCrossRefGoogle Scholar
  224. van der Beek MT, Vermont CL, Bredius RG et al (2013) Persistence and antiviral resistance of VZV in hematological patients. Clin Infect Dis 56:335–343PubMedCrossRefGoogle Scholar
  225. van Velzen M, van Loenen FB, Meesters RJ et al (2012) Latent acyclovir-resistant herpes simplex virus type 1 in trigeminal ganglia of immunocompetent individuals. J Infect Dis 205:1539–1543PubMedCrossRefGoogle Scholar
  226. van Velzen M, van de Vijver DA, van Loenen FB et al (2013) Acyclovir prophylaxis predisposes to antiviral-resistant recurrent herpetic keratitis. J Infect Dis 208:1359–1365PubMedCrossRefGoogle Scholar
  227. Verdonck LF, Cornelissen JJ, Smit J et al (1993) Successful foscarnet therapy for acyclovir-resistant mucocutaneous infection with herpes simplex virus in a recipient of allogeneic BMT. Bone Marrow Transplant 11:177–179PubMedGoogle Scholar
  228. Verkaik NJ, Hoek RA, van Bergeijk H et al (2013) Leflunomide as part of the treatment for multidrug-resistant cytomegalovirus disease after lung transplantation: case report and review of the literature. Transpl Infect Dis 15:E243–E249PubMedCrossRefGoogle Scholar
  229. Visse B, Dumont B, Huraux JM et al (1998) Single amino acid change in DNA polymerase is associated with foscarnet resistance in a varicella-zoster virus strain recovered from a patient with AIDS. J Infect Dis 178(Suppl 1):S55–S57PubMedCrossRefGoogle Scholar
  230. Visse B, Huraux JM, Fillet AM (1999) Point mutations in the varicella-zoster virus DNA polymerase gene confers resistance to foscarnet and slow growth phenotype. J Med Virol 59:84–90PubMedCrossRefGoogle Scholar
  231. Wade JC, McLaren C, Meyers JD (1983) Frequency and significance of acyclovir-resistant herpes simplex virus isolated from marrow transplant patients receiving multiple courses of treatment with acyclovir. J Infect Dis 148:1077–1082PubMedCrossRefGoogle Scholar
  232. Waldman WJ, Knight DA, Lurain NS et al (1999) Novel mechanism of inhibition of cytomegalovirus by the experimental immunosuppressive agent leflunomide. Transplantation 68:814–825PubMedCrossRefGoogle Scholar
  233. Weinberg A, Jabs DA, Chou S et al (2003) Mutations conferring foscarnet resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. J Infect Dis 187:777–784PubMedCrossRefGoogle Scholar
  234. Wolf DG, Lee DJ, Spector SA (1995a) Detection of human cytomegalovirus mutations associated with ganciclovir resistance in cerebrospinal fluid of AIDS patients with central nervous system disease. Antimicrob Agents Chemother 39:2552–2554PubMedPubMedCentralCrossRefGoogle Scholar
  235. Wolf DG, Smith IL, Lee DJ et al (1995b) Mutations in human cytomegalovirus UL97 gene confer clinical resistance to ganciclovir and can be detected directly in patient plasma. J Clin Invest 95:257–263PubMedPubMedCentralCrossRefGoogle Scholar
  236. Wong SW, Wahl AF, Yuan PM et al (1988) Human DNA polymerase alpha gene expression is cell proliferation dependent and its primary structure is similar to both prokaryotic and eukaryotic replicative DNA polymerases. Embo J 7:37–47PubMedPubMedCentralGoogle Scholar
  237. Xiong X, Smith JL, Chen MS (1997) Effect of incorporation of cidofovir into DNA by human cytomegalovirus DNA polymerase on DNA elongation. Antimicrob Agents Chemother 41:594–599PubMedPubMedCentralGoogle Scholar
  238. Zhang J, Chung DW, Tan CK et al (1991) Primary structure of the catalytic subunit of calf thymus DNA polymerase delta: sequence similarities with other DNA polymerases. Biochemistry 30:11742–11750PubMedCrossRefGoogle Scholar
  239. Ziyaeyan M, Alborzi A, Japoni A et al (2007) Frequency of acyclovir-resistant herpes simplex viruses isolated from the general immunocompetent population and patients with acquired immunodeficiency syndrome. Int J Dermatol 46:1263–1266PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Research Center in Infectious DiseasesLaval UniversityQuebec CityCanada

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