Polyomavirus T antigens activate an antiviral state

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Most viruses have mechanisms for evading or inhibiting the host’s innate immune response. We have found that the human polyomaviruses, BKV and JCV activate the interferon response and induce an antiviral state when expressed in primary mouse cells. Both the activation of the interferon pathway and the induction of an antiviral state depend on the expression of viral early proteins called T antigens. Polyomaviruses express multiple T antigens and we have shown that a protein common to all polyomaviruses, large T antigen (Tag) is necessary and sufficient to induce the innate immune response. Furthermore, Tag interaction with a known tumor suppressor, pRb may be necessary for this effect. These studies point to a possible link between polyomavirus Tag interaction with the innate immune response and their oncogenic properties.

The Polyomaviruses family consists of viruses with a double-stranded circular DNA genomes and a virion composed of three virus-encoded proteins. Polyomaviruses are ubiquitous, infecting hosts ranging from birds to mammals. Simian virus 40 (SV40) is among the best studied polyomaviruses. To date, thirteen polyomaviruses are known to infect humans. Human polyomaviruses typically establish life-long persistent infections with no apparent symptoms. However, some polyomaviruses can cause devastating disease in immunosuppressed individuals. For example, JCV causes progressive multifocal leukoencephalopathy in some AIDS patients and BKV is responsible for nephropathy following kidney transplantation. SV40, BKV, and JCV induce tumors when injected into newborn or immunosuppressed rodents and the molecular basis of by which these viruses induce tumorigenesis has been under intensive study for many years.

During the course of our investigations into oncogenesis induced by SV40 we performed microarray experiments showing that cells expressing Tag expressed higher levels of the mRNAs encoding many interferon-induced genes (ISGs) than control cells. In this investigation we extend on our previous studies to show that two human polyomaviruses, BKV and JCV also induce ISG expression. Normally, ISGs are induced in response to the release of interferons from infected cells. However, mouse cells expressing Tag appear to activate ISG expression without producing interferon. In this study we found that the Tag induction of ISGs requires the signaling protein STAT-1 and that cells expressing Tag are resistant to infection by viruses known to be sensitive to ISG induction (See figure below). Finally, this work shows that STAT-1 activation requires Tag’s interaction with the Rb family of tumor suppressors. We were surprised by this apparent connection between Tag’s manipulation of the interferon pathway to its oncogenic properties. However, we still do not understand how the activation of this response favors viral infection or contributes to tumorigenesis. 

figure

Polyomavirus T antigens activate an antiviral state.  (A)  This panel shows the growth of vesicular stomatitis virus (VSV) in plaque forming units per milliliter (pfu/mL) over forty-eight hours in mouse embryonic fibroblasts (MEFs). (B) The level of VSV produced from T antigen expressing MEFs is greatly reduced in when compared to wild-type over a forty-eight hour time course.

Introducing the Authors

Nick Giacobbi

Nicholas S. Giacobbi, Tushar Gupta, Andrew T. Coxon, James M. Pipas

Nick Giacobbi is a student who carried out most of the studies described in this manuscript.

About the Research

Polyomavirus T antigens activate an antiviral state

Virology, Volume 476, February 2015, Pages 377 – 385
Nicholas S. Giacobbi, Tushar Gupta, Andrew T. Coxon, James M. Pipas

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