NSF-ANR MCB/PHY: Viral/Nuclear Mechanodynamics Trigger Viral Fate

Viruses have preferences for the cell types that they can infect. In addition, some viruses can hide within the host genome, a process called viral integration. Viruses also have preferences for what types of cells that they can integrate into. This project will investigate the concept that the mechanical properties of a cell, and/or the mechanical environment in which a cell resides, can play a major role in whether Human Immunodeficiency Virus (HIV) can successfully be infectious and can integrate into the host cell genome. The outcomes of the project include improved understanding of how HIV infection affects host cell biology and further development of a theoretical model that describes attributes of the cell nucleus. The research could also inform new approaches to improve therapies that prevent or treat HIV infection. Through participation in this project, scientists in training will also gain expertise in a number of interdisciplinary techniques that will help enable their long-term career goals. The project has two major overarching goals. First, it will address how viral infection impacts the mechanical and morphological attributes of the nucleus, specifically in response to HIV infection. Second, it will interrogate how the mechanical environment of the cell impacts the success of HIV at executing key steps in its infection cycle. A key focus will be testing the hypothesis that the mechanical environment of the cell impacts the attributes of nuclear pore complexes embedded in the nuclear envelope that, in turn, influence the ability of HIV to successfully access the nucleoplasm. In addition, following up on the discovery of viral nuclear condensates (HIV-MLOs) that form in the nucleoplasm, the project will investigate how shear and/or compressive forces dictate the release of the newly synthesized viral DNA genome from HIV-MLOs. Last, the project will leverage the observations of the crosstalk between viral infection and attributes of nuclear force response to further develop a theoretical tensegrity model for emergent nuclear mechanics. This collaborative US/France project is supported by the US National Science Foundation and the French Agence Nationale de la Recherche, where NSF funds the US investigators and ANR funds the partners in France. The US investigators are jointly funded by the Genetic Mechanisms program/Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and by the Physics of Living Systems program in the Directorate for Mathematical and Physical Sciences. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.