HIV-1 employs its structural proteins to orchestrate assembly and budding at the plasma membrane of host cells, which depends on numerous cellular factors. Although cells evolved interferon inducible restriction factors such as tetherin that act as a first line of defense, enveloped viruses, including HIV-1, developed countermeasures in the form of tetherin antagonists such as Vpu that decrease the effect of tetherin and permits normal viral replication in vivo. Here we review recent advances in the understanding of the dynamic structural properties of tetherin that provide the basis to physically retain HIV-1 by bridging plasma and virion membranes after completion of budding.
"This viral release restriction factor contains a cytoplasmic N-terminal region, a transmembrane region, a coiled-coil ectodomain and a C-terminal glycosylphosphatidylinositol (GPI) anchor. Among the known proteins, this double-anchored topology is relatively unique and important for its antiviral restriction activity
. Tetherin incorporates one of its two membrane anchors into viral membranes, and thereby traps enveloped viral particles on the surface of infected cells, leading to their internalization and degradation. "
[Show abstract][Hide abstract] ABSTRACT: Background
Tetherin is an interferon-inducible host cell factor that blocks the viral particle release of the enveloped viruses. Most knowledge regarding the interaction between tetherin and viruses has been obtained using the primate lentiviral system. However, much less is known about the functional roles of tetherin on other lentiviruses. Equine infectious anemia virus (EIAV) is an important macrophage-tropic lentivirus that has been widely used as a practical model for investigating the evolution of the host-virus relationship. The host range of EIAV is reported to include all members of the Equidae family. However, EIAV has different clinical responses in horse and donkey. It’s intriguing to investigate the similarities and differences between the tetherin orthologues encoded by horse and donkey.
We report here that there are two equine tetherin orthologues. Compared to horse tetherin, there are three valine amino acid deletions within the transmembrane domain and three distinct mutations within the ectodomain of donkey tetherin. However, the antiviral activity of donkey tetherin was not affected by amino acid deletion or substitution. In addition, both tetherin orthologues encoded by horse and donkey are similarly sensitive to EIAV Env protein, and equally activate NF-κB signaling.
Our data suggest that both tetherin orthologues encoded by horse and donkey showed similar antiviral activities and abilities to induce NF-κB signaling. In addition, the phenomenon about the differential responses of horses and donkeys to infection with EIAV was not related with the differences in the structure of the corresponding tetherin orthologues.
"Structurally , tetherin is composed of a short cytoplasmic N-terminal domain and an extracellular 170Å a-helical domain that is flanked by the two membrane anchors. Disulfide bonds between extracellular cysteines stabilize tetherin dimers in a parallel coiled-coil conformation, but the N-terminal portion of the coiled coil appears quite flexible (Weissenhorn et al., 2012). Tetherin is mainly located in the trans-Golgi network (TGN) and at the cell surface and appears to continuously shuttle between these locations. "
[Show abstract][Hide abstract] ABSTRACT: Viral infections are often detrimental to host survival and reproduction. Consequently, hosts have evolved a variety of mechanisms to defend themselves against viruses. A component of this arsenal is a set of proteins, termed restriction factors, which exhibit direct antiviral activity. Among these are several classes of proteins (APOBEC3, TRIM5, Tetherin, and SAMHD1) that inhibit the replication of human and simian immunodeficiency viruses. Here, we outline the features, mechanisms, and evolution of these defense mechanisms. We also speculate on how restriction factors arose, how they might interact with the conventional innate and adaptive immune systems, and how an understanding of these intrinsic cellular defenses might be usefully exploited.
[Show abstract][Hide abstract] ABSTRACT: Tetherin (BST2/CD317) has emerged as a key host cell defense molecule, inhibiting the release and spread of diverse enveloped virions from infected cells. In this chapter, I review the molecular and cellular basis for tetherin's antiviral activities and the function of virally encoded countermeasures that disrupt its function. I further describe recent advances in our understanding of tetherin's associated role in viral pattern recognition and the evidence for its role in limiting viral pathogenesis in vivo.
Current topics in microbiology and immunology 05/2013; 371:67-104. DOI:10.1007/978-3-642-37765-5_3 · 4.10 Impact Factor
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