A rare missense variant abrogates the signaling activity of tetherin/BST-2 without affecting its effect on virus release
© Sauter et al.; licensee BioMed Central Ltd. 2013
Received: 8 March 2013
Accepted: 6 August 2013
Published: 10 August 2013
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.
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.
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.
Tetherin (BST-2, CD317, HM1.24) is an interferon-induced 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 . It contains a cytoplasmic N-terminal region, a transmembrane domain, a glycosylated coiled-coil extracellular domain, and a C-terminal glycosylphosphatidylinositol (GPI) anchor . 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 . The coiled-coil domain of tetherin seems to provide conformational flexibility to allow this anchoring process .
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  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 . In contrast, with a single documented exception , the rare HIV-1 group N, O, and P strains have apparently thus far failed to evolve effective antagonists during adaptation to humans [10, 13–15]. Thus, efficient tetherin antagonism may have been a prerequisite for the efficient spread of the AIDS pandemic . A recent study suggests that the cytoplasmic deletion not only rendered human tetherin resistant to Nef but also enhanced its ability to act as an innate sensor of HIV-1 assembly that induces NF-κB-dependent proinflammatory responses .
Like other antiviral host restriction factors, such as TRIM5α (tripartite motif 5-α) proteins that induce untimely uncoating of the viral capsid and APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) that causes lethal hypermutation of the viral genome, bst2 shows evidence of positive selection [18, 19]. It has been reported that polymorphisms in the human trim5, APOBEC3G and bst2 genes are associated with the clinical course of HIV-1 infection supporting a relevant role of these restriction factors in vivo [20–25]. Previous investigations of the bst2 gene focused on variations in the promoter or 3’ untranslated region that may affect the expression levels of this restriction factor . Here, we characterized seven rare variants of the human bst2 gene that change the amino acid sequence of this restriction factor (Y8H, R19H, N49S, D103N, E117A, D129E and V146L). We demonstrate that one of these missense variants, R19H, disrupts the signaling activity of human tetherin without impairing its ability to restrict HIV-1 release.
Non-synonymous polymorphisms in the human bst2 gene
Non-synonymous polymorphisms in the tetherin open reading frame
Amino acid change
G = 4/A = 8596
G = 0/A = 4406
G = 4/A = 13002
T = 2/C = 8598
T = 0/C = 4406
T = 2/C = 13004
C = 6/T = 8594
C = 0/T = 4406
C = 6/T = 13000
T = 1/C = 8599
T = 0/C = 4406
T = 1/C = 13005
G = 0/T = 8600
G = 1/T = 4405
G = 1/T = 13005
C = 0/G = 8600
C = 2/G = 4404
C = 2/G = 13004
A = 3/C = 8597
A = 1/C = 4405
A = 4/C = 13002
Missense variants of human tetherin do not impair its ability to restrict virion release
Since Y8H alters a previously described non-canonical YxY endocytosis signal , we also analyzed whether this mutation may affect the internalization rate of tetherin. We found that the Y8H variant showed a markedly reduced internalization rate compared to the major form of human tetherin (Figure 2C). However, the disruptive effect of the Y8H change alone was less severe than the combined mutation of both tyrosine residues (Y6A, Y8A).
Missense variants do not confer resistance to HIV-1 M Vpu or SIVtan Env
The R19H variant disrupts the signaling activity of human tetherin
To determine tetherin-dependent NF-κB activation in case of heterozygosity we cotransfected expression vectors for wild-type and R19H tetherin in equal amounts. Activation of NF-κB was significantly higher in mixed wt/R19H samples compared to R19H tetherin alone and comparable to wild-type tetherin (Figure 6B). Thus, wild-type tetherin is acting in a dominant fashion and may rescue signaling in wt/R19H heterozygous individuals.
