Thibault Lagache (Université Paris Diderot, ENS et Institut de la Vision (UPMC))

Modeling the early steps of viral infection

vendredi 11 février 2011, 13h30 - 14h30

Salle de réunion, espace Turing

Viral infection is a multi-step process that begins at the surface of the host cell where most viruses are internalized inside an endosomal compartment. At one point during the vesicular transport the viral genome must successfully escape the endosome in the cell cytoplasm, to further reach and translocate into the nucleus, the place of replication. Due to the central role of this endosomal escape in the infection process, it is fundamental to understand its nature and dynamics. The escape process relies on the conformational change of viral proteins involved in membrane fusion, and to examine the escape dynamics, we provide a biophysical model in which we estimate the time for proteins to change conformation and reach their fusogenic state, leading to fusion and genome release. Our analysis agrees with the measured rate of the influenza virus hemagglutinin (HA) conformational change. We further evaluate the role of key parameters such as the acidification rate and the size of the endosome. By this our model provides new insights into the conformational change kinetics of influenza HA and into the first steps of its infectious cycle. Once the viral genome is released in the cell cytoplasm, its motion entirely relies on diffusion and active transport along micotubules to reach a small nuclear pore, before being degraded by the cellular defense machinery. In a the second part of the talk, I will present the method we developed to describe viral intermittent motion with a continuous Langevin equation, and the asymptotic results we further obtained for the probability and the mean first passage time (MFPT) of the viral genome to a nuclear pore.