A Genetic Barcode Approach to Elucidate the Mechanisms of Polyomavirus Persistent Infection in vivo

Human polyomaviruses are highly prevalent in the general population and establish a long-term asymptomatic infection in healthy individuals. However, a change in the immune status or hormone levels can lead to life-threatening diseases, including tumors. These diseases typically require reactivation from a persistent infection. Currently, a long-standing question in the field of virology is understanding how polyomaviruses undergo a life-long persistent infection in their natural host. Indeed, despite the high seroprevalence of polyomaviruses, little is understood about the mechanisms allowing the establishment, maintenance or reactivation from a long-term persistent infection. The objective of my PhD thesis was to demonstrate whether polyomaviruses undergo a “smoldering” infection, as commonly suggested in literature, or a cryptic true latency, akin to Herpesviruses. In order to solve this enigma, I engineered an innovative genetic barcoded murine polyomavirus to tract single genomes in vivo and to define the early and late genes expression patterns associated to each genome involved in the persistent infection. This barcoded virus approach combined with a non-invasive urine-monitoring system that allows the longitudinal study of PyV persistence, will consent to elucidate for the first time the mode of polyomavirus persistence in vivo using a limited number of mice. Deciphering the mechanisms of persistence may lead to new therapies and preventive strategies against serious Human diseases.