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immunological response in cynomolgus macaques to porcine α-1,3 galactosyltransferase knockout viable skin xenotransplants-a pre-clinical study.allogeneic skin recovered from human deceased donors (hdd) has been a mainstay interim treatment for severe burns, but unfortunately risk of infectious disease and availability limitations exist. genetically engineered ɑ-1,3 galactosyltransferase knockout (galt-ko) porcine source animals for viable skin xenotransplants may provide a promising clinical alternative.202032781479
novel spheroid reservoir bioartificial liver improves survival of nonhuman primates in a toxin-induced model of acute liver failure.this study aims to evaluate the effectiveness and safety of the spheroid reservoir bioartificial liver (srbal) with porcine hepatocyte organoids in a preclinical nonhuman primate model of acute liver failure (alf). methods: thirty healthy rhesus monkeys were infused with α-amanitin and lipopolysaccharide and randomized into five groups (alf alone control group; sham no-cell srbal treatment group; groups a, b and c with srbal treatment started at 12 h, 24 h and 36 h after induction of alf, respec ...201830555564
long-term safety from transmission of porcine endogenous retrovirus after pig-to-non-human primate corneal transplantation.the risk of xenozoonosis mainly by porcine endogenous retrovirus (perv) has been considered as one of the main hurdles in xenotransplantation and therefore should be elucidated prior to the clinical use of porcine corneal grafts. accordingly, an investigation was performed to analyze the infectivity of pervs from porcine keratocytes to human cells, and the long-term risk of transmission of pervs was determined using pig-to-non-human primate (nhp) corneal transplantation models.201728503733
can antiretroviral drugs be used to treat porcine endogenous retrovirus (perv) infection after xenotransplantation?porcine endogenous retroviruses (pervs) are integrated in the genome of all pigs; they are released as infectious particles, and under certain conditions they can infect human cells. therefore, they represent a risk when pigs are used as sources of cells, tissues, or organs for xenotransplantation. xenotransplantation is under development due to the increasing shortage of human transplants. whereas most porcine microorganisms which may be able to induce a disease (zoonosis) in the transplant rec ...201728786944
inactivation of porcine endogenous retrovirus in pigs using crispr-cas9.xenotransplantation is a promising strategy to alleviate the shortage of organs for human transplantation. in addition to the concern on pig-to-human immunological compatibility, the risk of cross-species transmission of porcine endogenous retroviruses (pervs) has impeded the clinical application of this approach. earlier, we demonstrated the feasibility of inactivating perv activity in an immortalized pig cell line. here, we confirmed that pervs infect human cells, and observed the horizontal t ...201728798043
characterization of porcine endogenous retrovirus expression in neonatal and adult pig pancreatic islets.pig islets represent an alternative to the current modes of treatment for patients with diabetes. however, the concerns over pathogen transmission including that of perv limit their immediate, widespread usage in humans. it has been previously demonstrated that perv copy number and particularly expression levels can vary considerably between individuals and within different tissues of a single animal. in general, expression levels have been found to be particularly low in the pancreas compared t ...201728444910
three cysteine residues of slc52a1, a receptor for the porcine endogenous retrovirus-a (perv-a), play a critical role in cell surface expression and infectivity.porcine endogenous retrovirus-a (perv-a), a gammaretrovirus, infects human cells in vitro, thus raising the potential risk of cross-species transmission in xenotransplantation. two members of the solute carrier family 52 (slc52a1 and slc52a2) are perv-a receptors. site-directed mutagenesis of the cdna encoding slc52a1 identified that only one of two putative glycosylation signals is occupied by glycans. in addition, we showed that glycosylation of slc52a1 is not necessary for perv-a receptor fun ...201728437635
the resurgence of xenotransplantation.there has been an upsurge of interest in xenotransplantation in recent years. this resurgence can attributed to a combination of factors. first, there has been a dramatic improvement in efficacy in several preclinical models, with maximum xenograft survival times increasing to 950 days for islets, 945 days for hearts, and 310 days for kidneys. second, the rapid development of genome editing technology (particularly the advent of clustered regularly interspaced short palindromic repeats/cas9) has ...201728397351
transmission of porcine endogenous retrovirus produced from different recipient cells in vivo.humanized pigs have been developed to reduce the incidence of immune rejection in xenotransplantation, but significant concerns remain, such as transmission of viral zoonosis. porcine endogenous retroviruses (perv), which exist in the genome of pigs, are produced as infectious virions from all porcine cells and cause zoonosis. here, we examined the possibility of zoonosis of hosts under conditions of immune suppression or xenotransplantation of cells producing host-adapted viruses. upon transpla ...201627832080
