1887

Abstract

The difficulty of eliminating herpesvirus carriage makes host entry a key target for infection control. However, its viral requirements are poorly defined. Murid herpesvirus-4 (MuHV-4) can potentially provide insights into gammaherpesvirus host entry. Upper respiratory tract infection requires the MuHV-4 thymidine kinase (TK) and ribonucleotide reductase large subunit (RNR-L), suggesting a need for increased nucleotide production. However, both TK and RNR-L are likely to be multifunctional. We therefore tested further the importance of nucleotide production by disrupting the MuHV-4 ribonucleotide reductase small subunit (RNR-S). This caused a similar attenuation to RNR-L disruption: despite reduced intra-host spread, invasive inoculations still established infection, whereas a non-invasive upper respiratory tract inoculation did so only at high dose. Histological analysis showed that RNR-S, RNR-L and TK viruses all infected cells in the olfactory neuroepithelium but unlike wild-type virus then failed to spread. Thus captured host nucleotide metabolism enzymes, up to now defined mainly as important for alphaherpesvirus reactivation in neurons, also have a key role in gammaherpesvirus host entry. This seemed to reflect a requirement for lytic replication to occur in a terminally differentiated cell before a viable pool of latent genomes could be established.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.031542-0
2011-07-01
2020-01-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/92/7/1550.html?itemId=/content/journal/jgv/10.1099/vir.0.031542-0&mimeType=html&fmt=ahah

