== Knockdown of human BST-2 expression enhances infectious LASV release, but not ZEBOV or MARV spread. arenaviral (LASV and MACV) VLP release upon BST-2 overexpression. Furthermore, we did not observe colocalization of filoviral glycoproteins with BST-2 during infection with authentic viruses. None of the arenavirus-encoded proteins rescued budding of VLPs in the presence of BST-2. Our results demonstrate that BST-2 might be a broad antiviral factor with the ability to restrict release of a wide variety of human pathogens. However, at least filoviruses, RVFV, and CPXV are immune to its inhibitory effect. The host innate immune response acts as a first SSR 69071 line of defense against viral infections, preventing virus invasion or replication before more specific protection is generated by the adaptive immune system (23). Viral infection or recognition of viral nucleic acids initiates signaling pathways that lead to the synthesis of multiple cytokines, including type I interferons (IFNs), such as IFN- and IFN-, which evoke coordinated antiviral responses in the host. Viruses have evolved multiple strategies to counter the IFN system by suppressing IFN production, signaling, or IFN antiviral effector proteins, thereby facilitating infection (23). Bone marrow stromal antigen 2 (BST-2; also called CD317, HM1.24, or tetherin) is a glycosylphosphatidylinositol-anchored type II transmembrane protein that is upregulated on most cell types upon stimulation with type I IFNs or IFN- (8,24,33). BST-2 shuttles between the plasma membrane, where it is present predominantly in lipid rafts, and thetrans-Golgi network, via a clathrin-mediated pathway (33,55). Several groups have described the antiviral role of BST-2 as an inhibitor of retrovirus release (28,49,63), and demonstrated that human immunodeficiency virus type 1 (HIV-1) Vpu can antagonize this function. Specifically, cell lines that endogenously expressed SSR 69071 BST-2 or were stimulated with IFN- exhibited markedly decreased budding SSR 69071 of retroviral virus-like particles (VLPs) or Vpu-defective HIV-1 compared to BST-2-negative cells. Virions produced in BST-2-expressing cells were retained on the cell surface and subsequently internalized into BST-2-positive endosomal compartments. This restriction could be overcome by HIV-1 Vpu, which downregulates BST-2 from the cell surface via -TrCP and endolysosomal trafficking (16,45). Lake Victoria marburgvirus (MARV), Zaire ebolavirus (ZEBOV), Lassa virus (LASV), Machupo virus (MACV), and Nipah virus (NiV) are highly virulent NIAID Priority Pathogens. Marburgviruses and ebolaviruses, members of the familyFiloviridae, as well as Lassa and Machupo viruses, members of the familyArenaviridae, cause severe hemorrhagic fevers in humans and nonhuman primates with extraordinarily high case-fatality rates (22,31). NiV, an emerging zoonotic paramyxovirus (15), was implicated as the cause of a rapidly fatal, febrile human encephalitis. Currently, U.S. Food and Drug Administration-approved vaccines or antivirals are not available for preventing or treating the diseases caused by any of these agents (9,43). ZEBOV, MARV, LASV, MACV, and NiV are enveloped RNA viruses that egress from their host cells by membrane protrusion (budding). Expression of the matrix proteins of these pathogensVP40 (ZEBOV and MARV) (6,25,60), Z (LASV and MACV) (59), or M (NiV) (52,53)mimics this process and results in formation of VLPs that are released from the cell surface in FUBP1 a fashion similar to that of the HIV-1 matrix protein Gag (11,47). These VLPs structurally resemble infectious virions (6,19,52) and therefore represent a suitable tool for both molecular-biological studies of viral budding and the development of vaccines (20,38). Recent reports have suggested a broad antiviral activity of BST-2. In addition to retroviruses, BST-2 can also inhibit release of VLPs generated by expression of the matrix proteins of ZEBOV, MARV, or LASV (28,29,56). Furthermore, the ZEBOV glycoprotein, GP1,2, was found to antagonize the antiviral activity of BST-2 in the context of VLPs, similarly to HIV-1 Vpu (29). We examined here the hypothesis that BST-2 might be a general inhibitor of enveloped virus release. Only egress of infectious arenaviruses was affected by elevated BST-2 levels. The filovirus-encoded glycoprotein.
