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PLoS Pathog. 2013;9(7):e1003483. doi: 10.1371/journal.ppat.1003483. Epub 2013 Jul 18.

Mechanism of HIV-1 virion entrapment by tetherin.

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  • 1Howard Hughes Medical Institute, Laboratory of Retrovirology, Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, United States of America.


Tetherin, an interferon-inducible membrane protein, inhibits the release of nascent enveloped viral particles from the surface of infected cells. However, the mechanisms underlying virion retention have not yet been fully delineated. Here, we employ biochemical assays and engineered tetherin proteins to demonstrate conclusively that virion tethers are composed of the tetherin protein itself, and to elucidate the configuration and topology that tetherin adopts during virion entrapment. We demonstrate that tetherin dimers adopt an "axial" configuration, in which pairs of transmembrane domains or pairs of glycosylphosphatidyl inositol anchors are inserted into assembling virion particles, while the remaining pair of membrane anchors remains embedded in the infected cell membrane. We use quantitative western blotting to determine that a few dozen tetherin dimers are used to tether each virion particle, and that there is ∼3- to 5-fold preference for the insertion of glycosylphosphatidyl inositol anchors rather than transmembrane domains into tethered virions. Cumulatively, these results demonstrate that axially configured tetherin homodimers are directly responsible for trapping virions at the cell surface. We suggest that insertion of glycosylphosphatidyl inositol anchors may be preferred so that effector functions that require exposure of the tetherin N-terminus to the cytoplasm of infected cells are retained.

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