The great escape: viral strategies to counter BST-2/tetherin

Abstract

The interferon-induced BST-2 protein has the unique ability to restrict the egress of HIV-1, Kaposi's sarcoma-associated herpesvirus (KSHV), Ebola virus, and other enveloped viruses. The observation that virions remain attached to the surface of BST-2-expressing cells led to the renaming of BST-2 as "tetherin". However, viral proteins such as HIV-1 Vpu, simian immunodeficiency virus Nef, and KSHV K5 counteract BST-2, thereby allowing mature virions to readily escape from infected cells. Since the anti-viral function of BST-2 was discovered, there has been an explosion of research into several aspects of this intriguing interplay between host and virus. This review focuses on recent work addressing the molecular mechanisms involved in BST-2 restriction of viral egress and the species-specific countermeasures employed by various viruses.

Figure 1. Host and viral factors involved in virion release.

Schematics of human BST-2 (A), HIV-1 Vpu (B), and SIVmac239 Nef (C) proteins with salient features indicated. The coiled-coil domain of BST-2 was predicted using PCOILS (http://toolkit.tuebingen.mpg.de/pcoils) .

Figure 2. Potential mechanistic models of BST-2 tethering and viral antagonists against BST-2.

(A) BST-2 acting as a virion tether in the absence of any antagonist; (B) efficient virus release when BST-2 function is inhibited by a generic viral antagonist; (C) Vpu-mediated βTrCP-dependent degradation of BST-2 via the endosome/lysosome pathway; (D) Vpu-mediated βTrCP-dependent degradation of BST-2 via the ubiquitin/proteasome pathway; (E) HIV-2/SIV_AGM Env- or Vpu-mediated BST-2 sequestration; (F) SIV Nef-mediated BST-2 downregulation. Ub(n), mono- or poly-ubiquitin.

Figure 3. Compilation of BST-2 TM mutants evaluated for sensitivity to Vpu antagonism.

The schematic at the top represents human BST-2 with the sequence of the TM domain. Also shown are the five amino acids present in rhesus, but absent from human BST-2, that confer sensitivity to SIV Nef. Residues in purple have been shown to be under positive selection . Three laboratories have generated substitution mutants in human BST-2 that replace the human residue for the corresponding rhesus or AGM residue. Mutants made by each group are color-coded; Rong et al. in blue , Gupta et al. in red , and McNatt et al. in green . All three groups evaluated their mutants in similar infectious virus-release assays that compared the egress of wild-type HIV-1 to that of ΔVpu HIV-1. Mutants shown in boxes were identified in their respective publications as having a significant impact on sensitivity to Vpu with little to no effect on BST-2 tethering function.