1887

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Volume 82, Issue 11

Selection of the same mutation in the U69 protein kinase gene of human herpesvirus-6 after prolonged exposure to ganciclovir and Free

Abstract

After serial passage in the presence of increasing concentrations of ganciclovir (GCV) , a human herpesvirus-6 (HHV-6) mutant exhibiting a decreased sensitivity to the drug was isolated. Analysis of drug susceptibility showed that the IC of this mutant was 24-, 52- and 3-fold higher than that of the wild-type (wt) IC in the case of GCV, cidofovir and foscarnet, respectively. Genotypic analysis showed two single nucleotide changes as compared to the wild-type: an A→G substitution of the U69 protein kinase (PK) gene resulted in an MV amino acid substitution and the other change, located in the C-terminal part of the U38 gene, resulted in an AV amino acid substitution within the DNA polymerase. The MV change was located within the consensus sequence DISPMN of the putative catalytic domain VI of the PK. This change was homologous to the MV and MI changes that had been reported previously within the consensus sequence DITPMN of the human cytomegalovirus (HCMV) UL97 PK and associated with the resistance of HCMV to GCV. The MV change was also detected by PCR in HHV-6-infected PBMCs from an AIDS patient who had been treated with GCV for a long period of time and exhibited a clinically GCV-resistant HCMV infection. These findings provide strong circumstantial evidence that the MV change of the PK gene is associated with resistance to GCV and raise the question of cross resistance to this drug among different betaherpesviruses.

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© Microbiology Society
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2001-11-01
2024-04-27
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References