References

  1. Adler H. , Messerle M. , Wagner M. , Koszinowski U. H. . ( 2000; ). Cloning and mutagenesis of the murine gammaherpesvirus 68 genome as an infectious bacterial artificial chromosome. . J Virol 74:, 6964–6974. [CrossRef].[PubMed].
    [Google Scholar]
  2. Ator M. A. , Stubbe J. , Spector T. . ( 1986; ). Mechanism of ribonucleotide reductase from herpes simplex virus type 1. Evidence for 3′ carbon-hydrogen bond cleavage and inactivation by nucleotide analogs. . J Biol Chem 261:, 3595–3599.[PubMed].
    [Google Scholar]
  3. Brune W. , Ménard C. , Heesemann J. , Koszinowski U. H. . ( 2001; ). A ribonucleotide reductase homolog of cytomegalovirus and endothelial cell tropism. . Science 291:, 303–305. [CrossRef].[PubMed].
    [Google Scholar]
  4. Cameron J. M. , McDougall I. , Marsden H. S. , Preston V. G. , Ryan D. M. , Subak-Sharpe J. H. . ( 1988; ). Ribonucleotide reductase encoded by herpes simplex virus is a determinant of the pathogenicity of the virus in mice and a valid antiviral target. . J Gen Virol 69:, 2607–2612. [CrossRef].[PubMed].
    [Google Scholar]
  5. Coen D. M. , Kosz-Vnenchak M. , Jacobson J. G. , Leib D. A. , Bogard C. L. , Schaffer P. A. , Tyler K. L. , Knipe D. M. . ( 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:, 4736–4740. [CrossRef].[PubMed].
    [Google Scholar]
  6. Coleman H. M. , de Lima B. , Morton V. , Stevenson P. G. . ( 2003; ). Murine gammaherpesvirus 68 lacking thymidine kinase shows severe attenuation of lytic cycle replication in vivo but still establishes latency. . J Virol 77:, 2410–2417. [CrossRef].[PubMed].
    [Google Scholar]
  7. Conner J. , Marsden H. , Clements J. B. . ( 1994; ). Ribonucleotide reductase of herpes viruses. . Rev Med Virol 4:, 25–34. [CrossRef]
    [Google Scholar]
  8. Darby G. . ( 1993; ). The acyclovir legacy: its contribution to antiviral drug discovery. . J Med Virol 41: Suppl. 1 134–138. [CrossRef].[PubMed].
    [Google Scholar]
  9. Davison A. J. , Stow N. D. . ( 2005; ). New genes from old: redeployment of dUTPase by herpesviruses. . J Virol 79:, 12880–12892. [CrossRef].[PubMed].
    [Google Scholar]
  10. de Lima B. D. , May J. S. , Stevenson P. G. . ( 2004; ). Murine gammaherpesvirus 68 lacking gp150 shows defective virion release but establishes normal latency in vivo . . J Virol 78:, 5103–5112. [CrossRef].[PubMed].
    [Google Scholar]
  11. Efstathiou S. , Kemp S. , Darby G. , Minson A. C. . ( 1989; ). The role of herpes simplex virus type 1 thymidine kinase in pathogenesis. . J Gen Virol 70:, 869–879. [CrossRef].[PubMed].
    [Google Scholar]
  12. Faulkner G. C. , Krajewski A. S. , Crawford D. H. . ( 2000; ). The ins and outs of EBV infection. . Trends Microbiol 8:, 185–189. [CrossRef].[PubMed].
    [Google Scholar]
  13. Ganem D. . ( 2006; ). KSHV infection and the pathogenesis of Kaposi's sarcoma. . Annu Rev Pathol 1:, 273–296. [CrossRef].[PubMed].
    [Google Scholar]
  14. Gaspar M. , Gill M. B. , Lösing J. B. , May J. S. , Stevenson P. G. . ( 2008; ). Multiple functions for ORF75c in murid herpesvirus-4 infection. . PLoS ONE 3:, e2781. [CrossRef].[PubMed].
    [Google Scholar]
  15. Gill M. B. , Murphy J. E. , Fingeroth J. D. . ( 2005; ). Functional divergence of Kaposi's sarcoma-associated herpesvirus and related gamma-2 herpesvirus thymidine kinases: novel cytoplasmic phosphoproteins that alter cellular morphology and disrupt adhesion. . J Virol 79:, 14647–14659. [CrossRef].[PubMed].
    [Google Scholar]
  16. Gill M. B. , Wright D. E. , Smith C. M. , May J. S. , Stevenson P. G. . ( 2009; ). Murid herpesvirus-4 lacking thymidine kinase reveals route-dependent requirements for host colonization. . J Gen Virol 90:, 1461–1470. [CrossRef].[PubMed].
    [Google Scholar]
  17. Gill M. B. , May J. S. , Colaco S. , Stevenson P. G. . ( 2010; ). Important role for the murid herpesvirus 4 ribonucleotide reductase large subunit in host colonization via the respiratory tract. . J Virol 84:, 10937–10942. [CrossRef].[PubMed].
    [Google Scholar]
  18. Gillet L. , May J. S. , Colaco S. , Stevenson P. G. . ( 2007; ). The murine gammaherpesvirus-68 gp150 acts as an immunogenic decoy to limit virion neutralization. . PLoS ONE 2:, e705. [CrossRef].[PubMed].
    [Google Scholar]
  19. Gustafson E. A. , Chillemi A. C. , Sage D. R. , Fingeroth J. D. . ( 1998; ). The Epstein–Barr virus thymidine kinase does not phosphorylate ganciclovir or acyclovir and demonstrates a narrow substrate specificity compared to the herpes simplex virus type 1 thymidine kinase. . Antimicrob Agents Chemother 42:, 2923–2931.[PubMed].
    [Google Scholar]
  20. Hoagland R. J. . ( 1964; ). The incubation period of infectious mononucleosis. . Am J Public Health Nations Health 54:, 1699–1705. [CrossRef].[PubMed].
    [Google Scholar]
  21. Hoshino Y. , Katano H. , Zou P. , Hohman P. , Marques A. , Tyring S. K. , Follmann D. , Cohen J. I. . ( 2009; ). Long-term administration of valacyclovir reduces the number of Epstein–Barr virus (EBV)-infected B cells but not the number of EBV DNA copies per B cell in healthy volunteers. . J Virol 83:, 11857–11861. [CrossRef].[PubMed].
    [Google Scholar]
  22. Hutt-Fletcher L. M. . ( 2007; ). Epstein–Barr virus entry. . J Virol 81:, 7825–7832. [CrossRef].[PubMed].
    [Google Scholar]
  23. Jacobson J. G. , Leib D. A. , Goldstein D. J. , Bogard C. L. , Schaffer P. A. , Weller S. K. , Coen D. M. . ( 1989; ). A herpes simplex virus ribonucleotide reductase deletion mutant is defective for productive acute and reactivatable latent infections of mice and for replication in mouse cells. . Virology 173:, 276–283. [CrossRef].[PubMed].
