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Mutation of a single residue renders human tetherin resistant to HIV-1 Vpu-mediated depletion

PLoS pathogens, 2009-05, Vol.5 (5), p.e1000443-e1000443 [Peer Reviewed Journal]

COPYRIGHT 2009 Public Library of Science ;Gupta et al. 2009 ;2009 Gupta et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Gupta RK, Hué S, Schaller T, Verschoor E, Pillay D, et al. (2009) Mutation of a Single Residue Renders Human Tetherin Resistant to HIV-1 Vpu-Mediated Depletion. PLoS Pathog 5(5): e1000443. doi:10.1371/journal.ppat.1000443 ;ISSN: 1553-7374 ;ISSN: 1553-7366 ;EISSN: 1553-7374 ;DOI: 10.1371/journal.ppat.1000443 ;PMID: 19461879

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Title:
Mutation of a single residue renders human tetherin resistant to HIV-1 Vpu-mediated depletion
Author: Gupta, Ravindra K ; Hué, Stéphane ; Schaller, Torsten ; Verschoor, Ernst ; Pillay, Deenan ; Towers, Greg J
Hope, Thomas J.
Subjects: Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Antigens, CD - chemistry ; Antigens, CD - genetics ; Antigens, CD - immunology ; Antigens, CD - metabolism ; Bayes Theorem ; Cell Line ; Chlorocebus aethiops ; Cysteine Proteinase Inhibitors - pharmacology ; Development and progression ; Evolution ; Evolutionary Biology ; Evolutionary Biology/Bioinformatics ; Evolutionary Biology/Genomics ; Evolutionary Biology/Human Evolution ; Evolutionary Biology/Microbial Evolution and Genomics ; Gene mutations ; Genetic aspects ; GPI-Linked Proteins ; HIV (Viruses) ; HIV infection ; HIV-1 ; Human immunodeficiency virus 1 ; Human Immunodeficiency Virus Proteins - metabolism ; Humans ; Infectious Diseases ; Infectious Diseases/HIV Infection and AIDS ; Leupeptins - pharmacology ; Medical research ; Membrane Glycoproteins - chemistry ; Membrane Glycoproteins - genetics ; Membrane Glycoproteins - immunology ; Membrane Glycoproteins - metabolism ; Membrane proteins ; Molecular Biology ; Molecular Sequence Data ; Mutation ; Phylogeny ; Physiological aspects ; Primates ; Properties ; Proteins ; Selection, Genetic ; Sequence Alignment ; Viral infections ; Viral Regulatory and Accessory Proteins - metabolism ; Virology/Animal Models of Infection ; Virology/Host Antiviral Responses ; Virology/Immunodeficiency Viruses ; Virology/Mechanisms of Resistance and Susceptibility, including Host Genetics ; Virology/Virion Structure, Assembly, and Egress ; Virology/Virulence Factors and Mechanisms ; Virus Replication - drug effects ; Virus Replication - physiology
Is Part Of: PLoS pathogens, 2009-05, Vol.5 (5), p.e1000443-e1000443
Description: 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.
Publisher: United States: Public Library of Science
Language: English
Identifier: ISSN: 1553-7374
ISSN: 1553-7366
EISSN: 1553-7374
DOI: 10.1371/journal.ppat.1000443
PMID: 19461879
Source: Public Library of Science (PLoS) Journals Open Access
Geneva Foundation Free Medical Journals at publisher websites
MEDLINE
PubMed Central
ProQuest Central
DOAJ Directory of Open Access Journals

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Mutation of a single residue renders human tetherin resistant to HIV-1 Vpu-mediated depletion

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