  1. Ablashi D. V., Balachandran N., Josephs S. F., Hung C. L., Krueger G. R., Kramarsky B., Salahuddin S. Z., Gallo R. C. 1991; Genomic polymorphism, growth properties, and immunologic variations in human herpesvirus-6 isolates. Virology 184:545–552
     [Google Scholar]
  2. Ablashi D. V., Marsh S., Kaplan M., Whitman J. E. Jr, Pearson G. R. 1998; HHV-6 infection in HIV-infected asymptomatic and AIDS patients. Intervirology 41:1–9
     [Google Scholar]
  3. Ablashi D. V., Eastman H. B., Owen C. B., Roman M. M., Friedman J., Zabriskie J. B., Peterson D. L., Pearson G. R., Whitman J. E. 2000; Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. Journal of Clinical Virology 16:179–191
     [Google Scholar]
  4. Agut H., Guetard D., Collandre H., Dauguet C., Montagnier L., Miclea J. M., Baurmann H., Gessain A. 1988; Concomitant infection by human herpesvirus 6, HTLV-I, and HIV-2. Lancet 1:712
     [Google Scholar]
  5. Agut H., Kerouedan D., M’Pele P., Collandre H., Samba-Lefevre C., Rosenheim M., Ingrand D., Itoua-Ngaporo A., Gentilini M., Montagnier L. and others 1989; Co-cultivation of human herpesvirus 6 and HIV1 from blood lymphocytes. Research in Virology 140:23–26
     [Google Scholar]
  6. Andrei G., Snoeck R., De Clercq E., Esnouf R., Fiten P., Opdenakker G. 2000; 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 Virology 81:639–648
     [Google Scholar]
  7. Ansari A., Emery V. C. 1999; The U69 gene of human herpesvirus 6 encodes a protein kinase which can confer ganciclovir sensitivity to baculoviruses. Journal of Virology 73:3284–3291
     [Google Scholar]
  8. Aubin J. T., Collandre H., Candotti D., Ingrand D., Rouzioux C., Burgard M., Richard S., Huraux J. M., Agut H. 1992; Several groups among human herpesvirus 6 strains can be distinguished by Southern blotting and polymerase chain reaction. Journal of Clinical Microbiology 30:2524
     [Google Scholar]
  9. Baldanti F., Underwood M. R., Stanat S. C., Biron K. K., Chou S., Sarasini A., Silini E., Gerna G. 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. Journal of Virology 70:1390–1395
     [Google Scholar]
  10. Berti R., Soldan S. S., Akhyani N., McFarland H. F., Jacobson S. 2000; Extended observations on the association of HHV-6 and multiple sclerosis. Journal of Neurovirology 6:S85–S87
     [Google Scholar]
  11. Biron K. K., Stanat S. C., Sorrell J. B., Fyfe J. A., Keller P. M., Lambe C. U., Nelson D. J. 1985; Metabolic activation of the nucleoside analog 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine in human diploid fibroblasts infected with human cytomegalovirus. Proceedings of the National Academy of Sciences, USA 82:2473–2477
     [Google Scholar]
  12. Chou S., Erice A., Jordan M. C., Vercellotti G. M., Michels K. R., Talarico C. L., Stanat S. C., Biron K. K. 1995; Analysis of the UL97 phosphotransferase coding sequence in clinical cytomegalovirus isolates and identification of mutations conferring ganciclovir resistance. Journal of Infectious Diseases 171:576–583
     [Google Scholar]
  13. Cole P. D., Stiles J., Boulad F., Small T. N., O’Reilly R. J., George D., Szabolcs P., Kiehn T. E., Kernan N. A. 1998; Successful treatment of human herpesvirus 6 encephalitis in a bone marrow transplant recipient. Clinical Infectious Diseases 27:653–654
     [Google Scholar]
  14. Collandre H., Aubin J. T., Agut H., Bechet J. M., Montagnier L. 1991; Detection of HHV-6 by the polymerase chain reaction. Journal of Virological Methods 31:171–179
     [Google Scholar]
  15. Crumpacker C. S. 1996; Ganciclovir. New England Journal of Medicine 335:721–729
     [Google Scholar]
  16. Dominguez G., Dambaugh T. R., Stamey F. R., Dewhurst S., Inoue N., Pellett P. E. 1999; Human herpesvirus 6B genome sequence: coding content and comparison with human herpesvirus 6A. Journal of Virology 73:8040–8052
     [Google Scholar]
  17. Dorrucci M., Rezza G., Andreoni M., Pezzotti P., Nicastri E., Ventura L., Zignani M., Alliegro M. B., Tarantini G., Salassa B., Colangeli V., Mazzarello G., Ursitti M. A., Barbanera M., Pristera R., Castelli F., Ortona L. 1999; Serum IgG antibodies to human herpesvirus-6 (HHV-6) do not predict the progression of HIV disease to AIDS. Italian Seroconversion Study group. European Journal of Epidemiology 15:317–322
     [Google Scholar]
  18. Erice A. 1999; Resistance of human cytomegalovirus to antiviral drugs. Clinical Microbiology Reviews 12:286–297
     [Google Scholar]
  19. Freitas V. R., Smee D. F., Chernow M., Boehme R., Matthews T. R. 1985; Activity of 9-(1,3-dihydroxy-2-propoxymethyl)guanine compared with that of acyclovir against human, monkey, and rodent cytomegaloviruses. Antimicrobial Agents and Chemotherapy 28:240–245
     [Google Scholar]
  20. Garzino-Demo A., Chen M., Lusso P., Berneman Z., DiPaolo J. A. 1996; Enhancement of TAT-induced transactivation of the HIV-1 LTR by two genomic fragments of HHV-6. Journal of Medical Virology 50:20–24
     [Google Scholar]
