Central European Journal of Biology

, Volume 3, Issue 1, pp 19–30

Comparison of pathogenic properties of the murid gammaherpesvirus (MuHV 4) strains: a role for immunomodulatory proteins encoded by the left (5′-)end of the genome

Review Article

Abstract

The murid herpesvirus 4 (MuHV 4) species encompasses 7 isolates, out of which at least two (MHV-68, MHV-72) became in vitro propagated laboratory strains. Following intranasal inoculation, MuHV 4 induces an acute infectious mononucleosis-like syndrome with elevated levels of peripheral blood leukocytes, shifts in the relative proportion of lymphocytes along with the appearance of atypical mononuclear cells. At least two isolates exhibited spontaneous deletions at the left hand (5′-end) of their genome, resulting in the absence of M1, M2, M3 genes (strain MHV-72) and also of the M4 gene (strain MHV-76). Based on DNA sequence amplifications only, another two isolates (MHV-Šum and MHV-60) were shown to possess similar deletions of varying length. During latency (until 24 months post-infection), the mice infected with any MuHV 4 isolate (except MHV-76) developed lymphoproliferative disorders. The lack of tumor formation in MHV-76 infected mice was associated with persistent virus production at late post-infection intervals. In addition to careful analysis of spontaneously occurring 5′-end genome defects, our knowledge of the function of 5′-end genes relies on the behaviour of mutants with corresponding deletions and/or insertions. While M2 and M3 genes encode immune evasion proteins, M4 codes for a soluble glycopeptide acting as immunomodulator and/or immunostimulator.

Keywords

Murid gammaherpesvirus 4 Genome deletions Immune evasion genes Pathogenesis Tumor formation 

Abbreviations

HSV

herpes simplex virus

i.n.

intranasal

i.p.

intraperitoneal

p.i.

post-infection

MHV

mouse herpesvirus (murine gammaherpesvirus)

MuHV

murid herpesvirus (official nomenclature)

PCR

polymerase chain reaction

bp

base pair

kb

kilobase pair

nt(s)

nucleotide(s)

w.t.

