Regulation of Porcine Endogenous Retrovirus Release by Porcine and Human Tetherins

SUMMARY Xenotransplantation may be a solution to overcome the shortage of organs for the treatment of patients with organ failure, but it may be associated with the transmission of porcine microorganisms and the development of xenozoonoses. Whereas most microorganisms may be eliminated by pathogen-free breeding of the donor animals, porcine endogenous retroviruses (PERVs) cannot be eliminated, since these are integrated into the genomes of all pigs. Human-tropic PERV-A and -B are present in all pigs and are able to infect human cells. Infection of ecotropic PERV-C is limited to pig cells. PERVs may adapt to host cells by varying the number of LTR-binding transcription factor binding sites. Like all retroviruses, they may induce tumors and/or immunodeficiencies. To date, all experimental, preclinical, and clinical xenotransplantations using pig cells, tissues, and organs have not shown transmission of PERV. Highly sensitive and specific methods have been developed to analyze the PERV status of donor pigs and to monitor recipients for PERV infection. Strategies have been developed to prevent PERV transmission, including selection of PERV-C-negative, low-producer pigs, generation of an effective vaccine, selection of effective antiretrovirals, and generation of animals transgenic for a PERV-specific short hairpin RNA inhibiting PERV expression by RNA interference.

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“…However, overexpression of either human or porcine tetherin in pig cells significantly reduced PERV production (205).…”

Section: Pervsmentioning

confidence: 99%

Infection Barriers to Successful Xenotransplantation Focusing on Porcine Endogenous Retroviruses

2012

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“…In fact, inhibition of virus release by BST-2 is not HIV-1 specific but affects other lentiviruses, such as HIV-2 and simian immunodeficiency virus (SIV), as well as a wide variety of enveloped viruses, including Ebola virus, Lassa virus, Marburg virus, Kaposi sarcoma-associated herpesvirus (KSHV), porcine endogenous retrovirus (PERV), and endogenous betaretrovirus of sheep (18)(19)(20)(21)(22)(23). Three different lentiviral proteins, HIV-1 Vpu, HIV-2 Env, and SIV Nef, have been found to antagonize the activity of their natural host, BST-2, thus allowing for efficient particle release from BST-2-expressing cells.…”

mentioning

confidence: 99%

Functional Antagonism of Rhesus Macaque and Chimpanzee BST-2 by HIV-1 Vpu Is Mediated by Cytoplasmic Domain Interactions

Yoshida

Koyanagi

Strebel

2013

J Virol

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bHuman immunodeficiency virus type 1 (HIV-1) Vpu enhances the release of viral particles from infected cells by interfering with the function of BST-2/tetherin, a cellular protein inhibiting virus release. The Vpu protein encoded by NL4-3, a widely used HIV-1 laboratory strain, antagonizes human BST-2 but not monkey or murine BST-2, leading to the conclusion that BST-2 antagonism by Vpu is species specific. In contrast, we recently identified several primary Vpu isolates, such as Vpu of HIV-1 DH12 , capable of antagonizing both human and rhesus BST-2. Here we report that while Vpu interacts with human BST-2 primarily through their respective transmembrane domains, antagonism of rhesus BST-2 by Vpu involved an interaction of their cytoplasmic domains. Importantly, a Vpu mutant carrying two mutations in its transmembrane domain (A 14 L and W 22 A), rendering it incompetent for interaction with human BST-2, was able to interact with human BST-2 carrying the rhesus BST-2 cytoplasmic domain and partially neutralized the ability of this BST-2 variant to inhibit viral release. Bimolecular fluorescence complementation analysis to detect Vpu-BST-2 interactions suggested that the physical interaction of Vpu with rhesus or chimpanzee BST-2 involves a 5-residue motif in the cytoplasmic domain of BST-2 previously identified as important for the antagonism of monkey and great ape BST-2 by simian immunodeficiency virus (SIV) Nef. Thus, our study identifies a novel mechanism of antagonism of monkey and great ape BST-2 by Vpu that targets the same motif in BST-2 used by SIV Nef and might explain the expanded host range observed for Vpu isolates in our previous study.

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“…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).…”

mentioning

confidence: 99%

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

Yin

et al. 2014

J Virol

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Human tetherin is a host restriction factor that inhibits replication of enveloped viruses by blocking viral release. Tetherin has an unusual topology that includes an N-terminal cytoplasmic tail, a single transmembrane domain, an extracellular domain, and a C-terminal glycosylphosphatidylinositol anchor. Tetherin is not well conserved across species, so it inhibits viral replication in a species-specific manner. Thus, studies of tetherin activities from different species provide an important tool for understanding its antiviral mechanism. Here, we report cloning of equine tetherin and characterization of its antiviral activity. Equine tetherin shares 53%, 40%, 36%, and 34% amino acid sequence identity with feline, human, simian, and murine tetherins, respectively. Like the feline tetherin, equine tetherin has a shorter N-terminal domain than human tetherin. Equine tetherin is localized on the cell surface and strongly blocks human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus (SIV), and equine infectious anemia virus (EIAV) release from virus-producing cells. The antiviral activity of equine tetherin is neutralized by EIAV envelope protein, but not by the HIV-1 accessory protein Vpu, which is a human tetherin antagonist, and EIAV envelope protein does not counteract human tetherin. These results shed new light on our understanding of the species-specific tetherin antiviral mechanism.

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Regulation of Porcine Endogenous Retrovirus Release by Porcine and Human Tetherins

Cited by 42 publications

References 26 publications

Infection Barriers to Successful Xenotransplantation Focusing on Porcine Endogenous Retroviruses

Infection Barriers to Successful Xenotransplantation Focusing on Porcine Endogenous Retroviruses

Functional Antagonism of Rhesus Macaque and Chimpanzee BST-2 by HIV-1 Vpu Is Mediated by Cytoplasmic Domain Interactions

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

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