Mechanism and Evolutionary Origins of HIV-1 Virion Entrapment by Tetherin
type: CreativeWork
description: The cellular restriction factor, tetherin, prevents HIV-1 and other enveloped virus particles from being disseminated into the extracellular milieu by infiltrating their envelopes and by physically crosslinking them to the cell surface. However, the mechanisms underlying virion retention have not yet been fully delineated. In this body of work, we employed 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 demonstrated that tetherin dimers adopt an "axial" configuration, in which pairs of transmembrane domains or pairs of glycosylphosphatidyl inositol anchors are inserted into assembling particles, while the remaining pair of membrane anchors remains embedded in the infected cell membrane. We used quantitative western blotting to determine that a few dozen tetherin dimers are used to trap each virion particle, and that there is ~3-5 fold preference for the insertion of glycosylphosphatidyl inositol anchors rather than transmembrane domains into tethered virions. Cumulatively, these results demonstrated that axially configured tetherin homodimers are directly responsible for trapping virions at the cell surface. We propose 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. Allied to these efforts, we also endeavored to determine the evolutionary origins of tetherin. We used computational and biochemical approaches to build a case that tetherin arose via duplication of the neighboring PLVAP/PV1 gene. The PV1 and tetherin genes are located adjacent to each other in eutherian mammals and encode proteins with a shared and relatively unusual overall architecture. Phylogenetic analyses provided evidence that tetherin is ~147 MY old and that…
abstract: The cellular restriction factor, tetherin, prevents HIV-1 and other enveloped virus particles from being disseminated into the extracellular milieu by infiltrating their envelopes and by physically crosslinking them to the cell surface. However, the mechanisms underlying virion retention have not yet been fully delineated. In this body of work, we employed 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 demonstrated that tetherin dimers adopt an "axial" configuration, in which pairs of transmembrane domains or pairs of glycosylphosphatidyl inositol anchors are inserted into assembling particles, while the remaining pair of membrane anchors remains embedded in the infected cell membrane. We used quantitative western blotting to determine that a few dozen tetherin dimers are used to trap each virion particle, and that there is ~3-5 fold preference for the insertion of glycosylphosphatidyl inositol anchors rather than transmembrane domains into tethered virions. Cumulatively, these results demonstrated that axially configured tetherin homodimers are directly responsible for trapping virions at the cell surface. We propose 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. Allied to these efforts, we also endeavored to determine the evolutionary origins of tetherin. We used computational and biochemical approaches to build a case that tetherin arose via duplication of the neighboring PLVAP/PV1 gene. The PV1 and tetherin genes are located adjacent to each other in eutherian mammals and encode proteins with a shared and relatively unusual overall architecture. Phylogenetic analyses provided evidence that tetherin is ~147 MY old and that…
author: Venkatesh, Siddarth
keywords: tetherin, HIV-1 restriction, virion entrapment, GPI anchor, PV1 duplication, antiviral evolution, Life Sciences
date published: 2014-01-01T08:00:00Z
date modified: 2026-07-24T04:11:21Z
provider: Rockefeller
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Rockefeller