Mucosotropic human papillomaviruses (HPVs) are sexually transmitted agents and more than 80% of the population will experience an HPV infection during their life time. Despite the availability of excellent prophylactic vaccines, the disease burden caused by these viruses has not markedly decreased. No HPV specific antiviral compounds are on the market and the clinical management of HPV-associated lesions remains based on painful, invasive, ablative procedures. The HPV E6 and E7 genes are the main drivers of disease. E7 plays a key role in enabling the viral life cycle in terminally differentiated, post-mitotic epithelial cells by subverting major cellular pathways that signal growth arrest during differentiation. As a consequence, the failure to enact a growth arrest during differentiation causes activation of TP53, a transcription factor that induces expression of coding and non-coding genes that enact a cytotoxic response. In HPV infected cells, this cell-abortive TP53 response to E7 expression is muted by the co-expressed HPV E6 protein which targets TP53 for degradation. Inactivation of E6 reactivates the dormant TP53 response and triggers death of HPV infected cells. Because there are no methods available to directly inhibit E6, we propose to investigate whether TP53 mediated cell death is reactivated by modulating expression of molecules that cause TP53 activation and/or mediate the cytotoxic TP53 response. We have determined that two poorly studied long non- coding (lnc)RNAs, DINO and TRINGS, play important roles in mediating TP53 activation by E7 and modulate the cell death response to TP53 activation. Our proposal is based on the hypothesis that the dormant TP53 dependent cytotoxic response generated by E7 expression may be reactivated in HPV-infected cells by modulation of DINO and/or TRINGS. The work that we propose here will focus on determining the mechanism by which DINO (aim 1) and TRINGS (aim 2) modulate the TP53 mediated cell death response to metabolic stress and other stimuli.
Despite the availability of prophylactic vaccines, human papillomavirus (HPV) infections will continue to cause a significant burden of human disease and HPV-specific antiviral strategies are still lacking. Expression of the HPV E7 gene causes cellular stress which triggers a cytotoxic response that is muted by a second HPV protein, E6. This proposal is to test the hypothesis that the cytotoxic response to HPV E7 expression is mediated by two long noncoding RNAs and that modulating these molecules in HPV-infected cells may enable an antiviral strategy based on the reactivation of the dormant cytotoxic response.