In this study, we functionally characterized seven very rare sequence variants of human tetherin. Our results show that none of them significantly reduces the ability of tetherin to restrict HIV release or its sensitivity to antagonism by HIV-1 Vpu or SIVtan Env. However, although these variants are very rare and do most likely not directly affect the control of HIV-1 replication or transmission, they led to two interesting observations. First, mutation of Y8H that affected a previously described YxY motif in the cytoplasmic tail of tetherin  did not impair its antiviral or signaling activity. Second, we found that substitution of R19H disrupts the signaling activity of human tetherin without reducing its capability to inhibit virus release. Thus, these two key functions of human tetherin are genetically separable.
Our finding that the Y8H substitution that shows a minor allele frequency of about 0.05% in Caucasians and seems to be absent in African Americans (Table 1) did not significantly affect the antiviral activity of human tetherin is in agreement with previous findings, showing that the presence of one of these two tyrosine residues and not the conservation of an YxY-based motif is critical for endocytosis of tetherin and its signaling activity [17, 27, 33]. Interestingly, however, the Y8H substitution reduced the internalization rate of tetherin albeit not as drastically as the double Y6A/Y8A mutation. Thus, our data confirm, that efficient endocytosis of tetherin is not required for the activation of NF-κB . Notably, however, the relevance of the two N-terminal tyrosine residues for the steady state surface levels and endocytosis of human tetherin is somewhat controversial. Rollason and coworkers reported that tetherin was efficiently internalized if Y6 or Y8 were mutated individually, whereas the double mutant Y6A/Y8A was not endocytosed . In our experiments, however, the Y8H change clearly reduced the internalization rate of tetherin (Figure 2C). Notably, Rollason et al. mutated the tyrosine residues to alanine and the introduction of the aromatic histidine residue may explain the discrepancy. Masuyama et al. performed similar analyses and described a slightly increased surface expression of the single mutants compared to wild-type tetherin but did not observe any change of the internalization rate . A third study reported that even the double-mutant Y6A/Y8A was robustly endocytosed indicating that the YxY motif is not required for the constitutive internalization of tetherin .
The disruptive effect of the R19H substitution (MAF of 0.015%) on the signaling activity of tetherin came as a surprise since the Neil group has previously demonstrated that amino acids 9 to 11 (CRV) are critical for this function . In the previous study alanine substitutions at positions 17 to 21 (DKRCK) impaired tetherin-mediated signaling but also reduced its steady state expression levels thus precluding meaningful functional analyses . Notably, Galão and coworkers introduced triple alanine scanning mutations in the cytoplasmic domain of tetherin. Thus, their data do not contradict our finding that the arginine at position 19 is critical for the ability of tetherin to mediate efficient immune signaling but not for its antiviral activity or steady-state surface expression levels. It is tempting to speculate that both, residues 9 to 11 (CRV) and R19 may be important for the signaling activity of human tetherin because they are flanking a putative TRAF6 binding motif. The consensus motif (PxExx[Ar/Ac]) is only present in human tetherin and the CRV9-11 and R19 residues are flanking this site (CRVPMEDGDKR). Structural analyses have shown that at least eight amino acid residues (xxPxExx[Ar/(Ac]) are involved in TRAF6 binding , which may explain why mutation of CRV/AAA disrupted this interaction . Interestingly, this putative TRAF6 binding motif emerged due to a hominid-specific deletion of the DDIWK motif in tetherin. This deletion is generally absent in tetherin orthologues of non-human primate species which induce little if any NF-κB activation . Potentially, this may explain why deletion of the DDIWK motif enhanced NF-κB activation by an ape tetherin orthologue and vice versa its reintroduction into human tetherin severely impaired this signaling activity . In contradiction to an important functional role of this putative TRAF6 interaction motif it has been reported that mutations in this region (P12-D17) do not disrupt tetherin-mediated signaling . Notably, a recent study by Tokarev and colleagues could not co-immunoprecipitate tetherin with TRAF6  and we were also unable to detect an interaction between tetherin and TRAF6 although we employed a variety of experimental systems including co-immunoprecipitations, reporter protein complementation assays and in vitro binding assays using purified proteins (data not shown). Thus, further studies on the functional impact of R19H, the humanoid-specific deletion, and the potential TRAF6 binding site in tetherin seem highly warranted.
