Simian Immunodeficiency Virus SIV _agm from African Green Monkeys Does Not Antagonize Endogenous Levels of African Green Monkey Tetherin/BST-2

Abstract

The Vpu accessory gene that originated in the primate lentiviral lineage leading to human immunodeficiency virus type 1 is an antagonist of human tetherin/BST-2 restriction. Most other primate lentivirus lineages, including the lineage represented by simian immunodeficiency virus SIV agm from African green monkeys (AGMs), do not encode Vpu. While some primate lineages encode gene products other than Vpu that overcome tetherin/BST-2, we find that SIV agm does not antagonize physiologically relevant levels of AGM tetherin/BST-2. AGM tetherin/BST-2 can be induced by low levels of type I interferon and can potently restrict two independent strains of SIV agm . Although SIV agm Nef had an effect at low levels of AGM tetherin/BST-2, simian immunodeficiency virus SIV mus Vpu, from a virus that infects the related monkey Cercopithecus cephus, is able to antagonize even at high levels of AGM tetherin/BST-2 restriction. We propose that since the replication of SIV agm does not induce interferon production in vivo, tetherin/BST-2 is not induced, and therefore, SIV agm does not need Vpu. This suggests that primate lentiviruses evolve tetherin antagonists such as Vpu or Nef only if they encounter tetherin during the typical course of natural infection.

The Presence of a vpu Gene and the Lack of Nef-Mediated Downmodulation of T Cell Receptor-CD3 Are Not Always Linked in Primate Lentiviruses

“…One possible explanation for this seeming controversy is that primate lentiviruses that induce high levels of inflammation may need particularly effective tetherin antagonists. In accordance with this, the Vpu proteins of pathogenic HIV-1 strains seem to be more effective in counteracting tetherin than the Nef proteins of the nonpathogenic SIVagm and SIVsmm strains (26,33,48,63,64). However, it should be noted that the efficiency of tetherin antagonism of primate lentiviruses in primary cells and its relevance in vivo (46) remain largely unknown, since most data thus far are limited to transient transfection assays.…”

“…It has been reported that some primate lentiviruses, such as SIVagm, did not evolve tetherin antagonists because they do not induce chronic immune activation, and thus expression of type I interferons and tetherin, in their natural simian hosts (33). In contrast, we and others have shown that the SIVagm and SIVsmm Nef proteins are tetherin antagonists (26,48,64), although these viruses cause neither chronic inflammation nor disease in their natural African green monkey and sooty mangabey hosts (reviewed in references 42 and 54).…”

Ancient Adaptive Evolution of Tetherin Shaped the Functions of Vpu and Nef in Human Immunodeficiency Virus and Primate Lentiviruses

“…Human, chimpanzee, gorilla, C. cephus, and Francois' leaf monkey Tetherins were cloned from the cDNAs of the respective species and were ligated into a pLPCX lentiviral expression vector as untagged constructs, as described previously (24). Codon-optimized HIV-1 Lai Vpu was a gift from Stephan Bour (32), and codon-optimized HIV-1 Q23-17 Vpu, SIVcpzUS Vpu, SIVcpzUS Nef, SIVcpzTan3.1 Vpu, SIVgor Vpu, and SIVgor Nef were synthesized (GenScript).…”

“…Tetherin, also known as BST-2 or CD317, is an example of such an intrinsic antiviral protein that inhibits virus release by anchoring in the envelope of budding virions and directly tethering virions to the plasma membrane (35). This relatively nonspecific antiviral mechanism allows Tetherin to potently restrict a wide array of viruses, including human immunodeficiency virus (HIV) and other primate lentiviruses (16,17,24,31,39,51).…”

The HERV-K Human Endogenous Retrovirus Envelope Protein Antagonizes Tetherin Antiviral Activity

“…Numerous examples of independent viral proteins able to counteract Tetherin have been described in different viral families, suggesting it is important for viruses to escape its action. They include so-called accessory proteins, such as Vpu (from HIV-1 and some simian immunodeficiency virus [SIV] strains [20,32,33]) and Nef (in several SIV strains [33][34][35][36]), the ubiquitin ligase K5 from human herpesvirus 8 (HHV8) (37)(38)(39), and also glycoproteins, including retroviral Env proteins (e.g., in HIV-2 [40], some SIV strains [41], feline immunodeficiency virus [FIV] [42][43][44], and equine infectious anemia virus [EIAV] [45]) as well as Ebola glycoprotein (46). The mechanisms of action of these proteins are diverse and not always fully understood, but all result in restoring virus release.…”