Cell-cell interactions and subcellular protein dynamics during retrovirus cell-to-cell transmission

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Retroviruses can spread between cells through contact-dependent pathways. Cells transfer retrovirus particles to neighboring uninfected cells across sites of tight cell-cell contact. The concepts of cell-to-cell transmission are based on in vitro studies, in which donor cells establish long-lived contacts with uninfected cells for virus transfer. Cell-to-cell transmission in tissue culture can thereby overcome host restriction factors and broadly neutralizing antibodies, suggesting a role in retroviral pathogenesis. Recent studies, including our own work, confirm the contribution of cell contact-dependent pathways to retrovirus spread in vivo. Intravital imaging enabled us to visualize infected cells and retrovirus particles within lymphoid tissues of living animals and confirmed particle transfer between cells across long-lived cell contacts. The aim of this research proposal is to extend our knowledge about the mechanism of contact-dependent retroviral spread. We will use the model retrovirus murine leukemia virus (MLV) to study virus transmission between relevant primary leukocytes in vitro and in vivo. The subcellular dynamics of cellular and retroviral proteins will be analyzed at different steps during cell-to-cell transmission. Advanced real time imaging of single cell pairs will provide unknown details about cell-cell interactions during retrovirus spread. The information of cellular dynamics combined with single cell gene expression analysis will reveal the molecular mechanism of retrovirus cell-to-cell transmission. Key results of MLV spread will be confirmed under physiologic conditions in vivo using a mouse model. The novel insights are expected to contribute to the development of new strategies to interfere with the dissemination of retroviral infections in vivo.