Signaling Activities of Gammaherpesvirus Membrane Proteins

Finally, bioluminescence measured in vivo highly correlates with FL activity measured in vitro in the lysate of extracted tissues (53). Although we used only one strain of laboratory mice to study MHV-68 pathogenesis, the study of other inbred strains (e.g., 129 and C57BL/6) has shown only minor differences in pathogenesis and host response, with none being more resistant or susceptible, as seen with other viruses (8, 39). While the importance of DDR, mitogen-activated protein kinase (MAPK), and inhibitor of kappa-B kinase (IKK) signaling in MHV68 replication recently was demonstrated [24], [25], [26], [27], an understanding of how the kinases involved in these responses influence the overall phosphoprotein milieu within the host cell is not known. Further, BGHV8 infection of Vero cells and the human cell lines A549 and Huh7 was confirmed through quantitative PCR (qPCR) verification of viral transcription and BGHV8 genome amplification. MHV68 productively infects, and establishes latency in, all tested strains of Mus musculus. EBV and KSHV encode 25 and 12 pre-miRNAs, respectively (10, 11, 17–20). Inducers of the NF-κB pathway initiate the degradation of I-κB, allowing the NF-κB proteins to accumulate in the nucleus, where they bind to DNA and activate target genes (10, 40).

IFN-γ−/− mice have elevated numbers of cells reactivating from viral latency, as well as production of infectious virus after the establishment of latency, referred to here as persistent replication (18, 53). Importantly, B cell PTLD occurring after allogeneic HSC transplantation is almost always of donor origin and associated with EBV genomic DNA integration (11, 32). Another EBV-associated disease is NPC, a malignancy of the squamous epithelium situated in the nasopharynx (117). Despite immortalizing only fetal B cells in vitro (5), it colonizes adult lymphoid GCs in vivo (6) to establish a persistent infection of memory B cells (7–9). Lungs from mock-infected mice were completely normal (Fig. The persistence of increased numbers of MDSC during latency (Figure 2B) could be due to the long-lived nature of MDSC, as has been suggested [24]. γHV68 infection of BALB β2m−/− mice results in lymphoproliferation and lymphoma, providing a valuable tool for identifying viral and host genes involved in gammaherpesvirus-associated malignancies.

However, surprisingly, when we examined the role of XBP-1 in the setting of infection of mice-using mice that lack a functional XBP-1 gene in B cells-we failed to observe a role for XBP-1 in virus reactivation. The human viruses of this family, Epstein-Barr Virus (EBV) and Kaposi’s Sarcoma associated Herpesvirus (KSHV) are associated with a range of lymphoproliferative diseases and lymphomas in immunocompromised situations (reviewed in [1]). Here, we establish that murine gammaherpesvirus 68 induces the activation of tumor suppressor p53. These findings may open new avenues of consideration related to neuronal pathologies and infection with these viruses. We and others have therefore studied murine gammaherpesvirus 68 (γHV68) as a small-animal model for defining mechanisms of immune control of chronic gammaherpesvirus infection in vivo. The comparison of these three RTAs has allowed us to determine which domains of RTA are necessary for reactivation of MHV-68 and transactivation of viral lytic promoters. The switch between lytic and latent gene expression programs is controlled by the essential immediate-early lytic switch gene 50.

Evidence of long-term T-cell stimulation in infected normal mice further supports the existence of ongoing persistent replication during chronic gammaherpesvirus infection (2, 3). EBV has been linked to Burkitt’s lymphoma as well as nasopharyngeal carcinomas (9), and HHV-8 has been associated with Kaposi’s sarcoma, body cavity-based lymphomas, and multicentric Castleman’s disease (6). We conclude that Rta alone is able to disrupt latency, activate viral lytic replication, and drive the lytic cycle to completion. Virol. 8% at day 18). This occurred mainly in B cells. Acad.

Our data indicate that ORF49 may perform an important function in MHV-68 replication in cooperation with RTA. However, the impact of acute EBV infection on the generation of anti-malarial immunity is unknown. Sunil-Chandra, J. MHV-68 was originally isolated from the bank vole (Clethrionomys glareolus) in Slovakia and is a natural pathogen for mice (Blaskovic et al., 1980) (Fig. Efstathiou, and A. H. RNA obtained from an MHV-68 latently infected cell line, from cells lytically infected with MHV-68 in culture, and from the lung tissue of infected mice was used to probe the MHV-68 arrays.

They must therefore resist neutralization by antibody. We have sequenced 6162 bp at the left end of the MHV-68 genome and identified two unique open reading frames (ORFs) (ORF2 and ORF3) and an ORF (ORF1) which displays similarity to poxvirus members of the serpin family. Murine gammaherpesvirus 68 (MHV68) is a well-established model for KSHV. Host genes that regulate systemic inflammation upon chronic viral infection are incompletely understood. Upon viral infection, the major defense mounted by the host immune system is the activation of the interferon (IFN)-mediated antiviral pathway. Murine γ-herpesvirus 68 (MHV-68) infection of Mus musculus-derived strains of mice is an established model of γ-herpesvirus infection.