The Nef Protein of the Macrophage Tropic HIV-1 Strain AD8 Counteracts Human BST-2/Tetherin.

Sebastian Giese,Mark Marsh,Michela Mazzon,Scott P Lawrence,Bernadien M Nijmeijer

doi:10.3390/v12040459

Sebastian Giese, Mark Marsh + Show 3 more

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https://doi.org/10.3390/v12040459

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Abstract

Bone Marrow Stromal Cell Antigen 2 (BST-2)/tetherin inhibits the release of numerous enveloped viruses by physically tethering nascent particles to infected cells during the process of viral budding from the cell surface. Tetherin also restricts human immunodeficiency virus (HIV), and pandemic main (M) group HIV type 1s (HIV-1s) are thought to rely exclusively on their Vpu proteins to overcome tetherin-mediated restriction of virus release. However, at least one M group HIV-1 strain, the macrophage-tropic primary AD8 isolate, is unable to express Vpu due to a mutation in its translation initiation codon. Here, using primary monocyte-derived macrophages (MDMs), we show that AD8 Nef protein can compensate for the absence of Vpu and restore virus release to wild type levels. We demonstrate that HIV-1 AD8 Nef reduces endogenous cell surface tetherin levels, physically separating it from the site of viral budding, thus preventing HIV retention. Mechanistically, AD8 Nef enhances internalisation of the long isoform of human tetherin, leading to perinuclear accumulation of the restriction factor. Finally, we show that Nef proteins from other HIV strains also display varying degrees of tetherin antagonism. Overall, we show that M group HIV-1s can use an accessory protein other than Vpu to antagonise human tetherin.

Highlights

Human immunodeficiency virus type 1s (HIV-1s) are divided into four groups, M, N, O and P (Major, non-M/non-O, Outlier and ‘Pending the identification of further human cases’, respectively), each of which is believed to have originated from independent interspecies transmissions of simian immunodeficiency viruses (SIVs) into man
The tetherin N-terminal transmembrane domain remains embedded in the host plasma membrane (PM), but the C-terminal domain can be incorporated into the viral membrane, tethering nascent virions to the infected cell, preventing virus release and limiting viral spread [4]
M group human immunodeficiency virus (HIV)-1 infections account for more than 99% of HIV infections. The ability of these viruses to overcome the cellular restriction imposed by tetherin has been viewed as a key step in the global spread of HIV [2]; understanding how M group HIV-1s counteract tetherin is important

Summary

Introduction

Human immunodeficiency virus type 1s (HIV-1s) are divided into four groups, M, N, O and P (Major, non-M/non-O, Outlier and ‘Pending the identification of further human cases’, respectively), each of which is believed to have originated from independent interspecies transmissions of simian immunodeficiency viruses (SIVs) into man. 20 kDa glycoprotein that restricts a broad range of enveloped viruses by preventing their release from infected host cells [3]. Tetherin has two membrane-association domains: (1) a type-2 transmembrane domain at the N-terminus and (2) a glycophosphatidylinositol (GPI) linkage at the C-terminus. The tetherin N-terminal transmembrane domain remains embedded in the host plasma membrane (PM), but the C-terminal domain can be incorporated into the viral membrane, tethering nascent virions to the infected cell, preventing virus release and limiting viral spread [4]

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