POLYOMAVIRUS T ANTIGENS ACTIVATE AN ANTIVIRAL STATE by Nicholas Scott Giacobbi

The large T antigen (TAg) of the polyomavirus Simian virus 40 (SV40) is known to play an important role in several events during the viral life cycle, including DNA replication, transcription, and virion assembly. Recent analysis revealed that primary mouse embryonic fibroblasts (MEFs) expressing exogenous TAg showed increased transcription of interferon stimulated genes (ISGs). Interestingly, this activation was shown to be stimulated in the absence of interferon production. The mechanisms by which TAg upregulates the pathway(s) and the consequences of that upregulation remain unknown. Thus, investigation into this mechanism may allow the elucidation of novel host factors moderating the interferon response. I tested several mutants of TAg to understand what functions are necessary to induce the interferon response. My investigation has revealed that the early region of SV40 can activate an antiviral phenotype in MEFs, as seen by the attenuation of viral growth during productive infection. Furthermore, the amino terminus of TAg is sufficient to stimulate this response, and alternative splice forms from the early region (e.g. small T Antigen) do not seem to be critical to the upregulation of ISGs. Other experiments indicate that the STAT1 transcription factor is necessary for establishment of the antiviral state. I have also shown that two human polyomaviruses, Human Polyomavirus BK (BKV) and human Polyomavirus JC (JCV), follow suit with our observations of SV40 TAg. I hypothesize that the TAg-mediated activation of ISGs contributes to an environment inhibitory for viral growth and that this phenomenon is extended to multiple polyomaviruses. This research Todd A. Reinhart, PhD POLYOMAVIRUS T ANTIGENS ACTIVATE AN ANTIVIRAL STATE Nicholas Scott Giacobbi, M.S. University of Pittsburgh, 2014