Abstract
Tetherin/BST-2/CD317 is a recently identified antiviral protein that blocks the release of nascent retrovirus, and other virus, particles from infected cells. An HIV-1 accessory protein, Vpu, acts as an antagonist of tetherin. Here, we show that positive selection is evident in primate tetherin sequences and that HIV-1 Vpu appears to have specifically adapted to antagonize variants of tetherin found in humans and chimpanzees. Tetherin variants found in rhesus macaques (rh), African green monkeys (agm) and mice were able to inhibit HIV-1 particle release, but were resistant to antagonism by HIV-1 Vpu. Notably, reciprocal exchange of transmembrane domains between human and monkey tetherins conferred sensitivity and resistance to Vpu, identifying this protein domain as a critical determinant of Vpu function. Indeed, differences between hu-tetherin and rh-tetherin at several positions in the transmembrane domain affected sensitivity to antagonism by Vpu. Two alterations in the hu-tetherin transmembrane domain, that correspond to differences found in rh- and agm-tetherin proteins, were sufficient to render hu-tetherin completely resistant to HIV-1 Vpu. Interestingly, transmembrane and cytoplasmic domain sequences in primate tetherins exhibit variation at numerous codons that is likely the result of positive selection, and some of these changes coincide with determinants of HIV-1 Vpu sensitivity. Overall, these data indicate that tetherin could impose a barrier to viral zoonosis as a consequence of positive selection that has been driven by ancient viral antagonists, and that the HIV-1 Vpu protein has specialized to target the transmembrane domains found in human/chimpanzee tetherin proteins.
Highlights
Eukaryotic cells can constitutively or inducibly express a variety of molecules that inhibit the replication of viruses
Positive selection was tested using the REL(HyPhy) [18] and CODEML (PAML) [19] methods and these analyses revealed that codons exhibiting high dN/dS ratios, and likely to have been subjected to positive selection, were enriched in the N-terminal cytoplasmic and TM domains in primate tetherins (Fig. 7)
We reported that Vpu could reverse the inhibitory effect of IFN-alpha on HIV-1 particle release from human cells, but that Vpu failed to reverse such IFN-alpha induced inhibition in African green monkey cells [3]
Summary
Eukaryotic cells can constitutively or inducibly express a variety of molecules that inhibit the replication of viruses Among these antiviral defenses are components of the type-I interferon (IFN) induced innate immune system [1,2]. Ectopic expression of tetherin in cells that do not ordinarily express it results in the formation of proteasesensitive tethers that causes retention of retrovirus particles on the surface of infected cells, from where they can be internalized [4,5,7,8] This pronounced ability to retain and internalize HIV-1 particles is present constitutively in cells that normally express tetherin, but is suppressed when tetherin is depleted. Virions that are retained by tetherin are fully formed and mature, and have lipid bilayers that are discontinuous with cell membranes [4,7]
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