Antiviral Activity of the Interferon-Induced Cellular Protein BST-2/Tetherin

Department of Medicine, University of California San Diego, California 92093-0679, USA.
AIDS research and human retroviruses (Impact Factor: 2.33). 11/2009; 25(12):1197-210. DOI: 10.1089/aid.2009.0253
Source: PubMed


Pathogenic microorganisms encode proteins that antagonize specific aspects of innate or adaptive immunity. Just as the study of the HIV-1 accessory protein Vif led to the identification of cellular cytidine deaminases as host defense proteins, the study of HIV-1 Vpu recently led to the discovery of the interferon-induced transmembrane protein BST-2 (CD317; tetherin) as a novel component of the innate defense against enveloped viruses. BST-2 is an unusually structured protein that restricts the release of fully formed progeny virions from infected cells, presumably by a direct retention mechanism that is independent of any viral protein target. Its spectrum of activity includes at least four virus families: retroviruses, filoviruses, arenaviruses, and herpesviruses. Viral antagonists of BST-2 include HIV-1 Vpu, HIV-2 and SIV Env, SIV Nef, the Ebola envelope glycoprotein, and the K5 protein of KSHV. The mechanisms of antagonism are diverse and currently include viral cooption of cellular endosomal trafficking and protein degradation pathways, including those mediated by ubiquitination. Orthologs of human BST-2 are present in mammals. Primate BST-2 proteins are differentially sensitive to antagonism by lentiviral Vpu and Nef proteins, suggesting that BST-2 has subjected lentiviruses to evolutionary pressure and presents barriers to cross-species transmission. BST-2 functions not only as an effector of the interferon-induced antiviral response but also as a negative feedback regulator of interferon production by plasmacytoid dendritic cells. Future work will focus on the role and regulation of BST-2 during the innate response to viral infection, on the mechanisms of restriction and of antagonism by viral gene products, and on the role of BST-2 in primate lentiviral evolution. The augmentation of BST-2 activity and the inhibition of virally encoded antagonists, in particular Vpu, represent new approaches to the prevention and treatment of HIV-1 infection.

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    • "NMR studies have shown that BST-2 and Vpu directly contact between their transmembrane domains [16]. Studies have revealed that mutation in the transmembrane of either BST-2 (L22, L23, G25, I26, V30, I33, I34, I36, L37, L41, and T45) or Vpu (A14, A18 and W22) renders BST-2 resistant to Vpu [16,23-25]. "
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    ABSTRACT: BST-2 (bone marrow stromal cell antigen 2) is an interferon-inducible protein that inhibits virus release by tethering viral particles to the cell surface. This antiviral activity of BST-2 is antagonized by HIV-1 accessory protein Vpu. Vpu physically interacts with BST-2 through their mutual transmembrane (TM) domains. In this study, we utilized the BRET assay and molecular dynamics (MD) simulation method to further characterize the interaction of BST-2 and Vpu. Amino acids I34, L37, P40 and L41 in the TM domain of BST-2, and L11, A18 and W22 in the TM domain of Vpu were identified to be critical for the interaction between BST-2 and Vpu. The residues P40 in the TM domain of BST-2 and L11 in the TM domain of Vpu were shown, for the first time, to be important for their interaction. Furthermore, triple-amino-acid substitutions, 14--16 (AII to VAA) and 26--28 (IIE to AAA) in Vpu TM, not the single-residue mutation, profoundly disrupted BST-2/Vpu interaction. The results of MD simulation revealed significant conformational changes of the BST-2/Vpu complex as a result of mutating P40 of BST-2 and L11, 14--16 (AII to VAA) and 26--28 (IIE to AAA) of Vpu. In addition, disrupting the interaction between BST-2 and Vpu rendered BST-2 resistant to Vpu antagonization. Through use of the BRET assay, we identified novel key residues P40 in the TM domain of BST-2 and L11 in the TM domain of Vpu that are important for their interaction. These results add new insights into the molecular mechanism behind BST-2 antagonization by HIV-1 Vpu.
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    • "The comparison of 365 LTNP with 1,394 HIV-negative controls on 8,584 low-frequency SNPs revealed two independent associations: the HCP5 rs2395029 signal (P = 8.54 × 10−15), and the RICH2 rs2072255 SNP (P = 3.30 × 10−6). RICH2 is a factor contributing to the externalization of BST-2/Tetherin (Rollason et al., 2009), which prevents HIV-1 virion budding and release (Tokarev et al., 2009). The RICH2 rs2072255 SNP is in full LD with a coding polymorphism predicted to impact splicing, which could thus alter RICH2 expression and its subsequent effect on HIV production. "
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    • "BST-2 is an interferon (IFN)-responsive host restriction factor expressed in various cell types6. Type I IFNs, IFN-α and IFN-β, play a key role in host antiviral defenses by upregulating expression of antiviral genes, like BST-2, which inhibits dissemination of virus78. BST-2 physically ‘tethers' or retains budding virions at the cell surface, restricting virus release and ongoing infection8. "
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