Medicine

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Interactions of murine gammaherpesvirus 68 with B and T cell lines
(Academic Press, Elsevier, 1993) Sunil-Chandra, N.P.; Efstathiou, S.; Nash, A.A.
Murine gammaherpesvirus is a natural pathogen of wild rodents. We have established that in vivo the virus persists in B lymphocytes in a latent form and therefore has similar biological properties to Epstein-Barr virus and related gamma-I-herpesviruses. In this report we have established a persistent infection in mouse myeloma (B) cells (NSO cell line), but not in mouse thymoma (T) cells (BW 5147 cell line). The virus persists indefinitely in myeloma cells, without any apparent cytopathic effect, but with the production of infectious virus. We demonstrate that ACV abolishes the productive infection, but large numbers of cells harbor the virus in a latent form, as determined by an infectious center assay. Analysis of the viral DNA has shown that during a persistent infection linear virus genomes predominated, with low levels of circular DNA also present. Treatment of cells with ACV results in a significant reduction of linear genomes, but has no effect on the level of circular DNA molecules. These data provide further evidence to support our earlier observations on B cells as the site of latency and provides an in vitro model with which to study the molecular basis of MHV-68 latency/persistence.
Characterization of murine gammaherpesvirus 68 glycoprotein B (gB) homolog: similarity to Epstein-Barr virus gB (gp110)
(American Society for Microbiology, 1994) Stewart, J.P.; Janjua, N.J.; Sunil-Chandra, N.P.; Nash, A.A.; Arrand, J.R.
Murine gammaherpesvirus 68 (MHV-68) is a natural pathogen of murid rodents and displays similar pathobiological characteristics to those of the human gammaherpesvirus Epstein-Barr virus (EBV). However, in contrast to EBV, MHV-68 will replicate in epithelial cells in vitro. It has therefore been proposed that MHV-68 may be of use as a model for the study of gammaherpesviruses, EBV in particular, both in vitro and in vivo. The EBV homolog of herpes simplex virus glycoprotein B (gB), termed gp110, is somewhat unusual compared with those of many other herpesviruses. We therefore decided to characterize the homolog of gB encoded by MHV-68 (termed MHV gB) to observe the properties of a gammaherpesvirus gB produced in epithelial cells and also to test the relatedness of MHV-68 and EBV. The MHV gB-coding sequence was determined from cloned DNA. The predicted amino acid sequence shared closest homology with gammaherpesvirus gB homologs. Biochemical analysis showed that MHV gB was a glycoprotein with a molecular weight of 105,000. However, the glycans were of the N-linked, high-mannose type, indicating retention in the endoplasmic reticulum. In line with this, MHV gB was localized to the cytoplasm and nuclear margins of infected cells but was not detected on the cell surface or in virions. Additionally, anti-MHV gB antisera were nonneutralizing. Thus, the MHV gB was unlike many other herpesvirus gBs but was extremely similar to the EBV gB. This highlights the close relationship between MHV-68 and EBV and underlines the potential of MHV-68 as a model for EBV in epithelial cells both in vitro and in vivo.
Lymphoproliferative disease in mice infected with murine gammaherpesvirus 68
(American Assn. of Pathologists; Elsevier, 1994) Sunil-Chandra, N.P.; Arno, J.; Fazakerley, J.; Nash, A.A.
Murine gammaherpesvirus is a natural pathogen of wild rodents. In the laboratory it establishes an infection of epithelial cells and persists in B lymphocytes in a latent form. Inbred mice chronically infected with the virus develop a lymphoproliferative disease (LPD) similar to that seen in patients infected with Epstein-Barr virus. The frequency of LPD over a period of 3 years was 9% of all infected animals, with 50% of these displaying high grade lymphomas. The incidence of LPD was greatly increased when infected mice were treated with cyclosporin A. The majority of mice used in the experiments were BALB/c, although lymphomas were detected in mice on other genetic backgrounds, ie, CBA and B10Br. Lymphomas were associated with both lymphoid and nonlymphoid tissues (liver, lung, and kidney). In all cases of lymphomas studied thus far, there was a mixed B cell (B220+ve) and T cell (CD3+ve) phenotype. The B cells were light chain restricted, indicative of a clonal origin. Variable numbers of virus genome-positive cells were detected by in situ hybridization in and around the lymphomas. In contrast, no lytic antigen-positive cells were detected, indicating that genome-positive cells were either latently infected or undergoing an abortive infection. These observations suggest that murine gammaherpesvirus-infected mice may be an important model to study the pathogenesis of LPD associated with other gammaherpesviruses, such as Epstein-Barr virus.
Murine gammaherpesvirus 68 establishes a latent infection in mouse B lymphocytes in vivo
(Microbiology Society, 1992) Sunil-Chandra, N.P.; Efstathiou, S.; Nash, A.A.
Murine gammaherpesvirus 68 (MHV-68) is able to persist in spleen cells of infected mice. To determine the cell type harbouring persistent virus, spleen cells from infected animals were separated into immunoglobulin (Ig)-positive (B cell-enriched), Ig-negative (T cellenriched) and plastic-adherent (macrophage-enriched) fractions. These cells were co-cultivated with permissive BHK-21 cells in an infectious centre assay. The consistent recovery and enrichment of infectious centres in the Ig-positive fraction clearly demonstrates that B cells are a major site of virus persistence/latency. This observation indicates that MHV-68 is biologically similar to Epstein-Barr virus and other members of the B cell lymphotropic gammaherpesvirus 1 subgroup.

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