new phase of growth for xenogeneic-based bioartificial organs.in this article, we examine the advanced clinical development of bioartificial organs and describe the challenges to implementing such systems into patient care. the case for bioartificial organs is evident: they are meant to reduce patient morbidity and mortality caused by the persistent shortage of organs available for allotransplantation. the widespread introduction and adoption of bioengineered organs, incorporating cells and tissues derived from either human or animal sources, would help ad ...201627657057
chemiluminescent detection for estimating relative copy numbers of porcine endogenous retrovirus proviruses from chinese minipigs based on magnetic nanoparticles.chinese bama minipigs could be potential donors for the supply of xenografts because they are genetically stable, highly inbred, and inexpensive. however, porcine endogenous retrovirus (perv) is commonly integrated in pig genomes and could cause a cross-species infection by xenotransplantation. for screening out the pigs with low copy numbers of perv proviruses, we have developed a novel semiquantitative analysis approach based on magnetic nanoparticles (mnps) and chemiluminescence (cl) for esti ...201627427744
susceptibility of porcine endogenous retrovirus to anti-retroviral inhibitors.porcine endogenous retrovirus (perv) is an endogenous retrovirus that poses a risk of iatrogenic transmission in the context of pig-to-human xenotransplantation. the lack of a means to control perv infection in the context of pig-to-human xenotransplantation is a major concern in the field. in this study, we set out to evaluate the ability of currently licensed anti-hiv drugs, and other types of anti-retroviral compounds, to inhibit perv infection in vitro.201627028725
current status and future of clinical islet xenotransplantation.β-cell replacement therapy, including allogeneic pancreas and islet transplantation, can normalize hba1c levels in unstable type 1 diabetic (t1d) patients, but a donor shortage is a serious issue. to overcome this problem, xenotransplantation is an attractive option. in fact, islet transplantation from porcine pancreata was performed in the 1990s, which opened the door for islet xenotransplantation, but the possibility of porcine endogenous retrovirus (perv) infection was raised, which has restr ...201626987992
first update of the international xenotransplantation association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--chapter 2a: source pigs--preventing xenozoonoses.chapter 2 of the original consensus statement published in 2009 by ixa represents an excellent basis for the production of safe donor pigs and pig-derived materials for porcine islet xenotransplantation. it was intended that the consensus statement was to be reviewed at interval to remain relevant. indeed, many of the original salient points remain relevant today, especially when porcine islet xenotransplantation is performed in conjunction with immunosuppressants. however, progress in the field ...201626940608
characterization of complete genome sequences of a porcine endogenous retrovirus isolated from china bama minipig reveals an evolutionary time earlier than that of isolates from european minipigs.a porcine endogenous retroviruses (perv) isolate, perv-a-bm, was isolated from a guangxi bama minipig in china.201626915872
computational evaluation of the strict master and random template models of endogenous retrovirus evolution.transposable elements (tes) are dna sequences that are able to replicate and move within and between host genomes. their mechanism of replication is also shared with endogenous retroviruses (ervs), which are also a type of te that represent an ancient retroviral infection within animal genomes. two models have been proposed to explain te proliferation in host genomes: the strict master model (smm), and the random template (or transposon) model (tm). in smm only a single copy of a given te lineag ...201627649303
first update of the international xenotransplantation association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--chapter 5: recipient monitoring and response plan for preventing disease transmission.xenotransplantation of porcine cells, tissues, and organs may be associated with the transmission of porcine microorganisms to the human recipient. a previous, 2009, version of this consensus statement focused on strategies to prevent transmission of porcine endogenous retroviruses (pervs). this version addresses potential transmission of all porcine microorganisms including monitoring of the recipient and provides suggested approaches to the monitoring and prevention of disease transmission. pr ...201626918415
induction of perv antigen in porcine peripheral blood mononuclear cells by human herpesvirus 1.xenotransplantation represents one of alternative candidates for allotransplantation due to the chronic shortage of suitable human tissues; however, many obstacles remain. expression and release of endogenous retroviral antigens by porcine cells after transplantation may evoke adverse immune responses in human subjects. here, we examined whether human herpesvirus 1 (hhv-1) could induce the production of porcine endogenous retrovirus (perv) antigens in porcine peripheral blood mononuclear cells ( ...201525716804
