Abstract
BackgroundIn the absence of the Vpu protein, newly formed HIV-1 particles can remain attached to the surface of human cells due to the action of an interferon-inducible cellular restriction factor, BST-2/tetherin. Tetherin also restricts the release of other enveloped viral particles and is counteracted by a several viral anti-tetherin factors including the HIV-2 Env, SIV Nef and KSHV K5 proteins.ResultsWe observed that a fraction of tetherin is located at the surface of restricting cells, and that co-expression of both HIV-1 Vpu and HIV-2 Env reduced this population. In addition, Vpu, but not the HIV-2 Env, reduced total cellular levels of tetherin. An additional effect observed for both Vpu and the HIV-2 Env was to redirect tetherin to an intracellular perinuclear compartment that overlapped with markers for the TGN (trans-Golgi network). Sequestration of tetherin in this compartment was independent of tetherin's normal endocytosis trafficking pathway.ConclusionsBoth HIV-1 Vpu and HIV-2 Env redirect tetherin away from the cell surface and sequester the protein in a perinuclear compartment, which likely blocks the action of this cellular restriction factor. Vpu also promotes the degradation of tetherin, suggesting that it uses more than one mechanism to counteract tetherin restriction.
Highlights
Viral pathogens frequently disable components of both intrinsic and adaptive host immune responses
Tetherin is present at the cell surface and in a perinuclear compartment It has been suggested that tetherin could retain viruses at the cell surface by physically linking viral and plasma membranes [3,22]
Previous studies of rat and mouse tetherin have shown that the protein recycles between the plasma membrane and a perinuclear compartment that overlaps with cellular markers for the trans-Golgi network (TGN) [20,28], while human tetherin has been partially co-localized with both the TGN and recycling endosomes [29,30]
Summary
Viral pathogens frequently disable components of both intrinsic and adaptive host immune responses. Strategies include targeting the host anti-viral proteins or restriction factors for degradation through the recruitment of cullin-RING finger ubiquitin ligases, as occurs when Vif counteracts APOBEC3G, or Vpu targets CD4. The trafficking pathways used by the host factors can be altered to prevent expression at the cell surface, as occurs with Nef and CD4 or MHC class I. The HIV-1 Vpu protein counteracts an α-interferon-inducible host cell restriction, BST-2/ CD317/HM1.24 ("tetherin"), that prevents the release of newly formed virions from the cell surface [2,3,4]. In the absence of the Vpu protein, newly formed HIV-1 particles can remain attached to the surface of human cells due to the action of an interferon-inducible cellular restriction factor, BST-2/tetherin. Tetherin restricts the release of other enveloped viral particles and is counteracted by a several viral anti-tetherin factors including the HIV-2 Env, SIV Nef and KSHV K5 proteins
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