Differential Sensitivities of Tetherin Isoforms to Counteraction by Primate Lentiviruses

Abstract

The mammalian antiviral membrane protein tetherin (BST2/CD317) can be expressed as two isoforms derived from differential translational initiation. The shorter isoform of the human protein (S-tetherin) lacks the first 12 amino acids of the longer (Ltetherin) cytoplasmic tail, which includes a tyrosine motif that acts as both an endocytic recycling signal and a determinant of virus-induced NF-B activation. S-tetherin is also reported to be less sensitive to the prototypic viral antagonist human immunodeficiency virus type 1 (HIV-1) Vpu. Here we analyzed the relative sensitivities of L-and S-tetherins to primate lentiviral countermeasures. We show that the reduced sensitivity of S-tetherin to HIV-1 Vpu is a feature of all group M proteins, including those of transmitted founder viruses, primarily because it cannot be targeted for endosomal degradation owing to the truncation of its cytoplasmic tail. In contrast, both isoforms of the human and rhesus macaque tetherins display the same sensitivity to nondegradative lentiviral countermeasures of HIV-2 and SIVmac, respectively. Surprisingly, however, the Vpu proteins encoded by simian immunodeficiency viruses (SIVs) of African guenons, as well as that from recently isolated highly pathogenic HIV-1 group N, do not discriminate between tetherin isoforms. Together, these data suggest that the group M HIV-1 Vpu primarily adapted to target L-tetherin upon zoonotic transmission from chimpanzees, and further, we speculate that functions specifically associated with this isoform, such as proinflammatory signaling, play key roles in human tetherin's antiviral function in vivo. IMPORTANCEThe ability of HIV-1 and related viruses to counteract a host antiviral protein, tetherin, is strictly maintained. The adaptation of the HIV-1 Vpu protein to counteract human tetherin is thought to have been one of the key events in the establishment of the HIV/AIDS pandemic. Recent evidence shows that tetherin is expressed as two isoforms and that Vpu preferentially targets the longer form. Here we show that unlike other virus-encoded countermeasures, such as those from primate viruses related to HIV-1, the enhanced ability to counteract the long tetherin isoform is conserved among HIV-1 strains that make up the majority of the human pandemic. This correlates with the ability of Vpu to induce long tetherin degradation. We speculate that functions associated with the human version of this isoform, such as an inflammatory signaling capacity, selected for Vpu's enhanced targeting of long tetherin during its adaptation to humans.

Tetherin Antagonism by HIV-1 Group M Nef Proteins

“…Natural killer (NK) effector cells and CEM.NKR-CCR5 target cells were maintained as described previously (28). Jurkat-TAg parental (JTAg), Jurkat-TAg L-tetherin, and Jurkat-TAg S-tetherin cells were kindly provided by Stuart J. Neil, King's College London, and maintained in RPMI medium supplemented with 10% fetal calf serum and gentamicin, as previously described (29).…”

Differential Control of BST2 Restriction and Plasmacytoid Dendritic Cell Antiviral Response by Antagonists Encoded by HIV-1 Group M and O Strains

“…Interestingly, the ability of M-Vpu to displace residual BST2 molecules away from sites of virus budding was found to have a downregulatory role in the pDC IFN-I response since it promoted the engagement of BST2 with the ILT7 inhibitory receptor upon cell contacts between infected cells and pDCs (11). Thus, differential targeting of long and short BST2 isoforms seems to be a specific property of HIV-1 M-Vpu (23,28) and appears to be intended as a means to counteract BST2 restriction upon HIV-1 particle release, prevent the activation of NF-B signaling, and limit IFN-I production by pDCs upon sensing of infected cells.…”

“…In contrast, HIV-1 group M Vpu (M-Vpu) targets the long and short BST2 isoforms differentially using distinct mechanisms. While MVpu removes long BST2 molecules from the cell surface essentially via intracellular sequestration and degradation mechanisms, the short BST2 isoform is more resistant to M-Vpu-mediated downregulation and antagonism (23,28) and, as such, appears to be counteracted by displacement from sites of virus budding (11,(29)(30)(31). Interestingly, the ability of M-Vpu to displace residual BST2 molecules away from sites of virus budding was found to have a downregulatory role in the pDC IFN-I response since it promoted the engagement of BST2 with the ILT7 inhibitory receptor upon cell contacts between infected cells and pDCs (11).…”

“…For instance, both isoforms of human and rhesus macaque BST2 demonstrate similar sensitivities to HIV-2 Env and SIVmac Nef, respectively, and their counteraction involves the removal of the protein from the cell surface through enhanced internalization and intracellular sequestration (18,(25)(26)(27). The Vpu protein from the recently isolated highly pathogenic HIV-1 group N strain from Togo (N1.FR.2001) (17) also antagonizes both isoforms albeit without inducing their degradation or surface downregulation (28). In contrast, HIV-1 group M Vpu (M-Vpu) targets the long and short BST2 isoforms differentially using distinct mechanisms.…”

The Sheep Tetherin Paralog oBST2B Blocks Envelope Glycoprotein Incorporation into Nascent Retroviral Virions

“…ST2/tetherin is an interferon (IFN)-stimulated gene with potent antiviral properties against a variety of enveloped viruses (1)(2)(3)(4). Human bone marrow stromal cell antigen 2 (hBST2) restricts viral-particle release of human immunodeficiency virus type 1 (HIV-1) lacking the viral accessory protein Vpu by tethering nascent virions, which are subsequently endocytosed, to the cell membrane (2,5).…”