Presenter's Name(s)

Emily Elizabeth WhitakerFollow

Primary Faculty Mentor Name

Markus Thali

Status

Graduate

Student College

Larner College of Medicine

Program/Major

Cellular, Molecular and Biomedical Sciences

Second Program (optional)

Microbiology and Molecular Genetics

Primary Research Category

Biological Sciences

Secondary Research Category

Health Sciences

Presentation Title

Characterizing EWI-2 mediated fusion inhibition at the HIV Presynapse

Time

1:00 PM

Location

Silver Maple Ballroom - Health Sciences

Abstract

HIV can be as a cell free viral particle or through a virological synapse (VS), a highly efficient more of transmission. The VS is formed through cell-cell contact mediated by HIV envelope glycoprotein (Env) on the surface of an infected cell binding the viral receptor CD4 on the surface of an uninfected target cell. At first, it may seem likely that Env, because it is fusogenic at neutral pH, would likely facilitate frequent cell-cell fusion at the VS, thus resulting in the formation of multinucleated HIV infected cells (syncytia). However, while small, T cell-based syncytia are now recognized as a feature of early HIV infection, the majority of VSs ultimately resolve with complete cell separation. The VS is tightly regulated by both viral (Gag) and host proteins (ezrin, tetraspanins, and EWI-2). The viral structural protein, Gag, regulates fusion at the VS by binding and trapping Env in a non-fusogenic state. Cellular factors, including EWI-2 interacting partners, tetraspanins and ezrin, also contribute to efficient inhibition of syncytia formation at the HIV VS.

We have identified EWI-2, a known interacting partner of both tetraspanins and ezrin, as a member of the host fusion inhibitory complex partially responsible for efficiently preventing syncytia formation. Using microscopy and flow cytometry, we showed that EWI-2, while overall downregulated from the surface of HIV infected cells, co-accumulates with Gag at the producer cell side of the VS (i.e. the presynapse) to prevent cell-cell fusion. We now seek to determine the fusion inhibitory mechanism of EWI-2 by characterizing the domains required for EWI-2 mediated fusion inhibition, and whether tetraspanin-EWI-2 interactions are necessary for EWI-2 localization and fusion prevention at the HIV VS.

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Characterizing EWI-2 mediated fusion inhibition at the HIV Presynapse

HIV can be as a cell free viral particle or through a virological synapse (VS), a highly efficient more of transmission. The VS is formed through cell-cell contact mediated by HIV envelope glycoprotein (Env) on the surface of an infected cell binding the viral receptor CD4 on the surface of an uninfected target cell. At first, it may seem likely that Env, because it is fusogenic at neutral pH, would likely facilitate frequent cell-cell fusion at the VS, thus resulting in the formation of multinucleated HIV infected cells (syncytia). However, while small, T cell-based syncytia are now recognized as a feature of early HIV infection, the majority of VSs ultimately resolve with complete cell separation. The VS is tightly regulated by both viral (Gag) and host proteins (ezrin, tetraspanins, and EWI-2). The viral structural protein, Gag, regulates fusion at the VS by binding and trapping Env in a non-fusogenic state. Cellular factors, including EWI-2 interacting partners, tetraspanins and ezrin, also contribute to efficient inhibition of syncytia formation at the HIV VS.

We have identified EWI-2, a known interacting partner of both tetraspanins and ezrin, as a member of the host fusion inhibitory complex partially responsible for efficiently preventing syncytia formation. Using microscopy and flow cytometry, we showed that EWI-2, while overall downregulated from the surface of HIV infected cells, co-accumulates with Gag at the producer cell side of the VS (i.e. the presynapse) to prevent cell-cell fusion. We now seek to determine the fusion inhibitory mechanism of EWI-2 by characterizing the domains required for EWI-2 mediated fusion inhibition, and whether tetraspanin-EWI-2 interactions are necessary for EWI-2 localization and fusion prevention at the HIV VS.