complete genome sequence of a porcine endogenous retrovirus isolated from a bama minipig in guangxi, southern china.a porcine endogenous retrovirus (perv) strain, perv-a-bm, was isolated from a bama minipig in guangxi, china. this is the first entire genome sequence of perv isolated from guangxi bama minipigs. the isolate is closely related to isolates from wuzhishan miniature pigs and distantly related to isolates from large white pigs.201526067965
comparison between s+l- assay and lacz marker rescue assay for detecting replication-competent gammaretroviruses.to avoid contamination of adventitious gammaretroviruses in biological products such as vaccines, it is necessary to check the master seed cells for manufacturing. there are several assays to detect infectious gammaretroviruses. among these, sarcoma-positive, leukemia-negative (s+l-) assay is a classical infectivity assay, which is often recommended in governmental guidelines. the s+l- cells used in s+l- assay generate unique focus upon the infection of replication-competent gammaretroviruses. a ...201526164289
mutations altering the gammaretrovirus endoproteolytic motif affect glycosylation of the envelope glycoprotein and early events of the virus life cycle.previously, we found that mutation of glutamine to proline in the endoproteolytic cleavage signal of the perv-c envelope (rqkk to rpkk) resulted in non-infectious vectors. here, we show that rpkk results in a non-infectious vector when placed in not only a perv envelope, but also the envelope of a related gammaretrovirus, felv-b. the amino acid substitutions do not prevent envelope precursor cleavage, viral core and genome assembly, or receptor binding. rather, the mutations result in the format ...201525462351
no transmission of porcine endogenous retrovirus in an acute liver failure model treated by a novel hybrid bioartificial liver containing porcine hepatocytes.a novel hybrid bioartificial liver (hbal) was constructed using an anionic resin adsorption column and a multi-layer flat-plate bioreactor containing porcine hepatocytes co-cultured with bone marrow mesenchymal stem cells (mscs). this study aimed to evaluate the microbiological safety of the hbal by detecting the transmission of porcine endogenous retroviruses (pervs) into canines with acute liver failure (alf) undergoing hbal.201526459725
a study on the susceptibility of allogeneic human hepatocytes to porcine endogenous retrovirus.porcine endogenous retrovirus (perv) is a virus that can be integrated into porcine genome. it has been proved that perv can infect the cells of a variety of species. however, little is known about the infectivity of perv to human hepatocytes. the present study focused on the susceptibility of primary human hepatocytes to perv.201526439047
regulatory aspects of clinical xenotransplantation.xenotransplantation attracted interest from regulatory authorities, particularly after the demonstration of pig-to-human transmission of porcine endogenous retrovirus (1996). this added to the risk of a product, resulting in a guidance of the us food and drug administration (2003). this addresses the full flow chart in product manufacturing, starting with the designated pathogen-free status of the source animal; and special aspects regarding the recipient like informed consent and monitoring for ...201526408947
ultrasensitive detection and subtyping of porcine endogenous retrovirus provirus based on magnetic nanoparticles and chemiluminescence.porcine endogenous retrovirus (perv) is commonly integrated in pig genomes, and could cause a cross-species infection by xenotransplantation. in this study, we developed a rapid and ultrasensitive approach for detection and subtyping of perv provirus based on magnetic nanoparticles (mnps) and chemiluminescence (cl). the carboxylated mnps (cmnps) were covalently coupled with aminated probes for capturing biotinylated target fragments of perv, the product of polymerase chain reaction (pcr). agaros ...201526369124
distribution of porcine endogenous retrovirus in different organs of the hybrid of a landrace and a jeju domestic pig in korea.xenotransplantation offers a solution to the shortage of available organs for transplantation, and the pig represents an ideal source of such organs. however, porcine endogenous retrovirus (perv), whose genome is integrated in pigs, has been suggested to pose a potential risk of xenotransmission. expression of pervs in different organs of pigs was carefully measured at dna, mrna, and protein levels, providing information valuable for the application of pig organs in xenotransplantation. an analy ...201526293098
tolerance and immune response to the porcine endogenous retrovirus in german landrace pigs immunised with viral proteins.immunisation of goats, mice, rats, rabbits, guinea pigs, and hamsters with the recombinant ectodomain of the porcine endogenous retrovirus (perv) transmembrane envelope (tm) protein (p15e) induced binding and neutralising immune antibodies in all animals. in contrast, no antibodies were induced when pigs were immunised with p15e, indicating that pigs are tolerant to their endogenous retroviruses, at least to the tm protein. to answer the question of whether pigs are tolerant to other structural ...201526043980
differential sensitivity of porcine endogenous retrovirus to apobec3-mediated inhibition.pigs are considered to be suitable xenotransplantation organ donors. however, the risk of pathogen transmission from pigs to humans is a major concern in the transplantation of porcine tissues. the porcine endogenous retroviruses (pervs) perv-a, perv-a/c, and perv-b can infect human cells, but perv-c is an ecotropic virus infecting only pig cells. thus, several strategies have been proposed to reduce perv transmission in xenograft recipients. human apobec3g (hua3g) is a single-strand dna cytosin ...201526016442