wild-type

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. [1]
    Blaskovič D., Stančeková M., Svobodová J., Mistríková J., Isolation of five strains of herpesviruses from two species of free living small rodents, Acta Virol. 1980, 24, 468PubMedGoogle Scholar
  2. [2]
    Mistríková J., Blaškovič D., Ecology of the murine alphaherpesvirus and its isolation from lung of rodents in cell culture, Acta Virol., 1985, 29, 312–317PubMedGoogle Scholar
  3. [3]
    Svobodová J., Blaskovič D., Mistríková J., Growth characteristics of herpesviruses isolated from free living small rodents, Acta Virol., 1982, 26, 256–263PubMedGoogle Scholar
  4. [4]
    Efstathiou S., Ho Y.M., Hall S., Styles C.J., Scott S.D., Gompels U.A., Murine herpesvirus 68 is genetically related to the gammaherpesviruses Epstein-Barr virus and herpesvirus saimiri, J. Gen. Virol., 1990, 71, 1365–1372PubMedGoogle Scholar
  5. [5]
    Svobodová J., Stančekova M., Blaškovič D., Mistríková J., Leššo J., Russ G., et al., Antigenic relatedness of alphaherpesviruses isolated from free-living rodents, Acta Virol., 1982, 26, 438–443PubMedGoogle Scholar
  6. [6]
    Van Regenmortel M.H., Fauquet C.M., Bishop D.H., Herpesvirus family, In: Virus taxonomy: classification and nomenclature of viruses, 7th ICTV report, San Diego, New York, London, Tokyo, Academic Press, 2000, 220–226Google Scholar
  7. [7]
    Rajčáni J., Blaškovič D., Svobodová J., Čiampor F., Hučková D., Staneková D., Pathogenesis of acute and persistent murine herpesvirus infection in mice, Acta Virol., 1985, 29, 51–60PubMedGoogle Scholar
  8. [8]
    Rajčáni J., Bustamante de Contreras L.R., Svobodová J., Corneal inoculation of murine herpesvirus in mice: the absence of neural spread, Acta Virol., 1987, 31, 25–30PubMedGoogle Scholar
  9. [9]
    Blasdell K., McCracken C., Morris A., Nash T., Begon A., Bennett M., et al., The wood mouse is a natural host for Murid herpesvirus 4, J. Gen. Virol., 2003, 84, 111–113PubMedCrossRefGoogle Scholar
  10. [10]
    Telfer S., Bennett M., Carlslake D., Helyar S., Begon M., Thy dynamics of Murid gammaherpesvirus 4 within wild, sypatric populations of bank voles and wood mice, J. Wildlife Dis., 2007, 1, 32–39Google Scholar
  11. [11]
    Sunil-Chandra N.P., Efstathiou S., Arno J., Nash A.A., Virological and pathological features of mice infected with murine gamma-herpesvirus 68, J. Gen. Virol., 1992, 73, 2347–2356PubMedGoogle Scholar
  12. [12]
    Sunil-Chandra N.P., Efstathiou S., Nash A.A., Murine gammaherpesvirus 68 establishes a latent infection in mouse B lymphocytes in vivo, J. Gen. Virol., 1992, 3, 3275–3279CrossRefGoogle Scholar
  13. [13]
    Usherwood E.J., Stewart J.P., Robertson K., Allen D.J., Nash A.A., Absence of splenic latency in murine gammaherpesvirus 68-infected B cell-deficient mice, J. Gen. Virol., 1996, 77, 2819–2825PubMedGoogle Scholar
  14. [14]
    Sunil-Chandra N.P., Efstathiou S., Nash A.A., Interactions of murine gammaherpesvirus 68 with B and T cell lines, Virology, 1993, 193, 825–833PubMedCrossRefGoogle Scholar
  15. [15]
    Marques S., Efstathiou S., Smith K.G., Haury M., Simas J.P., Selective gene expression of latent murine gammaherpesvirus 68 in B lymphocytes, J. Virol., 2003, 77, 7308–7318PubMedCrossRefGoogle Scholar
  16. [16]
    Weck K.E., Kim S.S., Virgin IV H.W., Speck S.H., Macrophages are the major reservoir of latent murine gammaherpesvirus 68 in peritoneal cells, J. Virol., 1999, 73, 3273–3283PubMedGoogle Scholar
  17. [17]
