Direct Restriction of Virus Release and Incorporation of the Interferon-Induced Protein BST-2 into HIV-1 Particles

Abstract

Investigation of the Vpu protein of HIV-1 recently uncovered a novel aspect of the mammalian innate response to enveloped viruses: retention of progeny virions on the surface of infected cells by the interferon-induced, transmembrane and GPI-anchored protein BST-2 (CD317; tetherin). BST-2 inhibits diverse families of enveloped viruses, but how it restricts viral release is unclear. Here, immuno-electron microscopic data indicate that BST-2 is positioned to directly retain nascent HIV virions on the plasma membrane of infected cells and is incorporated into virions. Virion-incorporation was confirmed by capture of infectivity using antibody to the ectodomain of BST-2. Consistent with a direct tethering mechanism, we confirmed that proteolysis releases restricted virions and further show that this removed the ectodomain of BST-2 from the cell surface. Unexpectedly, enzymatic cleavage of GPI anchors did not release restricted virions, weighing against models in which individual BST-2 molecules span the virion and host cell membranes. Although the exact molecular topology of restriction remains unsolved, we suggest that the incorporation of BST-2 into viral envelopes underlies its broad restrictive activity, whereas its relative exclusion from virions and sites of viral assembly by proteins such as HIV-1 Vpu may provide viral antagonism of restriction.

The Tetherin/BST-2 Coiled-Coil Ectodomain Mediates Plasma Membrane Microdomain Localization and Restriction of Particle Release

“…cellular microvilli (Fig. 6A, WT), as has been previously described (7,9). In contrast, 4S tetherin staining at the plasma membrane revealed a diffuse pattern, in agreement with our immunofluorescence results (Fig.…”

C-terminal Hydrophobic Region in Human Bone Marrow Stromal Cell Antigen 2 (BST-2)/Tetherin Protein Functions as Second Transmembrane Motif

“…This would explain why C-terminal truncations in BST-2 result in loss of function but have only partial effects on the raft association of BST-2. Our data confirm a recent study that failed to observe enhanced virus release following PI-PLC treatment of cells (18). It cannot be ruled out of course that PI-PLC fails to cleave BST-2 when it is associated with tethered virions due to conformation constraints or steric hindrance.…”

Tetherin antagonism by Vpu protects HIV-infected cells from antibody-dependent cell-mediated cytotoxicity

“…BST-2 | CD317 | AIDS | lentivirus U nder conditions of IFN induction, tetherin is rapidly upregulated on the surface of infected cells and prevents virus release by physically bridging nascent virions to the cell membrane (1)(2)(3). This activity can be explained by the unusual topology of tetherin, which includes an N-terminal transmembrane domain and a C-terminal glycosyl-phosphatidylinositol tail that allow both ends of the molecule to be anchored in lipid membranes (4).…”