Mechanisms of Virus Entry into Cells and Antiviral Barriers Limiting Entry

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

We published two articles pertaining to this project in 2020 (Ahi et al., mBio, 2020; Rahman et al., eLife 2020), two articles in 2022 (Rahman et al., Journal of Molecular Biology, 2022; Majdoul et al., Nature Reviews Immunology, 2022), and one preprint so far in 2023 (Shi et al., bioRxiv, 2023). 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 examine how cholesterol binding by IFITM3 directly contributes to its antiviral activities by incorporating in silico analyses using molecular dynamics simulations. We will also assess how lipid binding by IFITM3 affects its trafficking through the cell and protein half-life. In addition, our findings will allow us to better understand the cellular roles played by IFITM3 and related proteins, including its ability to act as a scaffold for receptor tyrosine receptor signaling at lipid rafts in 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.