Role of Viral Envelope Proteins in Determining Susceptibility of Viruses to IFITM Proteins

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  Figure 1. Schematic representation of proposed models of IFITM proteins’ structure. The overall structure contains two membrane domains (M1 and M2) linked by a conserved intracellular loop (CIL) and flanked by a N-terminal domain (NTD) and a C-terminal domain (CTD). In the first model (left), there are two transmembrane domains, and the NTD and CTD are exposed extracellularly. In the second model (middle), both the NTD and CTD are exposed intracellularly, and the M1 and M2 domains do not span the membrane. The third model, which is currently the most accepted, proposes an intracellular NTD and an extracellular CTD, with the M1 not spanning the membrane, but the M2 being transmembrane.

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  Figure 2. Proposed mechanisms of envelope protein-driven viral resistance to IFITM proteins. The first mechanism of resistance to IFITMs is associated with the loss of interaction between IFITMs and viral envelope proteins. This phenomenon can occur in virion-producing cells (Panel A, illustrated with HIV as an example) and in virus target cells (Panel B, illustrated with IAV as an example). The second resistance mechanism involves reducing the exposure of viruses to IFITMs through modification of their entry pathway. This second mechanism occurs in target cells (Panel B, illustrated with examples of IAV and SARS-CoV-2) (A) Representation of the pathway of HIV-1 Env glycoprotein from its synthesis in the endoplasmic reticulum, processing and maturation in the Golgi complex, to its incorporation into viral particles at the plasma membrane. In this pathway, IFITM3 (in red) interacts with the Env of HIV-1 sensitive strains (in blue), resulting in a defect in processing and incorporation into virions or conformational modifications (in yellow) that render the viruses less infectious and more sensitive to neutralizing antibodies. In contrast, the Env of resistant strains (in red) escapes IFITM3…