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Modulation of viral gene expression and cellular immune responses by primate lentiviral proteins Vpu, Vpr and Nef

Background: Tetherin (or BST-2) is an antiviral host restriction factor that suppresses the release of HIV-1 and other enveloped viruses by tethering them to the cell surface. Recently, it has been demonstrated that tetherin also acts as an innate sensor of HIV-1 assembly that induces NF-κB-dependent proinflammatory responses. Furthermore, it has been reported that polymorphisms in the promoter and 3‘ untranslated region of the bst2 gene may affect the clinical outcome of HIV-1 infection. However, non-synonymous polymorphisms in the bst2 open reading frame have not yet been described or functionally characterized. Results: Mining of the Exome Variant Server database identified seven very rare naturally occurring missense variants of tetherin (Y8H, R19H, N49S, D103N, E117A, D129E and V146L) in human populations. Functional analyses showed that none of these sequence variants significantly affects the ability of tetherin to inhibit HIV-1 virion release or its sensitivity to antagonism by HIV-1 Vpu or SIVtan Env, although Y8H alters a potential YxY endocytic motif proposed to play a role in virion uptake. Thus, these variants do most likely not represent an evolutionary advantage in directly controlling HIV-1 replication or spread. Interestingly, however, the R19H variant selectively abrogated the signaling activity of tetherin. Conclusions: Restriction of HIV-1 virion release and immune sensing are two separable functions of human tetherin and the latter activity is severely impaired by a single amino acid variant (R19H) in the cytoplasmic part of tetherin. Background Tetherin (BST-2, CD317, HM1.24) is an interferoninduced host restriction factor that inhibits the release of HIV, Ebola, Lassa, Herpes and other enveloped viruses from infected cells by tethering nascent virions to the plasma membrane [1-5]. Tetherin is a dimeric type II transmembrane protein with a size of 30–36 kDa [6]. It contains a cytoplasmic N-terminal region, a transmembrane domain, a glycosylated coiled-coil extracellular domain, and a C-terminal glycosylphosphatidylinositol (GPI) anchor [6]. The unusual topology of this restriction factor with both a transmembrane domain and a GPI anchor allows it to directly tether budding virions to host cells with one membrane anchor sticking in the virion and the other one remaining in the cellular membrane [7]. The coiled-coil domain of tetherin seems to provide conformational flexibility to allow this anchoring process [8]. Most simian immunodeficiency viruses (SIVs), including the direct precursors of HIV-1 infecting chimpanzees and gorillas, use their accessory Nef protein to antagonize tetherin of their respective host species [9-11]. Human tetherin, however, contains a five amino acid deletion in its cytoplasmic domain that evolved in hominids after their divergence from chimpanzees [12] and confers resistance to Nef [9-11]. The pandemic major (M) group of HIV-1 managed to switch from Nef to Vpu to counteract the human tetherin orthologue [10]. In contrast, with a single documented exception [13], the rare HIV-1 group N, O, and P strains have apparently thus far failed to evolve effective antagonists during adaptation to humans * Correspondence: daniel.sauter@uni-ulm.de; frank.kirchhoff@uni-ulm.de Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany Full list of author information is available at the end of the article © 2013 Sauter et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Sauter et al. Retrovirology 2013, 10:85 http://www.retrovirology.com/content/10/1/85