Tetherin is a key effector of the antiretroviral activity of type I interferon in vitro and in vivo

Abstract

Tetherin (Bst-2 CD317) is a cell-surface protein whose expression is induced by IFNα. Although tetherin expression causes the retention of retrovirus particles on the surface of infected cells, it is not known whether tetherin inhibits retroviral replication or pathogenesis in vivo. Mutation of tetherin antagonists often has little effect on retroviral replication in vitro, and, although tetherin can reduce the yield of extracellular viral particles, some studies suggest that tetherin actually enhances direct cell-to-cell viral transmission. We generated tetherin-deficient mice to determine the effect of this protein on murine retrovirus replication and pathogenesis. We find that tetherin markedly inhibits the replication of Moloney murine leukemia virus (Mo-MLV) and is required for the antiretroviral activity of IFNα to be fully manifested in vitro. Surprisingly, Mo-MLV replication and disease progression was not significantly different in WT and tetherin-deficient mice, but this finding was explained by the fact that Mo-MLV infection did not induce detectable tetherin expression on candidate target cells in vivo. Indeed, IFNα induction was required to reveal the antiMo-MLV activity of tetherin in vivo. Moreover, LP-BM5, an MLV strain that has been demonstrated to induce immune activation and IFNα expression, achieved higher levels of viremia and induced exaggerated pathology in tetherin-deficient mice. These data indicate that tetherin is a bona fide antiviral protein and can reduce retroviral replication and disease in vivo.

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

“…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.…”

Role of retroviral restriction factors in the interferon-α–mediated suppression of HIV-1 in vivo

“…Similar to the neutralization of APO-BEC3 by HIV-1 Vif, BST-2 restriction is counteracted by an HIV-1 gene product, the 16-kDa viral protein U (Vpu). Vpu depletes BST-2 from the plasma membrane, allowing virions to detach from the cell and infect new targets (7). Consequently, the Vif-APO-BEC3 and Vpu-BST-2 axes are emerging as attractive targets for therapeutic intervention (14).…”

“…Recently, a number of innate immune factors have been identified in primates that suppress retroviral replication in vitro and therefore may constitute new avenues for therapeutic intervention (2)(3)(4). Three of these innate retroviral restriction factors-apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APO-BEC3) (5), bone marrow stromal cell antigen 2 (BST-2/tetherin/ CD317) (6,7), and TRIM5α (8, 9)-have garnered substantial attention, since they specifically inhibit HIV-1 replication in vitro, and their patterns of diversification across primate lineages are suggestive of historical coevolutionary conflicts with retroviral pathogens (10)(11)(12). However, unlike variants found in nonhuman primates such as the rhesus macaque, the human allelic variant of Trim5α confers little, if any, inhibitory activity against HIV-1 and may, in fact, underlie our unique susceptibility to HIV-1 infection (13).…”

“…In the absence of Vif expression, APOBEC3 is incorporated into virions, and the viral genome undergoes extensive G to A hypermutation in the coding strand, typically rendering it nonviable within a single replicative cycle (20). BST-2 is a type 2 integral membrane protein that inhibits retrovirus infection by restricting the release of fully formed progeny virions from infected cells (6,7). Similar to the neutralization of APO-BEC3 by HIV-1 Vif, BST-2 restriction is counteracted by an HIV-1 gene product, the 16-kDa viral protein U (Vpu).…”

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

“…Tetherin can inhibit retroviral replication in vivo as revealed by an IFN-dependent effect on the suppression of murine leukemia virus in WT, but not tetherin-deficient, mice (16). Instances of lentiviral adaptation to tetherin, including the acquisition of compensatory changes in gp41 of a nef-deleted strain of SIV passaged in rhesus macaques (17), and changes that restore the anti-tetherin activity of Nef in HIV-1-infected chimpanzees (18), further underscore the importance of tetherin antagonism for efficient virus replication in vivo.…”