Species-Specific Activity of SIV Nef and HIV-1 Vpu in Overcoming Restriction by Tetherin/BST2

Bin Jia,John Mackey,Andrew Rahmberg,William Neidermyer,David T Evans,Welkin E Johnson,Susan Westmoreland,Ismael Ben Fofana,Ruth Serra-Moreno,Michael Emerman

doi:10.1371/journal.ppat.1000429

Bin Jia, John Mackey + Show 8 more

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https://doi.org/10.1371/journal.ppat.1000429

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Abstract

Tetherin, also known as BST2, CD317 or HM1.24, was recently identified as an interferon-inducible host–cell factor that interferes with the detachment of virus particles from infected cells. HIV-1 overcomes this restriction by expressing an accessory protein, Vpu, which counteracts tetherin. Since lentiviruses of the SIVsmm/mac/HIV-2 lineage do not have a vpu gene, this activity has likely been assumed by other viral gene products. We found that deletion of the SIVmac239 nef gene significantly impaired virus release in cells expressing rhesus macaque tetherin. Virus release could be restored by expressing Nef in trans. However, Nef was unable to facilitate virus release in the presence of human tetherin. Conversely, Vpu enhanced virus release in the presence of human tetherin, but not in the presence of rhesus tetherin. In accordance with the species-specificity of Nef in mediating virus release, SIV Nef downregulated cell-surface expression of rhesus tetherin, but did not downregulate human tetherin. The specificity of SIV Nef for rhesus tetherin mapped to four amino acids in the cytoplasmic domain of the molecule that are missing from human tetherin, whereas the specificity of Vpu for human tetherin mapped to amino acid differences in the transmembrane domain. Nef alleles of SIVsmm, HIV-2 and HIV-1 were also able to rescue virus release in the presence of both rhesus macaque and sooty mangabey tetherin, but were generally ineffective against human tetherin. Thus, the ability of Nef to antagonize tetherin from these Old World primates appears to be conserved among the primate lentiviruses. These results identify Nef as the viral gene product of SIV that opposes restriction by tetherin in rhesus macaques and sooty mangabeys, and reveal species-specificity in the activities of both Nef and Vpu in overcoming tetherin in their respective hosts.

Highlights

Efforts to elucidate the function of the HIV-1 Vpu protein recently led to the identification of an interferon-inducible, hostcell factor that interferes with the detachment of virions from infected cells [1,2]
Tetherin was recently identified as a host–cell factor that interferes with the detachment of virus particles from infected cells
HIV-1 overcomes the antiviral effects of tetherin by expressing Vpu, which mediates the degradation of tetherin

Summary

Introduction

Efforts to elucidate the function of the HIV-1 Vpu protein recently led to the identification of an interferon-inducible, hostcell factor that interferes with the detachment of virions from infected cells [1,2]. Varthakavi and Spearman demonstrated that heterokaryon fusions of permissive and non-permissive cells exhibited a nonpermissive phenotype for the release of vpu-deleted HIV-1 [10]. These experiments pointed to the presence of an inhibitor of virus release in Dvpu-restrictive cells [10]. Subsequent studies revealed that the putative restriction factor was an interferon-inducible protein exposed on the cell surface [9,11] These observations quickly led Neil and Bieniasz to identify bone marrow stromal antigen 2 (BST2), known as CD317 or HM1.24, from an expression analysis of IFNa-treated cells as the cellular gene product responsible for the restriction of vpu-deficient HIV-1 [1]. For its role in inhibiting the detachment of virus particles from the surface of infected cells, BST2 was re-named ‘‘tetherin’’ [1]

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