Regulation of host fusion inhibitory proteins at the virological synapse and upon syncytia formation
Conference Year
January 2020
Abstract
Cell-to-cell transmission at the HIV-1 virological synapse (VS) is an efficient mode of spread. While the VS typically resolves with cell separation, it can result in cell-cell fusion, forming a multinucleated infected cell (syncytium). Fusion is largely prevented at the VS by the viral protein Gag and host proteins ezrin, tetraspanins, and EWI-2. We are now determining how these host proteins work together and are temporally regulated to prevent excessive HIV-1-induced syncytia formation using targeted manipulations of each protein and kinetic analysis of their recruitment to the HIV-1 VS.
Further, CD81 and EWI-2 are downregulated from the surface of mononucleated infected cells but partially restored on syncytia. We show that the increased level of surface protein is the result of an influx of protein from the (previously) uninfected cell that fused with an infected cell to form a syncytium. We predict that increased levels of fusion inhibitory proteins in syncytia makes them less fusogenic than mononucleated infected cells, possibly explaining why syncytia do not fuse indefinitely. We plan to determine whether syncytia maintain this altered surface profile or if these proteins are downregulated over time. Together, these studies will increase our understanding of how host proteins regulate HIV-1-induced cell-cell fusion.
Primary Faculty Mentor Name
Markus Thali
Faculty/Staff Collaborators
Menelaos Symeonides, PhD and Danielle Allen
Status
Graduate
Student College
Larner College of Medicine
Program/Major
Cellular, Molecular and Biomedical Sciences
Primary Research Category
Biological Sciences
Regulation of host fusion inhibitory proteins at the virological synapse and upon syncytia formation
Cell-to-cell transmission at the HIV-1 virological synapse (VS) is an efficient mode of spread. While the VS typically resolves with cell separation, it can result in cell-cell fusion, forming a multinucleated infected cell (syncytium). Fusion is largely prevented at the VS by the viral protein Gag and host proteins ezrin, tetraspanins, and EWI-2. We are now determining how these host proteins work together and are temporally regulated to prevent excessive HIV-1-induced syncytia formation using targeted manipulations of each protein and kinetic analysis of their recruitment to the HIV-1 VS.
Further, CD81 and EWI-2 are downregulated from the surface of mononucleated infected cells but partially restored on syncytia. We show that the increased level of surface protein is the result of an influx of protein from the (previously) uninfected cell that fused with an infected cell to form a syncytium. We predict that increased levels of fusion inhibitory proteins in syncytia makes them less fusogenic than mononucleated infected cells, possibly explaining why syncytia do not fuse indefinitely. We plan to determine whether syncytia maintain this altered surface profile or if these proteins are downregulated over time. Together, these studies will increase our understanding of how host proteins regulate HIV-1-induced cell-cell fusion.