    Weck K.E., Barkon M.L., Yoo L.I., Speck S.H., Virgin IV H.W., Mature B cells are required for acute splenic infection, but not for establishment of latency, by murine gammaherpesvirus 68, J. Virol., 1996, 70, 6775–6780PubMedGoogle Scholar
  18. [18]
    Stevenson P.G., Doherty P.C., Kinetic analysis of the specific host response to a murine gammaherpesvirus, J. Virol., 1998, 72, 943–949PubMedGoogle Scholar
  19. [19]
    Stevenson P.G., Belz G.T., Castrucci M.R., Altman J.D., Doherty P.C., A gamma-herpesvirus sneaks through a CD8(+) T cell response primed to a lyticphase epitope, Proc. Natl. Acad. Sci. USA, 1999, 96, 9281–9286PubMedCrossRefGoogle Scholar
  20. [20]
    Usherwood E.J., Ross A.J., Allen D.J., Nash A.A., Murine gammaherpesvirus-induced splenomegaly: a critical role for CD4 T cells, J. Gen. Virol., 1996, 77, 627–630PubMedGoogle Scholar
  21. [21]
    Stevenson P.G., Efstathiou S., Doherty P.C., Lehner P.J., Inhibition of MHC class I-restricted antigen presentation by gamma 2-herpesviruses, Proc. Natl. Acad. Sci. USA, 2000, 97, 8455–8460PubMedCrossRefGoogle Scholar
  22. [22]
    Belz G.T., Doherty P.C., Virus-specific and bystander CD8+ T-cell proliferation in the acute and persistent phases of a gammaherpesvirus infection, J. Virol., 2001, 75, 4435–4438PubMedCrossRefGoogle Scholar
  23. [23]
    Woodland D.L., Flano E., Usherwood E.J., Liu L., Kim I.J., Husain S.M., et al., Antigen expression during murine gamma-herpesvirus infection, Immunobiology, 2001, 204, 649–658PubMedCrossRefGoogle Scholar
  24. [24]
    Blackman M.A., Flano E., Usherwood E., Woodland D.L., Murine gamma-herpesvirus-68: a mouse model for IM?, Mol. Med. Today, 2000, 6, 488–490PubMedCrossRefGoogle Scholar
  25. [25]
    Mistríková J., Remeňová A., Leššo J., Stančeková M., Replication and persistence of murine herpesvirus 72 in lymphatic system and peripheral blood mononuclear cells of Balb/C mice, Acta Virol., 1994, 38, 151–156PubMedGoogle Scholar
  26. [26]
    Rašlová H., Mistríková J., Kúdelová M., Mishal Z., Sarasin A., Blangy D., et al., Immunophenotypic study of atypical lymphocytes generated in peripheral blood and spleen of nude mice after MHV-72 inoculation, Viral Immunol., 2000, 13, 313–327PubMedCrossRefGoogle Scholar
  27. [27]
    Hricová M., Mistríková J., Ecological characterization and epidemiological implication of the murine herpesvirus 68, Biologia, 2007 (submitted)Google Scholar
  28. [28]
    Mrmusova M., Horvathova M., Klobusicka M., Mistrikova J., Immunophenotyping of leukocytes in peripheral blood of BALB/c mice infected with mouse herpesvirus isolate 72, Acta Virol., 2002, 46, 19–24PubMedGoogle Scholar
  29. [29]
    Mistríková J., Mrmusová M., Detection of abnormal lymphocytes in the blood of Balb/c mice infected with murine gammaherpesvirus strain 72: the analogy with Epstein-Barr virus infection, Acta Virol., 1998, 42, 79–82PubMedGoogle Scholar
  30. [30]
    Sunil-Chandra N.P., Arno J., Fazakerly J., Nash A.A., Lymphoproliferative disease in mice infected with murine gammaherpesvirus 68, Am. J. Pathol., 1994, 145, 818–826PubMedGoogle Scholar
  31. [31]
    Mistriková J., Rajčáni J., Mrmusová M., Oravcová I., Chronic infection of Balb/c mice with murine herpesvirus 72 is associated with neoplasm development, Acta Virol., 1996, 40, 297–301.PubMedGoogle Scholar
  32. [32]
    Mistríková J., Mrmusová M., Ďurmanová V., Rajčáni J., Increased neoplasm development due to immunosuppressive treatment with FK-506 in BALB/C mice persistently infected with the mouse herpesvirus (MHV-72), Viral Immunol., 1999, 12, 237–247PubMedGoogle Scholar
  33. [33]