xenotransplantation literature update, march-april 2015. 201525988427
identification of porcine endogenous retrovirus (perv) packaging sequence and development of perv packaging viral vector system.studies of the retroviruses have focused on the specific interaction of the nucleocapsid protein with a packaging signal in the viral rna as important for this selectivity, but the packaging signal in porcine endogenous retrovirus (perv) has not been defined. herein, we identified and analyzed this packaging signal in perv and found hairpin structures with conserved tetranucleotides in their loops and nucleocapsid recognition sequences; both of which are key elements in the viral packaging signa ...201525935307
cytotoxic effects during knock out of multiple porcine endogenous retrovirus (perv) sequences in the pig genome by zinc finger nucleases (zfn).xenotransplantation has been proposed as a solution to the shortage of suitable human donors for transplantation and pigs are currently favoured as donor animals. however, xenotransplantation may be associated with the transmission of zoonotic microorganisms. whereas most porcine microorganisms representing a risk for the human recipient may be eliminated by designated pathogen free breeding, multiple copies of porcine endogenous retroviruses (pervs) are integrated in the genome of all pigs and ...201525909512
review on porcine endogenous retrovirus detection assays--impact on quality and safety of xenotransplants.xenotransplantation of porcine organs, tissues, and cells inherits a risk for xenozoonotic infections. viable tissues and cells intended for transplantation have to be considered as potentially contaminated non-sterile products. the demands on microbial testing, based on the regulatory requirements, are often challenging due to a restricted shelf life or the complexity of the product itself. in europe, the regulatory framework for xenogeneic cell therapy is based on the advanced therapy medicina ...201525641488
porcine endogenous retrovirus infection of human peripheral blood mononuclear cells. 201525511997
porcine endogenous retrovirus-a/c: biochemical properties of its integrase and susceptibility to raltegravir.porcine endogenous retroviruses (pervs) are present in the genomes of pig cells. the perv-a/c recombinant virus can infect human cells and is a major risk of zoonotic disease in the case of xenotransplantation of pig organs to humans. raltegravir (ral) is a viral integrase (in) inhibitor used in highly active antiretroviral treatment. in the present study, we explored the potential use of ral against perv-a/c. we report (i) a three-dimensional model of the perv-a/c intasome complexed with ral, ( ...201526296914
clinical porcine islet xenotransplantation under comprehensive regulation.xenotransplantation with porcine islets is a promising approach to overcome the shortage of human donors. this is the first report of phase 1/2a xenotransplantation study of encapsulated neonatal porcine islets under the current framework of regulations for xenotransplantation in new zealand.201425131091
microarray analysis of retroviral restriction factor gene expression in response to porcine endogenous retrovirus infection.microarray analysis has been used for screening genes involved in specific biological processes. many studies have shown that restriction factors may play an important role in xenotransplantation safety, but it is still unclear whether porcine endogenous retroviruses (pervs) may be inhibited by these factors. therefore, the present study focused on the microarray analysis retroviral restriction factors gene expression in normal human dermal fibroblasts (nhdfs) in response to pervs. perv infectiv ...201425115112
differential expression of tripartite motif-containing family in normal human dermal fibroblasts in response to porcine endogenous retrovirus infection.antiretroviral restriction factors may play an essential role in the safety of xenotransplantation. therefore, the present study focused on investigation of the changes in the tripartite motif-containing family (trim) gene expression in normal human dermal fibroblasts with and without lipopolysaccharide stimulation in response to porcine endogenous retrovirus infection. analysis of the expression profile of trims was performed using oligonucleotide microarrays and qrt-pcr. nine (trim1, trim2, tr ...201425056437
no expression of porcine endogenous retrovirus after pig to monkey xenotransplantation.this study was performed to investigate the expression of two porcine endogenous retrovirus (perv) elements, perv gag and full-length conserved perv, in blood cells collected periodically from organ-recipient monkeys that underwent pig to non-human primate xenotransplantation. the heart and kidney-respectively acquired from α-1,3-galactosyltransferase knockout (gt-ko) pigs that survived for24 and 25 days-were xenografted into cynomolgus monkeys. the two perv elements expressed in the xenografted ...201424999364
inhibition of budding/release of porcine endogenous retrovirus.perv is integrated into the genome of all pigs. perv-a and perv-b are polytropic and can productively infect human cell lines, whereas perv-c is ecotropic. recombinant perv-a/c can infect human cells and exhibits high titer replication. therefore, use of pigs for human xenotransplantation raises concerns about the risks of transfer of this infectious agent from donors to xenotransplantation recipients. to establish strategies to inhibit perv production from cells, in the present study, we invest ...201424931347