  21. Gompels U. A., Nicholas J., Lawrence G., Jones M., Thomson B. J., Martin M. E., Efstathiou S., Craxton M., Macaulay H. A. 1995; The DNA sequence of human herpesvirus-6: structure, coding content, and genome evolution. Virology 209:29–51
     [Google Scholar]
  22. Humar A., Malkan G., Moussa G., Greig P., Levy G., Mazzulli T. 2000; Human herpesvirus-6 is associated with cytomegalovirus reactivation in liver transplant recipients. Journal of Infectious Diseases 181:1450–1453
     [Google Scholar]
  23. Isegawa Y., Mukai T., Nakano K., Kagawa M., Chen J., Mori Y., Sunagawa T., Kawanishi K., Sashihara J., Hata A., Zou P., Kosuge H., Yamanishi K. 1999; Comparison of the complete DNA sequences of human herpesvirus 6 variants A and B. Journal of Virology 73:8053–8063
     [Google Scholar]
  24. Lawrence G. L., Chee M., Craxton M. A., Gompels U. A., Honess R. W., Barrell B. G. 1990; Human herpesvirus 6 is closely related to human cytomegalovirus. Journal of Virology 64:287–299
     [Google Scholar]
  25. Lurain N. S., Thompson K. D., Holmes E. W., Read G. S. 1992; Point mutations in the DNA polymerase gene of human cytomegalovirus that result in resistance to antiviral agents. Journal of Virology 66:7146–7152
     [Google Scholar]
  26. Lurain N. S., Spafford L. E., Thompson K. D. 1994; Mutation in the UL97 open reading frame of human cytomegalovirus strains resistant to ganciclovir. Journal of Virology 68:4427–4431
     [Google Scholar]
  27. Lusso P., Gallo R. C. 1995; Human herpesvirus 6 in AIDS. Immunology Today 16:67–71
     [Google Scholar]
  28. Manichanh C., Grenot P., Gautheret-Dejean A., Debre P., Huraux J. M., Agut H. 2000; Susceptibility of human herpesvirus 6 to antiviral compounds by flow cytometry analysis. Cytometry 40:135–140
     [Google Scholar]
  29. Mookerjee B. P., Vogelsang G. 1997; Human herpesvirus-6 encephalitis after bone marrow transplantation: successful treatment with ganciclovir. Bone Marrow Transplantation 20:905–906
     [Google Scholar]
  30. Ongradi J., Rajda C., Marodi C. L., Csiszar A., Vecsei L. 1999; A pilot study on the antibodies to HHV-6 variants and HHV-7 in CSF of MS patients. Journal of Neurovirology 5:529–532
     [Google Scholar]
  31. Ratnamohan V. M., Chapman J., Howse H., Bovington K., Robertson P., Byth K., Allen R., Cunningham A. L. 1998; Cytomegalovirus and human herpesvirus 6 both cause viral disease after renal transplantation. Transplantation 66:877–882
     [Google Scholar]
  32. Rieux C., Gautheret-Dejean A., Challine-Lehmann D., Kirch C., Agut H., Vernant J. P. 1998; Human herpesvirus-6 meningoencephalitis in a recipient of an unrelated allogeneic bone marrow transplantation. Transplantation 65:1408–1411
     [Google Scholar]
  33. Robert C., Massonneau V., Pothier P., Clement A., Hejblum G., Hubert P., Aubin J. T., Agut H. 1998; Selection and characterization of two specific monoclonal antibodies directed against the two variants of human herpesvirus-6. Research in Virology 149:403–411
     [Google Scholar]
  34. Rogers J., Rohal S., Carrigan D. R., Kusne S., Knox K. K., Gayowski T., Wagener M. M., Fung J. J., Singh N. 2000; Human herpesvirus-6 in liver transplant recipients: role in pathogenesis of fungal infections, neurologic complications, and outcome. Transplantation 69:2566–2573
     [Google Scholar]
  35. Salahuddin S. Z., Ablashi D. V., Markham P. D., Josephs S. F., Sturzenegger S., Kaplan M., Halligan G., Biberfeld P., Wong-Staal F., Kramarsky B. and others 1986; Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 234:596–601
     [Google Scholar]
  36. Schirmer E. C., Wyatt L. S., Yamanishi K., Rodriguez W. J., Frenkel N. 1991; Differentiation between two distinct classes of viruses now classified as human herpesvirus 6. Proceedings of the National Academy of Sciences, USA 88:5922–5926
     [Google Scholar]
  37. Sullivan V., Biron K. K., Talarico C., Stanat S. C., Davis M., Pozzi L. M., Coen D. M. 1993; A point mutation in the human cytomegalovirus DNA polymerase gene confers resistance to ganciclovir and phosphonylmethoxyalkyl derivatives. Antimicrobial Agents and Chemotherapy 37:19–25
     [Google Scholar]
  38. Taus C., Pucci E., Cartechini E., Fie A., Giuliani G., Clementi M., Menzo S. 2000; Absence of HHV-6 and HHV-7 in cerebrospinal fluid in relapsing-remitting multiple sclerosis. Acta Neurologica Scandinavica 101:224–228
     [Google Scholar]
  39. Teo I. A., Griffin B. E., Jones M. D. 1991; Characterization of the DNA polymerase gene of human herpesvirus 6. Journal of Virology 65:4670–4680
     [Google Scholar]
  40. Yamanishi K., Okuno T., Shiraki K., Takahashi M., Kondo T., Asano Y., Kurata T. 1988; Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1:1065–1067
     [Google Scholar]
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Selection of the same mutation in the U69 protein kinase gene of human herpesvirus-6 after prolonged exposure to ganciclovir in vitro and in vivo
J. Gen. Virol. 82, 2767 (2001); https://doi.org/10.1099/0022-1317-82-11-2767
/content/journal/jgv/10.1099/0022-1317-82-11-2767
/content/journal/jgv/10.1099/0022-1317-82-11-2767
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