Abstract
BackgroundThe anti-viral activity of the cellular restriction factor, BST-2/tetherin, was first observed as an ability to block the release of Vpu-minus HIV-1 from the surface of infected cells. However, tetherin restriction is also counteracted by primate lentiviruses that do not express a Vpu protein, where anti-tetherin functions are provided by either the Env protein (HIV-2, SIVtan) or the Nef protein (SIVsm/mac and SIVagm). Within the primate lentiviruses, Vpu is also present in the genomes of SIVcpz and certain SIVsyk viruses. We asked whether, in these viruses, anti-tetherin activity was always a property of Vpu, or if it had selectively evolved in HIV-1 to perform this function.ResultsWe found that despite the close relatedness of HIV-1 and SIVcpz, the chimpanzee viruses use Nef instead of Vpu to counteract tetherin. Furthermore, SIVcpz Nef proteins had activity against chimpanzee but not human tetherin. This specificity mapped to a short sequence that is present in the cytoplasmic tail of primate but not human tetherins, and this also accounts for the specificity of SIVsm/mac Nef for primate but not human tetherins. In contrast, Vpu proteins from four diverse members of the SIVsyk lineage all displayed an anti-tetherin activity that was active against macaque tetherin. Interestingly, Vpu from a SIVgsn isolate was also found to have activity against human tetherin.ConclusionsPrimate lentiviruses show a high degree of flexibility in their use of anti-tetherin factors, indicating a strong selective pressure to counteract tetherin restriction. The identification of an activity against human tetherin in SIVgsn Vpu suggests that the presence of Vpu in the ancestral SIVmus/mon/gsn virus believed to have contributed the 3' half of the HIV-1 genome may have played a role in the evolution of viruses that could counteract human tetherin and infect humans.
Highlights
The anti-viral activity of the cellular restriction factor, BST-2/tetherin, was first observed as an ability to block the release of Vpu-minus HIV-1 from the surface of infected cells
Specificity has been observed in the interaction between tetherins and SIV Nef proteins that depends on a short stretch of amino acids that is present in the cytoplasmic tail of primate tetherins such as chimpanzee, macaque, or African green monkey, but not in human tetherin [9,10]
We tested whether SIVcpz Vpu proteins have anti-tetherin activity by examining their ability to increase the release of HIV-1 virus like particles (VLPs) from HeLa cells, which naturally express human tetherin [2,3]
Summary
The anti-viral activity of the cellular restriction factor, BST-2/tetherin, was first observed as an ability to block the release of Vpu-minus HIV-1 from the surface of infected cells. Tetherin restriction is counteracted by primate lentiviruses that do not express a Vpu protein, where anti-tetherin functions are provided by either the Env protein (HIV-2, SIVtan) or the Nef protein (SIVsm/mac and SIVagm). The importance of overcoming this restriction for virus replication is reflected in the growing list of viral proteins that have been shown to possess anti-tetherin activities, with the primate lentiviruses in particular having evolved diverse approaches that include the HIV-1 Vpu, HIV-2 Env and certain SIV Nef and Env proteins [2,3,7,8,9,10,11,12]. Specificity has been observed in the interaction between tetherins and SIV Nef proteins that depends on a short stretch of amino acids that is present in the cytoplasmic tail of primate tetherins such as chimpanzee, macaque, or African green monkey, but not in human tetherin [9,10]
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