Mechanisms of Virus Entry into Cells and Antiviral Barriers Limiting Entry

Division Of Basic Sciences - Nci

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Linked publications & trials

Abstract

We published two articles pertaining to this project in 2020 (Ahi et al., mBio, 2020; Rahman et al., eLife 2020) and one article in 2022 (Rahman et al., Journal of Molecular Biology, 2022). Our work provides extensive insight into the function of IFITM proteins as well as the extended CD225 protein family to which they belong and will provide leverage for the development of new antiviral therapies. Notably, we identified an amphipathic alpha helix that is required for the antiviral activity of IFITM3 against multiple viruses, including HIV-1, Zika virus, and Influenza A virus (Chesarino, Compton et al. EMBO Reports, 2017). Subsequently, we showed that the amphipathic helix is required for the ability of IFITM3 to alter the biophysical properties of cellular membranes (membrane rigidity and curvature) (Rahman et al., eLife, 2020). Most recently, we demonstrated that the amphipathic helix exhibits direct cholesterol binding activity, providing a possible explanation for its impacts on membranes and a plausible mechanism for how IFITM3 restricts membrane fusion pore formation (Rahman et al., Journal of Molecular Biology, 2022). We now plan to directly measure cholesterol binding by IFITM3 contributes to its effect on membrane rigidity, a feature that is functionally tied to its capacity to inhibit virus entry. Furthermore, we plan to assess the functional role played by the amphipathic helix in the oncogenic functions of IFITM3, including its ability to act as a scaffold for PI3K signaling at the plasma membrane. Our findings will provide insight into the poorly characterized tumorigenic roles played by this family of proteins and provide therapeutic targets for inactivation.