Abstract 1380 Investigating TRIM25 antagonism by the Human Papilloma Virus

Antiviral response pathways like the RIG-I axis, recognize and respond to viral intrusion. Therefore, it is a common strategy for viruses to antagonize these pathways to avoid immune detection. The Human Papilloma Virus viral protein E6 has been shown to antagonize the RIG-I axis, essentially "turning down" innate immune signals. HPV E6 does this by engaging a well-established upstream RIG-I activator, TRIM25, and preventing TRIM25-mediated ubiquitination of RIG-I. In this work, we sought to better understand how the TRIM25-E6 interaction contributes to HPV infections and cancer pathology. In support of previous findings, we have demonstrated that E6 and TRIM25 interact. Using E6-targeting biologics, we have shown that disrupting the E6:TRIM25 interaction restores innate immune signaling by inducing ISG56 transcription. Further, using these biologics in HPV(+) cells, we have observed an increase in additional interferon-stimulated genes, supporting the functionality of our tools to disrupt the E6:TRIM25 interface. We have further derivatized our highest binding biologic to develop the first HPV-specific degrader to be used in vivo. Mouse data supports that E6 degradation reduces tumor burden and that the anti-tumor response is dependent on immune signaling. These data suggest that targeting the TRIM25:E6 interaction may restore innate immune signaling in HPV(+) environments and assist in stimulating an adaptive immune response. This work was supported by the American Cancer Society Postdoctoral Fellowship (PF-22-041-01-ET); Moffitt Center of Immunization and Infectious Cancer Research internal grant; and Aids Malignancy Consortium Scholar Award.