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

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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. 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. While tetherin has broad activity against diverse types of viruses, only a few of the primate AIDS viruses express Vpu. Simian immunodeficiency virus (SIV) does not have a vpu gene. Since SIV infection of the rhesus macaque is an important animal model for AIDS vaccine development, we set out to determine how SIV overcomes restriction by tetherin in this species. We found that the SIV Nef protein could counteract rhesus macaque tetherin, but not human tetherin. Conversely, the HIV-1 Vpu protein counteracted human tetherin, but not rhesus tetherin. The specificity of 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. These observations identify a role for the SIV Nef protein in counteracting tetherin, and reveal species-specificity in the activities of both Nef and Vpu in overcoming tetherin in their respective hosts.