The missense variants examined in the present study did not significantly affect the susceptibility of tetherin to antagonism by HIV-1 group M Vpu or SIVtan Env. It is noteworthy, however, that other viruses have also evolved antagonists of tetherin targeting the domains affected by these polymorphisms. For example, human Kaposi's sarcoma-associated herpesvirus (KSHV) encodes the RING-CH E3 ubiquitin ligase K5 that targets K18 in the cytoplasmic tail of tetherin for ubiquitination and subsequent degradation . Similar to SIVtan, HIV-2 also uses its envelope glycoprotein to counteract tetherin by targeting the extracellular domain of this restriction factor [30, 31]. Notably, the HIV-2 Env is only active against endogenous tetherin . Thus, we were unable to determine whether the polymorphisms affect the susceptibility of tetherin to HIV-2 Env counteraction. In support of a selective pressure some of the positions that are polymorphic in humans or adjacent residues show variations between different primate species. For example, changes of YxY to CxY or FxY are found in the tetherin ortholgues of Sykes’ monkeys, talapoins and new world monkeys, respectively. Furthermore, talapoin tetherin contains the R19H changes analyzed in the present study and African green monkeys, Patas monkeys and Francois’ leaf monkeys contain a cysteine instead of an arginine residue at this position . Thus, it will be of interest to further examine the effect of these variants analyzed on the susceptibility of tetherin to various viral antagonists.
The N49S substitution that was detected in European (MAF of 0.05%) but not in African Americans significantly reduced the tetherin surface expression and signaling activity by about 20% to 30% (Figures 2 and 6). We did not observe a significant effect of N49S on the anti-HIV-1 activity of human tetherin although the mutant tended to be slightly less active than the wild-type form (Figure 4). Recently, it has been reported that a 19-base-pair insertion polymorphism in the promoter region of bst2 may be associated with faster disease progression and reduced expression levels of this restriction factor . Whether or not the reduced surface expression of the N49S tetherin variant has an impact on the clinical outcome of HIV-1 infection remains to be determined and this will not be an easy task, given the rarity of this variant.
We show that seven very rare sequence variants (Y8H, R19H, N49S, D103N, E117A, D129E and V146L) do not significantly affect the potency of human tetherin in inhibiting the release of HIV-1 particles or its sensitivity to antagonism by HIV-1 Vpu or SIVtan Env. The R19H variant, however, selectively abrogated the ability of tetherin to induce NF-κB-dependent gene expression. Thus, inhibition of virus release and immune sensing are separable functions of human tetherin and the arginine residue at amino acid position 19 plays a critical role in the latter activity.
Bst2 was cloned into the CMV promoter-based pCGCG expression vector coexpressing DsRed2 as previously described . Single nucleotide polymorphisms were inserted using splicing by overlap extension PCR. To ensure expression of both isoforms  the genuine Kozak sequence was used. The pCAGGS vector expressing SIVtan Env was kindly provided by Ravindra Gupta . The NF-κB firefly luciferase reporter plasmids containing three or six NF-κB binding sites were kindly provided by Bernd Baumann.
A minimal promoter gaussia luciferase construct was purchased from Clontech (#631909) and used for normalization. It contains the TATA-like promoter (pTAL) region from the Herpes simplex virus thymidine kinase (HSV-TK) that is not responsive to NF-κB. The gaussia luciferase in the pTAL vector was replaced by firefly luciferase using NcoI/XbaI and the resulting construct was used as a negative control for the NF-κB reporter plasmid.
Cell culture and transfections
TZM-bl, 293T and 293 cells were grown under standard conditions in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, antibiotics and L-glutamine. 293T and 293 cells were transfected using the calcium-phosphate precipitation method.
