Abstract
BackgroundTetherin is a recently identified antiviral restriction factor that restricts HIV-1 particle release in the absence of the HIV-1 viral protein U (Vpu). It is reminiscent of APOBEC3G and TRIM5a that also antagonize HIV. APOBEC3G and TRIM5a have been demonstrated to evolve under pervasive positive selection throughout primate evolution, supporting the red-queen hypothesis. Therefore, one naturally presumes that Tetherin also evolves under pervasive positive selection throughout primate evolution and supports the red-queen hypothesis. Here, we performed a detailed evolutionary analysis to address this presumption.Methodology/Principal FindingsResults of non-synonymous and synonymous substitution rates reveal that Tetherin as a whole experiences neutral evolution rather than pervasive positive selection throughout primate evolution, as well as in non-primate mammal evolution. Sliding-window analyses show that the regions of the primate Tetherin that interact with viral proteins are under positive selection or relaxed purifying selection. In particular, the sites identified under positive selection generally focus on these regions, indicating that the main selective pressure acting on the primate Tetherin comes from virus infection. The branch-site model detected positive selection acting on the ancestral branch of the New World Monkey lineage, suggesting an episodic adaptive evolution. The positive selection was also found in duplicated Tetherins in ruminants. Moreover, there is no bias in the alterations of amino acids in the evolution of the primate Tetherin, implying that the primate Tetherin may retain broad spectrum of antiviral activity by maintaining structure stability.Conclusions/SignificanceThese results conclude that the molecular evolution of Tetherin may be attributed to the host–virus arms race, supporting the Red Queen hypothesis, and Tetherin may be in an intermediate stage in transition from neutral to pervasive adaptive evolution.
Highlights
To mitigate the susceptibility to various viruses, primates have evolved innate cellular defense systems to inhibit virus replication in cells or virus release from cells
It is reminiscent of the APOBEC3G and TRIM5a, another two well-known antiviral restriction factors, which counteract HIV
The APOBEC3G and TRIM5a have been demonstrated to evolve under pervasive positive selection throughout primate evolution, well supporting the red-queen hypothesis [17,18,19,35,36]
Summary
To mitigate the susceptibility to various viruses (e.g. human immunodeficiency virus, HIV), primates have evolved innate cellular defense systems to inhibit virus replication in cells or virus release from cells. It was found because it can restrict the release of fully formed virus particles from infected cells in the absence of the HIV-1 viral protein U (Vpu) [4,5]. Viral antagonists of Tetherin include HIV-1 Vpu, SIV Nef, HIV-2, SIV and Ebola envelope glycoproteins, and KSHV (Kaposi’s sarcoma-associated herpesvirus) K5 protein [8,11,12] Their antagonist mechanisms are involved in cellular endosomal trafficking pathway and ubiquitination-mediated protein degradation pathway [8]. Tetherin is a recently identified antiviral restriction factor that restricts HIV-1 particle release in the absence of the HIV-1 viral protein U (Vpu) It is reminiscent of APOBEC3G and TRIM5a that antagonize HIV.
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