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Primary macrophages rely on histone deacetylase 1 and 2 expression to induce type I interferon in response to gammaherpesvirus infection. J Virol 2014 Feb;88(4):2268-78



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Scopus ID

2-s2.0-84893504479   12 Citations


Type I interferon is induced shortly following viral infection and represents a first line of host defense against a majority of viral pathogens. Not surprisingly, both replication and latency of gammaherpesviruses, ubiquitous cancer-associated pathogens, are attenuated by type I interferon, although the mechanism of attenuation remains poorly characterized. Gammaherpesviruses also target histone deacetylases (HDACs), a family of pleiotropic enzymes that modify gene expression and several cell signaling pathways. Specifically, we have previously shown that a conserved gammaherpesvirus protein kinase interacts with HDAC1 and -2 to promote gammaherpesvirus replication in primary macrophages. In the current study, we have used genetic approaches to show that expression of HDAC1 and -2 is critical for induction of a type I interferon response following gammaherpesvirus infection of primary macrophages. Specifically, expression of HDAC1 and -2 was required for phosphorylation of interferon regulatory factor 3 (IRF3) and accumulation of IRF3 at the beta interferon promoter in gammaherpesvirus-infected primary macrophages. To our knowledge, this is the first demonstration of a specific role for HDAC1 and -2 in the induction of type I interferon responses in primary immune cells following virus infection. Furthermore, because HDAC1 and -2 are overexpressed in several types of cancer, our findings illuminate potential side effects of HDAC1- and -2-specific inhibitors that are currently under development as cancer therapy agents. IMPORTANCE Gammaherpesviruses establish chronic infection in a majority of the adult population and are associated with several malignancies. Infected cells counteract gammaherpesvirus infection via innate immune signaling mediated primarily through type I interferon. The induction of type I interferon expression proceeds through several stages using molecular mechanisms that are still incompletely characterized. In this study, we show that expression of HDAC1 and -2 by macrophages is required to mount a type I interferon response to incoming gammaherpesvirus. The involvement of HDAC1 and -2 in the type I interferon response highlights the pleiotropic roles of these enzymes in cellular signaling. Interestingly, HDAC1 and -2 are deregulated in cancer and are attractive targets of new cancer therapies. Due to the ubiquitous and chronic nature of gammaherpesvirus infection, the role of HDAC1 and -2 in the induction of type I interferon responses should be considered during the clinical development of HDAC1- and -2-specific inhibitors.

Author List

Mounce BC, Mboko WP, Kanack AJ, Tarakanova VL


Vera Tarakanova PhD Associate Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Blotting, Western
Chromatin Immunoprecipitation
DNA Primers
Herpesviridae Infections
Histone Deacetylase 1
Histone Deacetylase 2
Interferon Regulatory Factor-3
Interferon Type I
Mice, Inbred C57BL
Real-Time Polymerase Chain Reaction
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a