Feline Tetherin Efficiently Restricts Release of Feline Immunodeficiency Virus but Not Spreading of Infection

Abstract

Innate resistance to retroviral infection and replication is induced by interferons (IFNs). IFN-inducible factors restricting viral replication include the cytidine deaminase APOBEC3G (40, 60) and the E3 ubiquitin ligase TRIM5 (1), both of which target replication primarily during the process of viral entry. A third IFN-inducible activity, tetherin (BST-2/ CD317/HM1.24), acts to restrict viral release (13,35,36,41,62). The importance of these factors in controlling viral replication is underlined by the requirement for lentiviral genomes to encode trans-acting countermeasures; lentiviral Vif proteins (33,54,55) and spumaviral Bet proteins (28, 42, 51) counteract APOBECs whereas HIV-1 Vpu, HIV-2 Nef, and HIV-2 and simian immunodeficiency virus (SIV) Envs may counteract tetherins (15,18,26,35,36,62,65).Tetherin is a type II single-pass transmembrane protein. It is anchored to the cell membrane by both N-terminal transmembrane domain and C-terminal glycophosphatidylinositol (GPI) anchors that are linked by an extracellular coiled-coil domain that promotes dimerization of adjacent tetherin molecules. Accordingly, tetherin in both the cell membrane and the envelope of the budding virus can prevent virion release either by direct cross-linking or by the formation of dimers between adjacent coiled-coil domains (41). The primary role for tetherin remains unclear; however, it is likely that, by trapping enveloped viruses at the cell surface, tetherin prevents the further dissemination of nascent virions. However, given the constitutive high-level expression of tetherin on plasmacytoid dendritic cells (pDC [type I IFN-producing cells]) (5), tetherin may play a more fundamental role in the initiation and perpetuation of a virus-specific immune response (58).The domestic cat lineage has faced multiple invasions by viruses from the family Retroviridae. In addition to an exogenous gammaretrovirus (feline leukemia virus [FeLV]), a lentivirus (feline immunodeficiency virus [FIV]), and a spumavirus (feline foamy virus [FFV]), cats also harbor the endogenous RD114 gamma retrovirus (47, 48) and full-length endogenous FeLVs (50). While lentiviruses have spread throughout the Felidae, from lions in Africa to pumas in North America and Pallas cats in Mongolia (61), the gamma retroviruses are restricted solely to domestic cats (3,4,47,48), although occasional cross-species transmission events have been recorded in Florida panthers (37) and Iberian lynxes (30). The limited distribution of the gamma retroviruses among felids suggests that they entered the domestic cat population after the divergence of the Felis lineage from the other felids circa 6.2 million years ago (19). The presence of three exogenous members and one endogenous member of the Retroviridae in domestic cats offers an intriguing insight into the retrovirus-host interaction. As cats express a truncated TRIM5 lacking a capsid-binding B30.2/SPRY domain (29), their ability to suppress retroviral replication may be impaired. If tetherin is to have a major role in the contro...

How Samhd1 changes our view of viral restriction

“…Therefore, because HIV-1 cannot counteract SAMHD1, it seems that, in contrast to other restriction factors, overcoming SAMHD1 is dispensable for efficient HIV-1 spread. This is in contrast, for example, to BST-2, because BST-2 nonspecifically targets the lipidic outlayer of enveloped viruses and has a broad impact on viral release [33][34][35][36][37][38][39][40][41]. Consequently, viruses have evolved distinct means to counteract this hurdle to viral budding.…”

Refrex-1, a Soluble Restriction Factor against Feline Endogenous and Exogenous Retroviruses

“…For example, the Fv-4 gene in mice encodes a full-length Env protein which closely resembles ecotropic murine leukemia virus (MLV) and confers resistance to ecotropic MLV infection by receptor interference (19,20). Host defense against retroviral infection is common, and feline APOBEC and BST-2 are known to function as retroviral restriction factors in cats (21)(22)(23). Interestingly, feline TRIM5 lacks antiretroviral activity (24).…”

Equine Tetherin Blocks Retrovirus Release and Its Activity Is Antagonized by Equine Infectious Anemia Virus Envelope Protein

“…Cells were treated for 24 h with or without 1,000 units/ml alpha interferon (IFN-␣) (Kingfisher Biotech), and the total RNA was extracted as described above. One hundred nanograms of total RNA was subjected to reverse transcription using SuperScript II reverse transcriptase and oligo(dT) [12][13][14][15][16][17][18] as a primer (Invitrogen). Synthesized cDNAs were then subjected to real-time PCR using a SYBR green Master Mix kit (Invitrogen) according to the manufacturer's protocols.…”

“…Later, it was found that human tetherin has very broad antiviral activities, which also target many other enveloped viruses, including retroviruses, filoviruses, arenaviruses, paramyxoviruses, herpesviruses, and rhabdoviruses (2)(3)(4)(5)(6)(7)(8)(9). Human tetherin orthologs have been isolated from several other species, including monkey, cat, pig, mouse, cattle, and sheep, which all show similar antiviral activities (10)(11)(12)(13)(14)(15)(16)(17).…”