A rare missense variant abrogates the signaling activity of tetherin/BST-2 without affecting its effect on virus release.
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.
Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany. daniel.sauter@uni-ulm.de
Daniel
D
Sauter
Dominik
D
Hotter
Susanne
S
Engelhart
Fabian
F
Giehler
Arnd
A
Kieser
Christian
C
Kubisch
Frank
F
Kirchhoff
D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020125:Mutation, Missense; D015398:Signal Transduction; D057074:Virus Release; D000074010:Bone Marrow Stromal Antigen 2
D015703:Antigens, CD; D058851:GPI-Linked Proteins; D050505:Mutant Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2