1887

Abstract

Gammaherpesviruses infect at least 90 % of the world's population. Infection control is difficult, in part because some fundamental features of host colonization remain unknown, for example whether normal latency establishment requires viral lytic functions. Since human gammaherpesviruses have narrow species tropisms, answering such questions requires animal models. Murid herpesvirus-4 (MuHV-4) provides one of the most tractable. MuHV-4 genomes delivered to the lung or peritoneum persist without lytic replication. However, they fail to disseminate systemically, suggesting that the outcome is inoculation route-dependent. After upper respiratory tract inoculation, MuHV-4 infects mice without involving the lungs or peritoneum. We examined whether host entry by this less invasive route requires the viral thymidine kinase (TK), a gene classically essential for lytic replication in terminally differentiated cells. MuHV-4 TK knockouts delivered to the lung or peritoneum were attenuated but still reached lymphoid tissue. In contrast, TK knockouts delivered to the upper respiratory tract largely failed to establish a detectable infection. Therefore TK, and by implication lytic replication, is required for MuHV-4 to establish a significant infection by a non-invasive route.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.010603-0
2009-06-01
2019-11-17
Loading full text...

Full text loading...

/deliver/fulltext/jgv/90/6/1461.html?itemId=/content/journal/jgv/10.1099/vir.0.010603-0&mimeType=html&fmt=ahah