    Oda W., Mistriková J., Stančeková M., Dutia B.M., Basah A.A., Takahata H., et al., Analysis of genomic homology of murine gammaherpesvirus MHV-72 to MHV-68 and impact of the survival and tumorigenesis in the MHV-72-infected CB17 scid/scid and CB17+/+ mice, Pathol. Int., 2005, 55, 558–568PubMedCrossRefGoogle Scholar
  34. [34]
    Mistríková J., Blaškovičová J., Pappová M., Hricová M., Establishment and characterization of a tumor cell line derived from a mouse infected with murine gammaherpesviurs 78, Acta Virol., 2006, 50, 223–227PubMedGoogle Scholar
  35. [35]
    Usherwood E.J., Stewart J.P., Nash A.A., Characterization of tumor cell lines derived from murine gammaherpevirus-68-infected cells, J. Virol., 1996, 70, 6516–6518PubMedGoogle Scholar
  36. [36]
    Tarakanova V.L., Suarez F., Tibbetts S.A., Jacoby M.A., Weck K.E., Hess J.L., et al., Murine gmmaherpesvirus 68 infection is Associated with lymphoroliferative disease and lymophioma in Balb/c b2 microglobulin-deficient mice, J. Virol., 2005, 79, 14668–14679PubMedCrossRefGoogle Scholar
  37. [37]
    Rašlová H., Berebbi M., Rajčáni J., Sarasin A., Matis J., Kúdelová M., Susceptibility of mouse mammary glands to murine gammaherpesvirus 72 (MHV-72) infection: evidence of MHV-72 transmission via breast milk, Microb. Pathog., 2001, 31, 47–58PubMedCrossRefGoogle Scholar
  38. [38]
    Mistriková J., Mrmusová-Šupolíková M., Rajčáni J., Leukemia-like syndrome in Balb/c mice infected with the lymphotropic gamma herpesvirus MHVŠumava: an analogy to EBV infection, Neoplasma, 2004, 51, 71–76PubMedGoogle Scholar
  39. [39]
    Mrmusová-Šupolíková M., Pappová M., Mistríková J., Pathogenesis of murine lymphotropic gammaherpesvirus isolate 78, Acta Veter. Brno, 2003, 72, 371–376Google Scholar
  40. [40]
    Pappová M., Stančeková M., Spiššáková I., Ďurmanová V., Mistríková J., Pathogenetical characterization of isolate MHV-60 of mouse herpesvirus, Acta Virol., 2004, 48, 1–11Google Scholar
  41. [41]
    Chalupková A., Hricová M., Hrabovská Z., Mistríková J., Pathogenetical characterization of MHV-76: a spontaneous 9.5 kbp deletion mutant of MuHV-4, Acta Vet. Brno, 2008 (accepted)Google Scholar
  42. [42]
    Macrae A.I., Dutia B., Milligan S., Brownstein D., Allen D.J., Mistrikova J., et al., Analysis of a novel strain of murine gammaherpesvirus reveals a genomic locus important for acute pathogenesis, J. Virol., 2001, 75, 5315–5327PubMedCrossRefGoogle Scholar
  43. [43]
    Rajčáni J., Kúdelová M., Murine herpesvirus pathogenesis: a model for the analysis of molecular mechanisms of human gammaherpesvirus infection, Acta Microbiol. Immunol. Hung., 2005, 52, 41–71PubMedCrossRefGoogle Scholar
  44. [44]
    Virgin H.W., Latreille P., Wamsley P., Hallsworth K., Weck K.E., Dal Canto A.J., et al., Complete sequence and genomic analysis of murine gammaherpesvirus 68, J. Virol., 1997, 71, 5894–5904PubMedGoogle Scholar
  45. [45]
    Bowden R.J., Simas J.P., Davis A.J., Efstathiou S., Murine gammaherpesvirus 68 encodes tRNA-like sequences which are expressed during latency, J. Gen. Virol., 1997, 78, 1675–1687PubMedGoogle Scholar
  46. [46]
    Simas J.P., Bowden R.J., Palge V., Efstathiou S., Four tRNA like sequences and a serpin homologue encoded by murine gammaherpevirus are dispensable for lytic replication in vitro and latency in vivo, J. Gen. Virol., 1998, 79, 149–153PubMedGoogle Scholar
  47. [47]
    Simas J.P., Swann D., Bowden R., Efstathiou S., Analysis of murine gammaherpesvirus-68 transcription during lytic and latent infection, J. Gen. Virol., 1999, 80, 75–82PubMedGoogle Scholar
