Mutation of a single residue renders human tetherin resistant to HIV-1 Vpu-mediated depletion.
The recently identified restriction factor tetherin/BST-2/CD317 is an interferon-inducible trans-membrane protein that restricts HIV-1 particle release in the absence of the HIV-1 countermeasure viral protein U (Vpu). It is known that Tantalus monkey CV1 cells can be rendered non-permissive to HIV-1 release upon stimulation with type 1 interferon, despite the presence of Vpu, suggesting species-specific sensitivity of tetherin proteins to viral countermeasures such as Vpu. Here we demonstrate that Tantalus monkey tetherin restricts HIV-1 by nearly two orders of magnitude, but in contrast to human tetherin the Tantalus protein is insensitive to HIV-1 Vpu. We have investigated tetherin's sensitivity to Vpu using positive selection analyses, seeking evidence for evolutionary conflict between tetherin and viral countermeasures. We provide evidence that tetherin has undergone positive selection during primate evolution. Mutation of a single amino acid (showing evidence of positive selection) in the trans-membrane cap of human tetherin to that in Tantalus monkey (T45I) substantially impacts on sensitivity to HIV-1 Vpu, but not on antiviral activity. Finally, we provide evidence that cellular steady state levels of tetherin are substantially reduced by Vpu, and that the T45I mutation abrogates this effect. This study provides evidence that tetherin is important in protecting mammals against viral infection, and that the HIV-1 Vpu-mediated countermeasure is specifically adapted to act against human tetherin. It also emphasizes the power of selection analyses to illuminate the molecular details of host-virus interactions. This work suggests that tetherin binding agents might protect it from viral encoded countermeasures and thus make powerful antivirals.
Gupta
Ravindra K
RK
Medical Research Council Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London, United Kingdom.
Hué
Stéphane
S
Schaller
Torsten
T
Verschoor
Ernst
E
Pillay
Deenan
D
Towers
Greg J
GJ
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001499:Bayes Theorem; D002460:Cell Line; D002522:Chlorocebus aethiops; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D058851:GPI-Linked Proteins; D015497:HIV-1; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D012641:Selection, Genetic; D016415:Sequence Alignment; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
D015703:Antigens, CD; D015853:Cysteine Proteinase Inhibitors; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D007976:Leupeptins; D008562:Membrane Glycoproteins; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde