Simian immunodeficiency virus envelope glycoprotein counteracts tetherin/BST-2/CD317 by intracellular sequestration

Abstract

Tetherin is an IFN-inducible restriction factor that inhibits HIV-1 particle release in the absence of the HIV-1 countermeasure, viral protein U (Vpu). Although ubiquitous in HIV-1 and simian immunodeficiency viruses from chimpanzees, greater spot nosed monkeys, mustached monkeys, and Mona monkeys, other primate lentiviruses do not encode a Vpu protein. Here we demonstrate that SIV from Tantalus monkeys (SIVtan) encodes an envelope glycoprotein (SIVtan Env) able to counteract tetherin from Tantalus monkeys, rhesus monkeys, sooty mangabeys, and humans, but not from pigs. We show that sensitivity to Vpu but not SIVtan Env can be transferred with the human tetherin transmembrane region. We also identify a mutation in the tetherin extracellular domain, which almost completely abolishes sensitivity of human tetherin to SIVtan Env without compromising antiviral activity or sensitivity to Vpu. SIVtan Env expression results in a reduction of surface tetherin, as well as reduction in tetherin co-localization with mature surface-associated virus. Immuno-electron microscopy reveals co-localization of SIVtan Env with tetherin in intracellular tubulo-vesicular structures, suggesting that tetherin is sequestered away from budding virions at the cell surface. Along with HIV-1 Vpu and SIV Nef, envelope glycoprotein is the third and most broadly active lentiviral-encoded tetherin countermeasure to be described. Our observations emphasize the importance of tetherin in protecting mammals against viral infection and suggest that HIV-1 Vpu inhibitors may select active envelope mutants.HIV ͉ restriction ͉ innate immunity

The Restriction Factors of Human Immunodeficiency Virus

“…Indeed, prior to the identification of tetherin, the envelope glycoproteins of certain HIV-2 isolates were shown to have "Vpu-like" activity that could rescue the release of Vpu-deficient HIV-1 from restrictive cells (62). Tetherin antagonism by Env depends on physical interaction between Env and tetherin and on a conserved tyrosine-based endocytosis motif (YXX) in the cytoplasmic tail of the Env transmembrane protein gp41 (59,60,63). The residues that contribute to Env-tetherin interactions are not well defined but appear to be located in the extracellular domains of both proteins based on analyses of recombinant forms of Env and tetherin (60,64) and on the identification of defined amino acid changes in the ectodomains of gp41 and tetherin that disrupt anti-tetherin activity (64 -66).…”

Interferon-Induced Tetherin Restricts Vesicular Stomatitis Virus Release in Neurons

“…K5 induces a speciesspecific downregulation of human tetherin and endosomal degradation as well. SIV negative regulatory factor (Nef) antagonizes nonhuman primate orthologs of tetherin (Bartee et al, 2006;Gupta et al, 2009;Jia et al, 2009;Zhang et al, 2009).…”

Functions of the Lentiviral Accessory Protein Nef During the Distinct Steps of HIV and SIV Replication Cycle

“…Tetherin is antagonized by the HIV-1 protein Vpu (Neil et al, 2008;Van Damme et al, 2008). Vpu interact directly with the transmembrane domain of Tetherin with a high specificity (Gupta et al, 2009;McNatt et al, 2009). The mechanism by which Vpu remove Tetherin from the cell surface was proposed as Vpu recruits -TrCP, a substrate adaptor for an SCF E3 ubiquitin ligase complex, to remove Tetherin via post-endocytic membrane trafficking events Mitchell et al, 2009).…”

“…Analyses of the interactions between Tetherins from different primate species and the antagonist proteins used by viruses that infect those hosts have revealed a high degree of species-specificity. For example, the HIV-1 Vpu protein antagonizes human but not monkey Tetherin (Gupta et al, 2009;McNatt et al, 2009). These antiviral factors have sequence divergences that may constitute barriers to zoonotic viral transmission from animal reservoirs.…”

“…HIV-2 on the other hand, uses its envelope glycoprotein Env (and not Nef) to downmodulate Tetherin (Bour et al, 1996;Le Tortorec and Neil, 2009;Ritter et al, 1996). SIVtan from Tantalus monkeys uses both Env and Nef to antagonize Tetherin (Gupta et al, 2009;Zhang et al, 2009). Analyses of the interactions between Tetherins from different primate species and the antagonist proteins used by viruses that infect those hosts have revealed a high degree of species-specificity.…”