  48. [48]
    Tugwood J.D., Lau W.H., Tsao S.Y., Martin W.M., Shiu W., Desgranges C., et al., Epstein-Barr virusspecific transcription in normal and malignant nasopharyngeal biopsies and in lymphocytes from healthy donors and IM patients, J. Gen. Virol., 1987, 68, 1081–1091PubMedGoogle Scholar
  49. [49]
    Pfeffer S., Sewer A., Quintana M.L., Sheridan R., Sander Ch., Gässer F.A., et al., Identification of microRNAs of the herpesvirus family, Nature Methods, 2005, 2, 269–276PubMedCrossRefGoogle Scholar
  50. [50]
    Valovičová M., Belvončíková P., Halasová Z., Rajčáni J., Kúdelová M., Mapping of the left end of murine herpesvirus 72 (MHV-72) genome, Acta Microbiol. Immunol. Hung., 2007, 54, 138–139Google Scholar
  51. [51]
    Clambey E.T., Virgin H.W., Speck S.H., Characterization of a spontaneous 9.5-kilobase-deletion mutant of murine gammaherpesvirus 68 reveals tissue-specific genetic requirements for latency, J. Virol., 2002, 76, 6532–6544PubMedCrossRefGoogle Scholar
  52. [52]
    Blaškovičová J., Tomášková J., Šupolíková M., Mistríková J., Kopáček J., Unique deletion identified in the genomic region encompassing the terminal repeats of Murid herpesvirus 4 (MuHV 4), isolate Šumava, Acta Virol., 51, 143–148Google Scholar
  53. [53]
    Komiyama T., Ray C.A., Pickup D.J., Howard A.D., Thornberry N.A., Peterson E.P., et al., Inhibition of interleukin-1 beta converting enzyme by the cowpox virus serpin CrmA. An example of cross-class inhibition, J. Biol. Chem., 1994, 269, 19331–19337PubMedGoogle Scholar
  54. [54]
    Clambey E.T., Virgin H.W., Speck S.H., Disruption of the murine gammaherpesvirus 68 M1 open reading frame leads to enhanced reactivation from latency, J. Virol., 2000, 74, 1973–1984PubMedCrossRefGoogle Scholar
  55. [55]
    Virgin H.W., Presti R.M., Li X.Y., Liu C., Speck S.H., Three distinct regions of the murine gammaherpesvirus 68 genome are transcriptionally active in latently infected mice, J. Virol., 1999, 73, 2321–2332PubMedGoogle Scholar
  56. [56]
    Husain S.M., Usherwood E.J., Dyson H., Coleclough C., Coppola M.A., Woodland D.L., et al., Murine gammaherpesvirus M2 gene is latency-associated and its protein a target for CD8(+) T lymphocytes, Proc. Natl. Acad. Sci. USA, 1999, 96, 7508–7513PubMedCrossRefGoogle Scholar
  57. [57]
    Macrae A.I., Usherwood E.J., Husein S.M., Murid herpesvirus strain 68 M2 protein is a B cell associated antigen important for latency but not lymphocytosis, J. Virol., 2003, 77, 9700–9709PubMedCrossRefGoogle Scholar
  58. [58]
    Liang X., Shin Y.C., Means R.E., Jung J.U., Inhibition of interferon-mediated antiviral activity by murine gammaherpesvirus 68 latency-associated M2 protein, J. Virol., 2004, 78, 12416–12427PubMedCrossRefGoogle Scholar
  59. [59]
    Usherwood E.J., Ward K.A., Blackman M.A., Stewart J.P., Woodland D.L., Latent antigen vaccination in a model gammaherpesvirus infection, J. Virol., 2001, 75, 8283–8288PubMedCrossRefGoogle Scholar
  60. [60]
    Jacoby M.A., Virgin H.W., Speck S.H., Disruption of the M2 gene of murine gammaherpesvirus 68 alters splenic latency following intranasal, but not intraperitoneal, inoculation, J. Virol., 2002, 76, 1790–1801PubMedCrossRefGoogle Scholar
  61. [61]
    Bridgeman A., Stevenson P.G., Simas J.P., Efstathiou S., A secreted chemokine binding protein encoded by murine gammaherpesvirus 68 is necessary for the establishment of a normal latent load, J. Exp. Med., 1997, 194, 301–312CrossRefGoogle Scholar
  62. [62]
