Role of B-Cell Proliferation in the Establishment of Gammaherpesvirus Latency

Thus, the FL reporter can be detected in most anatomic sites, although the light coming from within is attenuated by overlying tissues of the mice (36). We reasoned, therefore, that the normal pathogenesis of MHV-68 infection may be significantly different than that observed in laboratory mice and that an analysis of MHV-68 infection of a natural host may provide important new insights into gammaherpesvirus biology. Further, given the ease of generating MHV68 mutants and the capacity to perform controlled experimental infections of various wild-type (WT), knockout, and transgenic mice, MHV68 offers an attractive system for understanding the virus-host dynamic during productive viral replication [18], [19], [20]. Transmissibility and infectivity of the novel BGHV8 were established by transferring supernatant from MVI-it cells onto African green monkey (Vero) cells. Murine gammaherpesvirus 68 (MHV68, formally identified as murid herpesvirus 4) is a natural pathogen of murid rodents used to study virus–host interactions in the context of a whole animal. Mammalian miRNAs are known to participate in cell differentiation, metabolism, homeostasis, apoptosis, and cancer. Because latency is established specifically in lymphocytes, we investigated the possibility that suppression involved a lymphocyte-specific factor.

Interestingly, the absence of IFN-γ signaling has no effect on the acute phase of γHV68 infection (43, 61). That the bone marrow may serve as a site for latent infection is highlighted by a number of reports of herpesvirus association with bone marrow-related diseases, including posttransplant lymphoproliferative disease (PTLD) and hemophagocytic lymphohistiocytosis (HLH). In other areas of the world, however, the occurrence of BL is more sporadic and a lower percentage of these lymphomas are EBV positive (65). Those that infect experimentally tractable mammals are particularly useful for establishing cause and effect in a realistic context. On day 5, the lungs of both WT and cycKO virus-infected mice showed signs of mild, acute pneumonia (Fig. M3) were readily present (Figure 2C). γHV68-infected cells were common in ALH lesions as measured by in situ hybridization with a probe specific for viral tRNAs (vtRNAs), but they were scarce in γHV68-infected spleens with normal histology.


In the case of gammaherpesviruses, which are associated with the development of lymphoproliferative disorders, including lymphomas, reactivation from latently infected B lymphocytes occurs upon terminal differentiation of these cells to plasma cells-the cell type that produces antibodies. Competing interests: The authors have declared that no competing interests exist. IMPORTANCE Gammaherpesviruses are oncogenic herpesviruses that establish lifelong chronic infections. We have also determined that the infection is predominately lytic. Disease caused by gammaherpesviruses during chronic infection is associated with latent infection and/or reactivation from latency and is more common in immunocompromised individuals. This is in contrast to EBV, a type 1 gammaherpesvirus, which generally requires the cooperativity of two viral proteins, Zebra and RTA, for lytic replication and reactivation (6-8, 12, 38). Similar to other herpesviruses, the lytic replication of γHV68 is mediated by sequential immediate-early, early, and late viral gene expression (1, 34).

EBV and KSHV persistently replicate at mucosal sites, including the oropharynx and genital tract (1, 25). The gammaherpesviruses are an important group of pathogens that cause serious disease in humans and animals. To test the functions of MHV-68 Rta in reactivation, a plasmid expressing Rta was transfected into a latently infected cell line, S11E, which was established from a B-cell lymphoma in an MHV-68-infected mouse. W. Thus, infections with doses as small as 0.1 PFU of gammaHV68 result in stable levels of acute-phase replication and latent infection. These analyses also demonstrated that a significant percentage of MHV68-infected splenocytes at the peak of viral latency are plasma cells (ca. Global gene expression analysis using an MHV-68 DNA array showed that PGE(2) increased production of multiple viral gene products, and NS-398 inhibited production of many of the same genes.

Maximising IFN-I induction with poly(I:C) increased virus tagging in lung macrophages, but the tagged virus spread poorly. 71:2550-2554, 1997; Lukac et al., Virology 252:304-312, 1998; Sun et al., Proc. Only the RHV GMPs recruited the bromo- and extra terminal domain (BET) proteins BRD2 and BRD4 to the site of chromatin remodeling. The FLAG-tagged ORF49 protein promoted the ability of RTA to activate downstream target promoters and enhanced virus replication from the ORF50null virus in the presence of RTA. Children living in Sub-Saharan Africa are seropositive for Epstein Barr Virus (EBV) by the age of 6 months. Murine gammaherpesvirus gammaHV68 is genetically and biologically related to human gammaherpesviruses and herpesvirus saimiri and has been reported to be associated with lymphoproliferative disease in mice (N. Until recently, mechanistic studies of the role of immunity in gammaherpesvirus infection have been hampered by the species specificity of the human herpesviruses, Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8), and the difficulties and costs inherent in analyzing pathogenesis, tumor induction, and mechanisms of immunity in primate models.

P. D., 3rd, Dezalia, M. However, unlike KSHV or EBV, MHV-68 readily infects fibroblast and epithelial cell lines derived from several mammalian species, providing a system to study productive and latent infections as well as reactivation of gammaherpesviruses in vivo and in vitro.