To determine the cell surface expression levels of tetherin, 293T cells were transfected with expression vectors for GFP (1 μg) and tetherin (4 μg). To analyze the effect on SIVtan Env on tetherin surface expression levels, 293T cells were cotransfected with expression vectors for GFP (1 μg), tetherin (1 μg) and SIVtan Env (4 μg). Two days post transfection cells were analyzed by flow cytometry essentially as described previously . Briefly, cells were stained with an unconjugated anti-BST-2 antibody from Chugai Pharmaceuticals or eBioscience and an APC-conjugated secondary anti-mouse antibody (Invitrogen). Fluorescence of stained cells was detected by two-color flow cytometry and tetherin expression was determined as mean fluorescence intensity of tetherin-APC in GFP expressing cells. Notably, the previously described epitope (L116-L127) of the antibody from Chugai Pharmaceuticals  is disrupted by the E117A substitution and the D129E substitution impaired the interaction with the eBioscience antibody (Figure 2).
To monitor tetherin expression, 293T cells were transfected with expression vectors for tetherin (2.5 μg) and GFP (2.5 μg). Two days post transfection cells were harvested, lysed in M-PER buffer (Thermo Scientific) and cell lysates were separated in 4-12% Bis-Tris gels (Invitrogen). After gel electrophoresis proteins were transferred to PVDF membranes and probed with an anti-BST-2 antibody from Chugai Pharmaceuticals or eBioscience. For internal controls, blots were incubated with antibodies specific for GFP (290-50, abcam) and β-actin (8227-50, abcam). Subsequently, blots were probed with anti-mouse or anti-rabbit IRDye Odyssey antibodies and proteins detected using a LI-COR Odyssey scanner.
To determine the internalization rate of tetherin, 293T cells were cotransfected with GFP and tetherin expression vectors. 40 h post transfection, surface tetherin was stained as described above and cells were incubated for 0, 5, 10, 20, 30 or 60 min at 37°C to allow internalization of tetherin. After incubation, surface staining was removed with an acidic wash (pH 2.0) in one half of the samples. The other half remained untreated for normalization. The amount of stained tetherin was quantified by flow cytometry. The internalization rate was determined by dividing the MFI of the internalized tetherin (samples with acidic wash) by the MFI of the cells without acidic wash.
Virus release assay
To determine the ability of tetherin to restrict the release of infectious virions, 293T cells were seeded in six-well plates and transfected with 5 μg of HIV-1 NL4-3 IRES eGFP (wild-type or vpu-deficient) and different dilutions of tetherin expression vectors (250, 100, 50, 25, 12.5, and 6.25 ng). To determine the ability of SIVtan Env to antagonize tetherin, 293T cells were cotransfected with 4 μg of vpu-deficient HIV-1 NL4-3 IRES eGFP, 1 μg of vectors expressing SIVtan or HIV-1 M NL4-3 Env and varying amounts of tetherin expression vectors. Two days post transfection supernatants were harvested and the yield of infectious HIV-1 was determined by a 96-well infection assay on TZM-bl indicator cells.
NF-κB reporter assay
Transfections for luciferase assays were performed in 96-well plates and each transfection was performed in triplicates. Tetherin expression plasmids (75 ng) were transfected in 293T cells along with NF-κB-dependent or -independent firefly luciferase constructs (125 ng) and a pTAL promoter gaussia luciferase reporter plasmid (25 ng). 48 h post transfection, dual luciferase assays were performed. Firefly luciferase signals were normalized to the corresponding gaussia luciferase signals.
All statistical calculations were performed with a two-tailed unpaired Students-t-test using Graph Pad Prism Version 5.0. P values <0.05 were considered significant.
Single nucleotide variants were accessed from the Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA (URL: ) (April 2012).
The authors thank Bernd Baumann and Thomas Wirth for the NF-κB firefly luciferase reporter plasmids and Ravindra Gupta for the SIVtan Env expression vector. The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). This work was supported by the Deutsche Forschungsgemeinschaft and the EU.
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