    [Google Scholar]
  24. Jordan A. , Reichard P. . ( 1998; ). Ribonucleotide reductases. . Annu Rev Biochem 67:, 71–98. [CrossRef].[PubMed].
    [Google Scholar]
  25. Kayhan B. , Yager E. J. , Lanzer K. , Cookenham T. , Jia Q. , Wu T. T. , Woodland D. L. , Sun R. , Blackman M. A. . ( 2007; ). A replication-deficient murine gamma-herpesvirus blocked in late viral gene expression can establish latency and elicit protective cellular immunity. . J Immunol 179:, 8392–8402.[PubMed].[CrossRef]
    [Google Scholar]
  26. Langelier Y. , Bergeron S. , Chabaud S. , Lippens J. , Guilbault C. , Sasseville A. M. , Denis S. , Mosser D. D. , Massie B. . ( 2002; ). The R1 subunit of herpes simplex virus ribonucleotide reductase protects cells against apoptosis at, or upstream of, caspase-8 activation. . J Gen Virol 83:, 2779–2789.[PubMed].
    [Google Scholar]
  27. Milho R. , Smith C. M. , Marques S. , Alenquer M. , May J. S. , Gillet L. , Gaspar M. , Efstathiou S. , Simas J. P. , Stevenson P. G. . ( 2009; ). In vivo imaging of murid herpesvirus-4 infection. . J Gen Virol 90:, 21–32. [CrossRef].[PubMed].
    [Google Scholar]
  28. Moorman N. J. , Lin C. Y. , Speck S. H. . ( 2004; ). Identification of candidate gammaherpesvirus 68 genes required for virus replication by signature-tagged transposon mutagenesis. . J Virol 78:, 10282–10290. [CrossRef].[PubMed].
    [Google Scholar]
  29. Moser J. M. , Farrell M. L. , Krug L. T. , Upton J. W. , Speck S. H. . ( 2006; ). A gammaherpesvirus 68 gene 50 null mutant establishes long-term latency in the lung but fails to vaccinate against a wild-type virus challenge. . J Virol 80:, 1592–1598. [CrossRef].[PubMed].
    [Google Scholar]
  30. Pica F. , Volpi A. . ( 2007; ). Transmission of human herpesvirus 8: an update. . Curr Opin Infect Dis 20:, 152–156. [CrossRef].[PubMed].
    [Google Scholar]
  31. Pontarin G. , Fijolek A. , Pizzo P. , Ferraro P. , Rampazzo C. , Pozzan T. , Thelander L. , Reichard P. A. , Bianchi V. . ( 2008; ). Ribonucleotide reduction is a cytosolic process in mammalian cells independently of DNA damage. . Proc Natl Acad Sci U S A 105:, 17801–17806. [CrossRef].[PubMed].
    [Google Scholar]
  32. Rawlinson W. D. , Farrell H. E. , Barrell B. G. . ( 1996; ). Analysis of the complete DNA sequence of murine cytomegalovirus. . J Virol 70:, 8833–8849.[PubMed].
    [Google Scholar]
  33. Shannon-Lowe C. , Adland E. , Bell A. I. , Delecluse H. J. , Rickinson A. B. , Rowe M. . ( 2009; ). Features distinguishing Epstein–Barr virus infections of epithelial cells and B cells: viral genome expression, genome maintenance, and genome amplification. . J Virol 83:, 7749–7760. [CrossRef].[PubMed].
    [Google Scholar]
  34. Song M. J. , Hwang S. , Wong W. H. , Wu T. T. , Lee S. , Liao H. I. , Sun R. . ( 2005; ). Identification of viral genes essential for replication of murine gamma-herpesvirus 68 using signature-tagged mutagenesis. . Proc Natl Acad Sci U S A 102:, 3805–3810. [CrossRef].[PubMed].
    [Google Scholar]
  35. Stevenson P. G. , May J. S. , Smith X. G. , Marques S. , Adler H. , Koszinowski U. H. , Simas J. P. , Efstathiou S. . ( 2002; ). K3-mediated evasion of CD8+ T cells aids amplification of a latent gamma-herpesvirus. . Nat Immunol 3:, 733–740.[PubMed].
    [Google Scholar]
  36. Stevenson P. G. , Simas J. P. , Efstathiou S. . ( 2009; ). Immune control of mammalian gamma-herpesviruses: lessons from murid herpesvirus-4. . J Gen Virol 90:, 2317–2330. [CrossRef].[PubMed].
    [Google Scholar]
  37. Terry L. A. , Stewart J. P. , Nash A. A. , Fazakerley J. K. . ( 2000; ). Murine gammaherpesvirus-68 infection of and persistence in the central nervous system. . J Gen Virol 81:, 2635–2643.[PubMed].
    [Google Scholar]
  38. Tibbetts S. A. , Suarez F. , Steed A. L. , Simmons J. A. , Virgin H. W. IV . ( 2006; ). A gamma-herpesvirus deficient in replication establishes chronic infection in vivo and is impervious to restriction by adaptive immune cells. . Virology 353:, 210–219. [CrossRef].[PubMed].
    [Google Scholar]
  39. Upton J. W. , Kaiser W. J. , Mocarski E. S. . ( 2010; ). Virus inhibition of RIP3-dependent necrosis. . Cell Host Microbe 7:, 302–313. [CrossRef].[PubMed].
    [Google Scholar]
  40. Virgin H. W. IV , Latreille P. , Wamsley P. , Hallsworth K. , Weck K. E. , Dal Canto A. J. , Speck S. H. . ( 1997; ). Complete sequence and genomic analysis of murine gammaherpesvirus 68. . J Virol 71:, 5894–5904.[PubMed].
    [Google Scholar]
  41. Wnuk S. F. , Robins M. J. . ( 2006; ). Ribonucleotide reductase inhibitors as anti-herpes agents. . Antiviral Res 71:, 122–126. [CrossRef].[PubMed].
    [Google Scholar]
  42. Yamada Y. , Kimura H. , Morishima T. , Daikoku T. , Maeno K. , Nishiyama Y. . ( 1991; ). The pathogenicity of ribonucleotide reductase-null mutants of herpes simplex virus type 1 in mice. . J Infect Dis 164:, 1091–1097. [CrossRef].[PubMed].
    [Google Scholar]
  43. Yao Q. Y. , Ogan P. , Rowe M. , Wood M. , Rickinson A. B. . ( 1989; ). Epstein–Barr virus-infected B cells persist in the circulation of acyclovir-treated virus carriers. . Int J Cancer 43:, 67–71. [CrossRef].[PubMed].
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.031542-0
Loading
/content/journal/jgv/10.1099/vir.0.031542-0
Loading

Data & Media loading...

Most cited articles

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error