Abstract
MHV68 is a murine gammaherpesvirus that infects laboratory mice and thus provides a tractable small animal model for characterizing critical aspects of gammaherpesvirus pathogenesis. Having evolved with their natural host, herpesviruses encode numerous gene products that are involved in modulating host immune responses to facilitate the establishment and maintenance of lifelong chronic infection. One such protein, MHV68 M1, is a secreted protein that has no known homologs, but has been shown to play a critical role in controlling virus reactivation from latently infected macrophages. We have previous demonstrated that M1 drives the activation and expansion of Vβ4+ CD8+ T cells, which are thought to be involved in controlling MHV68 reactivation through the secretion of interferon gamma. The mechanism of action and regulation of M1 expression are poorly understood. To gain insights into the function of M1, we set out to evaluate the site of expression and transcriptional regulation of the M1 gene. Here, using a recombinant virus expressing a fluorescent protein driven by the M1 gene promoter, we identify plasma cells as the major cell type expressing M1 at the peak of infection in the spleen. In addition, we show that M1 gene transcription is regulated by both the essential viral immediate-early transcriptional activator Rta and cellular interferon regulatory factor 4 (IRF4), which together potently synergize to drive M1 gene expression. Finally, we show that IRF4, a cellular transcription factor essential for plasma cell differentiation, can directly interact with Rta. The latter observation raises the possibility that the interaction of Rta and IRF4 may be involved in regulating a number of viral and cellular genes during MHV68 reactivation linked to plasma cell differentiation.
Highlights
MHV68 is a naturally occurring murid gammaherpesvirus that has significant genetic and functional homology to the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV)
We show that M1 gene expression is regulated by both cellular and viral factors, which allow the virus to fine-tune gene expression in response to environmental signals
In EBV, structural protein gp350, as well as latent membrane proteins LMP-1 and LMP-2A have been shown to activate expression of an endogenous human retroviral superantigen, HERV-K18, which results in a Vb13+ T cell expansion [13,14,15]
Summary
MHV68 is a naturally occurring murid gammaherpesvirus that has significant genetic and functional homology to the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV). Every herpesvirus, having co-evolved with its host during speciation, has acquired unique genes - many of which function to modulate and/or evade the host immune response Coevolution of with their hosts has led to some divergence of host-pathogen interactions; unique genes may reveal homologous functions required for chronic infection of the host. One such gene is the MHV68 M1, which is found in a cluster of unique genes at the left end of the MHV68 genome. In addition to the strain specific reactivation phenotype, a strain specific expansion of Vb4+CD8+ T cells had previously been observed in response to MHV68 infection [3]. M1 was shown to be a secreted protein capable of stimulating Vb4+CD8+ T cells to produce IFNc and TNFa [2]
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