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.
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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
References
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, 468
Mistríková J., Blaškovič D., Ecology of the murine alphaherpesvirus and its isolation from lung of rodents in cell culture, Acta Virol., 1985, 29, 312–317
Svobodová J., Blaskovič D., Mistríková J., Growth characteristics of herpesviruses isolated from free living small rodents, Acta Virol., 1982, 26, 256–263
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, 1365–1372
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, 438–443
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, 220–226
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, 51–60
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, 25–30
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, 111–113
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, 32–39
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, 2347–2356
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, 3275–3279
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, 2819–2825
Sunil-Chandra N.P., Efstathiou S., Nash A.A., Interactions of murine gammaherpesvirus 68 with B and T cell lines, Virology, 1993, 193, 825–833
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, 7308–7318
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, 3273–3283
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, 6775–6780
Stevenson P.G., Doherty P.C., Kinetic analysis of the specific host response to a murine gammaherpesvirus, J. Virol., 1998, 72, 943–949
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, 9281–9286
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, 627–630
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, 8455–8460
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, 4435–4438
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, 649–658
Blackman M.A., Flano E., Usherwood E., Woodland D.L., Murine gamma-herpesvirus-68: a mouse model for IM?, Mol. Med. Today, 2000, 6, 488–490
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, 151–156
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, 313–327
Hricová M., Mistríková J., Ecological characterization and epidemiological implication of the murine herpesvirus 68, Biologia, 2007 (submitted)
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, 19–24
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, 79–82
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, 818–826
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.
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, 237–247
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, 558–568
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, 223–227
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, 6516–6518
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, 14668–14679
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, 47–58
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, 71–76
Mrmusová-Šupolíková M., Pappová M., Mistríková J., Pathogenesis of murine lymphotropic gammaherpesvirus isolate 78, Acta Veter. Brno, 2003, 72, 371–376
Pappová M., Stančeková M., Spiššáková I., Ďurmanová V., Mistríková J., Pathogenetical characterization of isolate MHV-60 of mouse herpesvirus, Acta Virol., 2004, 48, 1–11
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)
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, 5315–5327
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, 41–71
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, 5894–5904
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, 1675–1687
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, 149–153
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, 75–82
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, 1081–1091
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, 269–276
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, 138–139
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, 6532–6544
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, 143–148
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, 19331–19337
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, 1973–1984
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, 2321–2332
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, 7508–7513
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, 9700–9709
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, 12416–12427
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, 8283–8288
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, 1790–1801
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, 301–312
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, 4524–4529
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, 573–578
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, 54–62
Alcami A., Structural basis of the herpesvirus M3-chemokine interaction, Trends Microbiol., 2003, 11, 191–192
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, 10829–10832
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, 758–767
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, 803–807
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, 905–914
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, 520–531
Rajčáni J., Kúdelová M., Gammaherpesviruses: pathogenesis of infection and cell signalling, Folia Microbiol. (Praha), 2003, 48, 291–318
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, 1393–1400
Nevins J.R., Cell transformation by viruses, In: Fields Virology 4th Ed., vol.1, Lippincott Williams and Wilkins, Philadelphia, 2001, 245–283
Kúdelová M., Rajčáni J., Gammaherpesviruses and oncogenesis, In: L.T. Johannes (Ed.) Oncogenic Viruses Research Trends, Nova Science Publishers, 2007, 102–136
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, 818–826
Mistríková J., Moško T., Mrmusová M., Pathogenic characterization of a mouse herpesvirus isolate Šumava, Acta Virol., 2002, 46, 41–46
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Mistríková, J., Rajčáni, J. 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. cent.eur.j.biol. 3, 19–30 (2008). https://doi.org/10.2478/s11535-008-0002-0
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DOI: https://doi.org/10.2478/s11535-008-0002-0