Bone marrow stromal cell antigen 2 (BST-2) restricts mouse mammary tumor virus (MMTV) replication in vivo

Abstract

BackgroundBone marrow stromal cell antigen 2 (BST-2) is a cellular factor that restricts the egress of viruses such as human immunodeficiency virus (HIV-1) from the surface of infected cells, preventing infection of new cells. BST-2 is variably expressed in most cell types, and its expression is enhanced by cytokines such as type I interferon alpha (IFN-α). In this present study, we used the beta-retrovirus, mouse mammary tumor virus (MMTV) as a model to examine the role of mouse BST-2 in host infection in vivo.ResultsBy using RNA interference, we show that loss of BST-2 enhances MMTV replication in cultured mammary tumor cells and in vivo. In cultured cells, BST-2 inhibits virus accumulation in the culture medium, and co-localizes at the cell surface with virus structural proteins. Furthermore, both scanning electron micrograph (SEM) and transmission electron micrograph (TEM) show that MMTV accumulates on the surface of IFNα-stimulated cells.ConclusionsOur data provide evidence that BST-2 restricts MMTV release from naturally infected cells and that BST-2 is an antiviral factor in vivo.

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

“…For example, BST‐2 expression restricts MMTV release and inhibits MMTV replication 4. However, chronic MMTV infection down‐regulates BST‐2 in hematopoietic cells but upregulates BST‐2 in mammary gland and tumor tissues 153.…”

“…Moreover, BST‐2 deficiency impairs CHIKV‐induced inflammatory response that manifests as reduced levels of IFN‐α, IFN‐γ, and CD40 ligand 45. Aside from its role in alphavirus replication, BST‐2 inhibits replication of retroviruses including MMTV and MLV in mice 3, 4, 58. Inhibition of retrovirus replication is thought to be partly the result of endocytosed BST‐2‐mediated induction of IFNγ production and degranulation of effector cells (NK and CD8+ T cells) 58.…”

“…In various cells, BST‐2 is induced by type I IFN (IFNα and IFNβ), type II IFN (IFNγ), and type III IFN (IFNλ) 38, 145. Induction of BST‐2 by IFNs occur in a broad range of cell lines, primary cells, and in vivo 4, 8, 28, 38, 45. The effect of IFNs is cell type dependent.…”

The Size and Conservation of a Coiled-coil Structure in the Ectodomain of Human BST-2/Tetherin Is Dispensable for Inhibition of HIV-1 Virion Release

“…Structural studies suggest that the BST-2 ectodomain assumes a rod-like structure of about 16 -17 nm (25-28), which constitutes the maximum distance between membranes that can be bridged by BST-2. Indeed, immune electron microscopy identified BST-2 on virions tethered to the cell surface and on particles tethered to each other (30,(35)(36)(37)(38). Curiously, the distance between these structures frequently exceeded the 17-nm limit imposed by the BST-2 ectodomain, a phenomenon that has remained unexplained.…”

Equine Tetherin Blocks Retrovirus Release and Its Activity Is Antagonized by Equine Infectious Anemia Virus Envelope Protein

“…Human tetherin (huTHN) was first identified as a cellular restriction factor that blocks human immunodeficiency virus type 1 (HIV-1) particle release from infected cells in the absence of the HIV-1 accessory protein Vpu (1). Later, it was found that human tetherin has very broad antiviral activities, which also target many other enveloped viruses, including retroviruses, filoviruses, arenaviruses, paramyxoviruses, herpesviruses, and rhabdoviruses (2)(3)(4)(5)(6)(7)(8)(9). Human tetherin orthologs have been isolated from several other species, including monkey, cat, pig, mouse, cattle, and sheep, which all show similar antiviral activities (10)(11)(12)(13)(14)(15)(16)(17).…”