    van Berkel V., Preiter K., Virgin H.W., Speck S.H., Identification and initial characterization of the murine gammaherpesvirus 68 gene M3, encoding an abundantly secreted protein, J. Virol., 1999, 73, 4524–4529PubMedGoogle Scholar
  63. [63]
    Parry C.M., Simas J.P., Smith V.P., Stewart C.A., Minson A.C., Efstathiou S., et al., A broad spectrum secreted chemokine binding protein encoded by a herpesvirus, J. Exp. Med., 2000, 191, 573–578PubMedCrossRefGoogle Scholar
  64. [64]
    Sarawar S.R., Lee B.J., Anderson M., Teng Y.C., Zuberi R., Von Gesjen S., Chemokine induction and leukocyte trafficking to the lungs during murine gammaherpesvirus 68 (MHV-68) infection, Virology, 2002, 293, 54–62PubMedCrossRefGoogle Scholar
  65. [65]
    Alcami A., Structural basis of the herpesvirus M3-chemokine interaction, Trends Microbiol., 2003, 11, 191–192PubMedGoogle Scholar
  66. [66]
    Obar J.J., Donovan D.C., Crist S.G., Silvia O., Stewart J.P., Usherwood E.J., T-cell responses to the M3 immune evasion protein of murid gammaherpesvirus 68 are partially protective and induced with lytic antigen kinetics, J. Virol., 2004, 78, 10829–10832PubMedCrossRefGoogle Scholar
  67. [67]
    Townsley A.C., Dutia B. M., Nash A.A., The m4 gene of murine gammaherpesvirus modulates productive and latent infection in vivo, J. Virol., 2004, 78, 758–767PubMedCrossRefGoogle Scholar
  68. [68]
    H.M. Geere, Y. Ligertwood, K.M. Templeton, I. Bennet, B. Gandagharan, Rhind S.M., et al., The M4 gene of murine gammaherpesvirus 68 modulates latent infection, J. Gen. Virol., 2006, 87, 803–807PubMedCrossRefGoogle Scholar
  69. [69]
    vanBerkel V., Levine B., Kapadia S.B., Goldman J.E., Speck S.H., Virgin H.V., Clinical role for a high affinity chemokine binding protein g-herpesvirus induced lethal meningitis, J. Clin. Invest., 2002, 109, 905–914CrossRefGoogle Scholar
  70. [70]
    Evans A.G., Moorman N.J., Willer D.O., Speck S.H., The M4 gene of gHV68 encodes a secreted glycoprotein and is required for the efficient establishment of splenic latency, Virology, 2006, 344, 520–531PubMedCrossRefGoogle Scholar
  71. [71]
    Rajčáni J., Kúdelová M., Gammaherpesviruses: pathogenesis of infection and cell signalling, Folia Microbiol. (Praha), 2003, 48, 291–318Google Scholar
  72. [72]
    Dutia B.M., Roy D.J., Ebrahimi B., Gangadharan B., Efstathiou S., Stewart J.P., et al., Identification of a region of the virus genome involved in murine gammaherpesvirus 68-induced splenic pathology, J. Gen. Virol., 2004, 85, 1393–1400PubMedCrossRefGoogle Scholar
  73. [73]
    Nevins J.R., Cell transformation by viruses, In: Fields Virology 4th Ed., vol.1, Lippincott Williams and Wilkins, Philadelphia, 2001, 245–283Google Scholar
  74. [74]
    Kúdelová M., Rajčáni J., Gammaherpesviruses and oncogenesis, In: L.T. Johannes (Ed.) Oncogenic Viruses Research Trends, Nova Science Publishers, 2007, 102–136Google Scholar
  75. [75]
    Sunil-Chandra N.P., Arno J., Fazakerley J., Nash A.A., Lymphoproliferative disease in mice infected with murine gammaherpesvirus 68, Am. J. Pathol., 1994, 145, 818–826PubMedGoogle Scholar
  76. [76]
    Mistríková J., Moško T., Mrmusová M., Pathogenic characterization of a mouse herpesvirus isolate Šumava, Acta Virol., 2002, 46, 41–46PubMedGoogle Scholar

Copyright information

© Versita Warsaw and Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  1. 1.Department of Microbiology and Virology, Faculty of Microbiology and Natural SciencesComenius UniversityBratislavaSlovakia
  2. 2.Institute of VirologySlovak Academy of SciencesBratislavaSlovakia

Personalised recommendations