VirMechaFate

Since the beginning of life on Earth, viruses have been at the origin of numerous pandemics that have threatened the lives of thousands of people. Many studies explored the biochemical and molecular interactions between viral and host factors in a cell-free context. However, the physical microenvironment created during viral infection and its impact on the virus-host relationship has not yet been deeply investigated. As an example of this concept, viruses that replicate in the host nucleus can apply forces on the cell nucleus that remodel the chromatin landscape, thereby impacting both functional (e.g. gene expression and genome integrity) and physical (e.g. mechanical stiffness) properties of the nucleus. We hypothesize that altered nuclear mechanobiology could transiently create a favorable environment for viral infection and could also impact the establishment of viral reservoirs, which represent ill-defined microenvironments. Our proposal aims to address the following questions that employ the Human Immunodeficiency Virus (HIV) as a model: a) how viral infection impacts the mechanical and morphological attributes of the nuclear periphery, and how engineering such changes modulates the post-nuclear entry steps of viral infection; b) how viruses specifically hijack some nuclear pore complexes and whether this determines the position of viral nuclear condensates (HIV-MLOs); c) how shear and/or compressive forces dictate the release of the newly synthesized viral DNA genome from HIV-MLOs; d) how mechanical tension impacts the final viral integration step. The Di Nunzio and King groups aim to combine their knowledge and cutting-edge approaches linked to real-time imaging and biophysical tools to discover how a model pandemic virus invades host cells in their native mechanical environment, focusing on the mechanodynamics of the early steps of the viral life cycle that establish viral reservoirs.