Ebola Virus Glycoprotein Counteracts BST-2/Tetherin Restriction in a Sequence-Independent Manner That Does Not Require Tetherin Surface Removal

Abstract

BST-2/tetherin is an interferon-inducible protein that restricts the release of enveloped viruses from the surface of infected cells by physically linking viral and cellular membranes. It is present at both the cell surface and in a perinuclear region, and viral anti-tetherin factors including HIV-1 Vpu and HIV-2 Env have been shown to decrease the cell surface population. To map the domains of human tetherin necessary for both virus restriction and sensitivity to viral anti-tetherin factors, we constructed a series of tetherin derivatives and assayed their activity. We found that the cytoplasmic tail (CT) and transmembrane (TM) domains of tetherin alone produced its characteristic cellular distribution, while the ectodomain of the protein, which includes a glycosylphosphatidylinositol (GPI) anchor, was sufficient to restrict virus release when presented by the CT/TM regions of a different type II membrane protein. To counteract tetherin restriction and remove it from the cell surface, HIV-1 Vpu required the specific sequence present in the TM domain of human tetherin. In contrast, the HIV-2 Env required only the ectodomain of the protein and was sensitive to a point mutation in this region. Strikingly, the anti-tetherin factor, Ebola virus GP, was able to overcome restriction conferred by both tetherin and a series of functional tetherin derivatives, including a wholly artificial tetherin molecule. Moreover, GP overcame restriction without significantly removing tetherin from the cell surface. These findings suggest that Ebola virus GP uses a novel mechanism to circumvent tetherin restriction.

Post-exposure treatments for Ebola and Marburg virus infections

“…Through an incompletely understood mechanism, filovirus GP is able to circumvent the binding ability of tetherin and hence allow for productive budding of infectious particles 113,114 .…”

The role of BST‐2/Tetherin in host protection and disease manifestation

“…Ebola GP antagonizes BST‐2 tethering function without removing BST‐2 from lipid rafts 31. In the presence of Ebo GP surface BST‐2 protein is greatly reduced 32 without affecting total protein levels, suggesting that GP may downregulate BST‐2 from the cell surface.…”

The Restriction Factors of Human Immunodeficiency Virus

“…Tetherin antagonism by Env depends on physical interaction between Env and tetherin and on a conserved tyrosine-based endocytosis motif (YXX) in the cytoplasmic tail of the Env transmembrane protein gp41 (59,60,63). The residues that contribute to Env-tetherin interactions are not well defined but appear to be located in the extracellular domains of both proteins based on analyses of recombinant forms of Env and tetherin (60,64) and on the identification of defined amino acid changes in the ectodomains of gp41 and tetherin that disrupt anti-tetherin activity (64 -66). Interaction with Env does not result in the degradation of tetherin but instead leads to internalization and sequestration of tetherin away from sites of virus release at the plasma membrane by a clathrin-dependent pathway (57,60,63).…”