A rare missense variant abrogates the signaling activity of tetherin/BST-2 without affecting its effect on virus release
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A rare missense variant abrogates the signaling activity of tetherin/BST-2 without affecting its effect on virus release. / Sauter, Daniel; Hotter, Dominik; Engelhart, Susanne; Giehler, Fabian; Kieser, Arnd; Kubisch, Christian; Kirchhoff, Frank.
In: RETROVIROLOGY, Vol. 10, 01.01.2013, p. 85.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A rare missense variant abrogates the signaling activity of tetherin/BST-2 without affecting its effect on virus release
AU - Sauter, Daniel
AU - Hotter, Dominik
AU - Engelhart, Susanne
AU - Giehler, Fabian
AU - Kieser, Arnd
AU - Kubisch, Christian
AU - Kirchhoff, Frank
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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.
AB - 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.
KW - Antigens, CD
KW - GPI-Linked Proteins
KW - HIV-1
KW - Humans
KW - Mutant Proteins
KW - Mutation, Missense
KW - Signal Transduction
KW - Virus Release
U2 - 10.1186/1742-4690-10-85
DO - 10.1186/1742-4690-10-85
M3 - SCORING: Journal article
C2 - 23937976
VL - 10
SP - 85
JO - RETROVIROLOGY
JF - RETROVIROLOGY
SN - 1742-4690
ER -