References

  1. Boname, J. M., de Lima, B. D., Lehner, P. J. & Stevenson, P. G. ( 2004; ). Viral degradation of the MHC class I peptide loading complex. Immunity 20, 305–317.[CrossRef]
    [Google Scholar]
  2. 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]
    [Google Scholar]
  3. 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]
    [Google Scholar]
  4. 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]
    [Google Scholar]
  5. 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]
    [Google Scholar]
  6. Faulkner, G. C., Krajewski, A. S. & Crawford, D. H. ( 2000; ). The ins and outs of EBV infection. Trends Microbiol 8, 185–189.[CrossRef]
    [Google Scholar]
  7. Gaspar, M., Gill, M. B., Loesing, J. B., May, J. S. & Stevenson, P. G. ( 2008; ). Multiple functions for ORF75c in murid herpesvirus-4 infection. PLoS One 3, e2781 [CrossRef]
    [Google Scholar]
  8. Gillet, L. & Stevenson, P. G. ( 2007; ). Evidence for a multiprotein gamma-2 herpesvirus entry complex. J Virol 81, 13082–13091.[CrossRef]
    [Google Scholar]
  9. Gillet, L., Adler, H. & Stevenson, P. G. ( 2007; ). Glycosaminoglycan interactions in murine gammaherpesvirus-68 infection. PLoS One 2, e347 [CrossRef]
    [Google Scholar]
  10. Hayashi, K., Hayashi, M., Jalkanen, M., Firestone, J. H., Trelstad, R. L. & Bernfield, M. ( 1987; ). Immunocytochemistry of cell surface heparan sulfate proteoglycan in mouse tissues. A light and electron microscopic study. J Histochem Cytochem 35, 1079–1088.[CrossRef]
    [Google Scholar]
  11. Hoagland, R. J. ( 1964; ). The incubation period of infectious mononucleosis. Am J Public Health Nations Health 54, 1699–1705.[CrossRef]
    [Google Scholar]
  12. Janz, A., Oezel, M., Kurzeder, C., Mautner, J., Pich, D., Kost, M., Hammerschmidt, W. & Delecluse, H. J. ( 2000; ). Infectious Epstein–Barr virus lacking major glycoprotein BLLF1 (gp350/220) demonstrates the existence of additional viral ligands. J Virol 74, 10142–10152.[CrossRef]
    [Google Scholar]
  13. 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 γ-herpesvirus blocked in late viral gene expression can establish latency and elicit protective cellular immunity. J Immunol 179, 8392–8402.[CrossRef]
    [Google Scholar]
  14. Kozuch, O., Reichel, M., Lesso, J., Remenová, A., Labuda, M., Lysy, J. & Mistríková, J. ( 1993; ). Further isolation of murine herpesviruses from small mammals in southwestern Slovakia. Acta Virol 37, 101–105.
    [Google Scholar]
  15. May, J. S., Smith, C. M., Gill, M. B. & Stevenson, P. G. ( 2008; ). An essential role for the proximal but not the distal cytoplasmic tail of glycoprotein M in murid herpesvirus 4 infection. PLoS One 3, e2131 [CrossRef]
    [Google Scholar]
  16. 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]
    [Google Scholar]
  17. 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]
    [Google Scholar]
  18. Nash, A. A., Dutia, B. M., Stewart, J. P. & Davison, A. J. ( 2001; ). Natural history of murine γ-herpesvirus infection. Philos Trans R Soc Lond B Biol Sci 356, 569–579.[CrossRef]
    [Google Scholar]
  19. Raulo, E., Chernousov, M. A., Carey, D. J., Nolo, R. & Rauvala, H. ( 1994; ). Isolation of a neuronal cell surface receptor of heparin binding growth-associated molecule (HB-GAM). Identification as N-syndecan (syndecan-3). J Biol Chem 269, 12999–13004.
    [Google Scholar]
  20. Rosa, G. T., Gillet, L., Smith, C. M., de Lima, B. D. & Stevenson, P. G. ( 2007; ). IgG Fc receptors provide an alternative infection route for murine gamma-herpesvirus-68. PLoS One 2, e560 [CrossRef]
    [Google Scholar]
  21. Smith, C. M., Gill, M. B., May, J. S. & Stevenson, P. G. ( 2007; ). Murine gammaherpesvirus-68 inhibits antigen presentation by dendritic cells. PLoS One 2, e1048 [CrossRef]
    [Google Scholar]
  22. Sokal, E. M., Hoppenbrouwers, K., Vandermeulen, C., Moutschen, M., Léonard, P., Moreels, A., Haumont, M., Bollen, A., Smets, F. & Denis, M. ( 2007; ). Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein–Barr virus vaccine in healthy young adults. J Infect Dis 196, 1749–1753.[CrossRef]
    [Google Scholar]
  23. Stevenson, P. G. ( 2004; ). Immune evasion by gamma-herpesviruses. Curr Opin Immunol 16, 456–462.[CrossRef]
    [Google Scholar]
  24. Stevenson, P. G. & Efstathiou, S. ( 2005; ). Immune mechanisms in murine gammaherpesvirus-68 infection. Viral Immunol 18, 445–456.[CrossRef]
    [Google Scholar]
  25. Stevenson, P. G., Belz, G. T., Castrucci, M. R., Altman, J. D. & Doherty, P. C. ( 1999; ). A γ-herpesvirus sneaks through a CD8+ T cell response primed to a lytic-phase epitope. Proc Natl Acad Sci U S A 96, 9281–9286.[CrossRef]
    [Google Scholar]
  26. 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 γ-herpesvirus. Nat Immunol 3, 733–740.
    [Google Scholar]
  27. Thorley-Lawson, D. A. ( 2001; ). Epstein–Barr virus: exploiting the immune system. Nat Rev Immunol 1, 75–82.[CrossRef]
    [Google Scholar]
  28. Thorley-Lawson, D. A. & Geilinger, K. ( 1980; ). Monoclonal antibodies against the major glycoprotein (gp350/220) of Epstein–Barr virus neutralize infectivity. Proc Natl Acad Sci U S A 77, 5307–5311.[CrossRef]
    [Google Scholar]
  29. Tibbetts, S. A., Suarez, F., Steed, A. L., Simmons, J. A. & Virgin, H. W. ( 2006; ). A γ-herpesvirus deficient in replication establishes chronic infection in vivo and is impervious to restriction by adaptive immune cells. Virology 353, 210–219.[CrossRef]
    [Google Scholar]
  30. Valyi-Nagy, T., Gesser, R. M., Raengsakulrach, B., Deshmane, S. L., Randazzo, B. P., Dillner, A. J. & Fraser, N. W. ( 1994; ). A thymidine kinase-negative HSV-1 strain establishes a persistent infection in SCID mice that features uncontrolled peripheral replication but only marginal nervous system involvement. Virology 199, 484–490.[CrossRef]
    [Google Scholar]
  31. Virgin, H. W. & Speck, S. H. ( 1999; ). Unraveling immunity to γ-herpesviruses: a new model for understanding the role of immunity in chronic virus infection. Curr Opin Immunol 11, 371–379.[CrossRef]
    [Google Scholar]
  32. Yao, Q. Y., Rickinson, A. B. & Epstein, M. A. ( 1985; ). A re-examination of the Epstein–Barr virus carrier state in healthy seropositive individuals. Int J Cancer 35, 35–42.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.010603-0
Loading
/content/journal/jgv/10.1099/vir.0.010603-0
Loading

Data & Media loading...

Most Cited This Month

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