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

Abstract

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.

Biological and pathogenetic characterization of different isolates of murine gammaherpesvirus 68 (MHV-68) in the context of study of human oncogenic gammaherpesviruses

“…We described the oncogenic potential of all murine gammaherpesvirus isolates in vivo and in vitro as well (Mistríková et al, 1996bOda et al, 2005;Mrmusová-Šupolíková et al, 2003;Pappová et al, 2004). Through pathogenetic characterization of a deletion mutant MHV-76 we sug- Blaškovičová et al (2007) gested a possible association of M4 gene with oncogenic potential of the virus (Macrae et al, 2001;Mistríková and Rajčáni, 2008;Chalupková et al, 2008) (Table 2). Several cell lines were derived from murine gammaherpesvirusinfected mice with lymphoproliferative disorders.…”

Partial genome analysis of murine gammaherpesvirus 4556

“…Furthermore, Mhv-4556 causes a reduced and by about 10 days delayed splenomegaly in comparison to personal communication). long-term infection associated with neoplasm development that has been observed with murine gammaherpesviruses was so far not recorded for Mhv-4556 (Mistríková and rajčáni, 2008). Despite of these findings, the only genetic difference between Mhv-4556 and Mhv-68 is that within the rInG-ch finger domain of Mk3 that is known to play a major role in the establishment of latency and to be necessary for the ubiquitination of Mhc class I proteins (Stevenson et al, 2002;lybarger et al, 2003;Boname et al, 2005b).…”

“…relatively high incidence of abnormal lymphocytes in the blood of virus-infected Balb/c or nude mice were described for Mhv-72 but not for Mhv-68, thus supporting the similarity between Mhv-72 and eBv infections (Blackman et al, 2000;rašlová et al, 2000a). A long-term-infection of immuno-suppressed as well as immuno-competent mice induced lPDs and neoplasmas in similar or higher rate compared to Mhv-68 (Mistríková et al, 2000;Mistríková and rajčáni, 2008).…”

“…Mistríková et al (2002) identified some pathogenetical features distinguishing Mhv-Šumava from Mhv-68, Mhv-72, and Mhv-76. namely, Balb/c mice infected with Mhv-Šumava showed (i) a strong leukocytosis, (ii) as many as 60% atypical lymphocytes in peripheral blood during acute infection and (iii) the highest frequency of tumours in chronic infection among murine gammaherpesviruses (14.6% vs 11% for Mhv-68 or Mhv-72 and 0% for Mhv-76) (Mistríková and rajčáni, 2008).…”

Partial genome sequence of murine gammaherpesvirus 72 and its analysis

“…Abnormal lymphocytes in the blood of virus-infected BALB/c or nude mice were described for MHV-72 but not for MHV-68, thus supporting the similarity between MHV-72 and EBV infections of man (Blackman et al, 2000;Rašlová et al, 2000a). However, studies of a long-term-infection of Balb/c as well as wtCB17 mice with MHV-72 revealed a similar or higher malignancy development rate in relation to MHV-68 (Mistríková et al, 2000;Mistríková and Rajčáni 2008;Oda et al, 2005). This rate even increased in case of mice immunosuppressed with antifungal agent FK-506 and the frequency of virus recovery from tumors reached ~38% (Mistríková et al, 1996).…”