In this project systems biology was used to develop temporal and spatiotemporal models to understand how high risk Human Papillomaviruses (HPV-16,) affect cell fate choices through 16E6 viral protein in order to affect tissue homeostasis, hence the balance between cell proliferation and differentiation.
This is an important problem for society because even though vaccines exist against HPVs, they are prophilactic vaccines and therefore the development of antiviral therapies is of pivotal importance. Understanding how HPVs affect cell fate choices in a phenomenological way under tissue biology approaches as well as a mechanistic perspective under a pathway understanding is of pivotal importance in order to properly understand viral perstistence and reservior. This will help to better understand under a rigorous approach the key regulators that has to be targeted and how to optimally target them in order to develop novel antiviral effective therapies.
The objectives were to understand the important question about how HPV affects tissue homeostasis through E6 both phenomenologically through the development of a cell state model describing cell states (proliferative, differentiation) in the infected epithelium. The objectives were also related to study how E6 could affect Notch pathway in order to mechanistically understand, through a pathway understanding, how cell fate choices in terms of cell proliferation and differentiation are controlled as well as explore antiviral therapies hypothesis through model simulations.
In conclusion, STEPV project reached its major goals, and it was possible to validate with biological experiments a stochastic mathematical model explaining the competitve advantage of HPV over wild type (healthy) cells in terms of cell fate choices (i.e. symmetric/asymmetric division, commitment to differentiation). The model was expanded into a 2D stochastic lattice grid model capable to reproduce in space and time the HPV competitve advantage in terms of the balance between cell proliferation and differentiation at a tissue level. The model was specialized with Notch/DLL1 pathway in order to understand how HPV E6 is altering such a pathway to make stronger hypothesis about HPV competitive advantage. The model was also used as a simulator to test different biological hypothesis also regarding antiviral therapies.