lack of antibody response in pigs immunized with the transmembrane envelope protein of porcine endogenous retroviruses.recently, we immunized different mammalian species (goats, mice, rats, rabbits, guinea pigs and hamsters) with the recombinant ectodomain of the transmembrane envelope (tm) protein p15e of porcine endogenous retrovirus (perv). in all cases, neutralizing immune sera were induced, which recognized epitopes in the fusion peptide proximal region and the membrane proximal external region of p15e. in order to analyse whether pigs are also able to produce such antibodies, and whether such antibodies ca ...201424828332
microbiological safety of the first clinical pig islet xenotransplantation trial in new zealand.xenotransplantation using pig cells, tissues, or organs may be associated with the transmission of porcine microorganisms and the development of zoonoses. among all porcine microorganisms porcine endogenous retroviruses (pervs) represent a special risk because they are integrated in the genome of all pigs and able to infect human cells. in previous preclinical and retrospective clinical trials of xenotransplantation, no transmission of perv was observed. the first clinical trial of (alginate-enc ...201424801820
tetherins of various species inhibit the release of porcine endogenous retrovirus from human cells.pigs are considered as suitable xenotransplantation organ donors. however, the risk of pathogen transmission from pigs to human is a major concern in the transplantation of porcine tissues since it had been shown that porcine endogenous retroviruses (pervs) can infect human cells. tetherin has recently been described as a host restriction factor that blocks the release of virus particles from cells infected with some enveloped viruses. we compared tetherins derived from various species in their ...201424717029
detection of porcine endogenous retrovirus in xenotransplantation.xenotransplantation can provide a virtually limitless supply of cells, tissues and organs for a variety of therapeutic procedures. cells and tissues for use in human transplantation procedures could be supplied using material taken from pigs. however, there is a potential risk of transmission of porcine infectious agents, including porcine endogenous retroviruses (pervs), to a novel human host, with as yet unknown consequences. three subtypes of perv have been identified, of which both perv-a an ...201424607257
porcine endogenous retrovirus (perv) infection of hek-293 cell line alters expression of human endogenous retrovirus (herv-w) sequences.the risk of infections of human recipients after xenotransplantations is now mainly represented by porcine endogenous retroviruses (pervs) as these particles are part of the porcine genome. as in all vertebrates, human genome harbours its own numerous genetic sequences of retroviral origin; it is estimated that they comprise about 8 % of the human genome. because some of them play an important role in human physiology, it is valuable to estimate whether the presence of pervs in human cells influ ...201424594055
comparison of the effects of retroviral restriction factors involved in resistance to porcine endogenous retrovirus.three major classes of retroviral restriction factors (apobec3g, tetherin, and trim5α) have been identified in mammals. restriction factors are cellular proteins that are able to limit viral replication by targeting specific steps of the viral life cycle. to evaluate which restriction factor is the most effective to inhibit the replication of porcine endogenous retroviruses (pervs), the antiviral activity of each restriction factor was compared. in pseudotype assay, the antiviral activity of hum ...201424448163
comparison of porcine endogenous retroviruses infectious potential in supernatants of producer cells and in cocultures.porcine endogenous retroviruses (perv) pose a zoonotic risk potential in pig-to-human xenotransplantation given that perv capacity to infect different human cell lines in vitro has been clearly shown in the past. however, perv infectious potential for human peripheral blood mononuclear cells (hupbmc) has been also demonstrated, albeit with controversial results. as productive perv infection of hupbmc involves immune suppression that may attract opportunistic pathogens as shown for other retrovir ...201424447212
ghb receptor targets in the cns: focus on high-affinity binding sites.γ-hydroxybutyric acid (ghb) is an endogenous compound in the mammalian brain with both low- and high-affinity receptor targets. ghb is used clinically in the treatment of symptoms of narcolepsy and alcoholism, but also illicitly abused as the recreational drug fantasy. major pharmacological effects of exogenous ghb are mediated by gaba subtype b (gabab) receptors that bind ghb with low affinity. the existence of ghb high-affinity binding sites has been known for more than three decades, but the ...201424269284
optimization of virus detection in cells using massively parallel sequencing.massively parallel sequencing (mps)-based virus detection has potential regulatory applications. we studied the ability of one of these approaches, based on degenerate oligonucleotide primer (dop)-polymerase chain reaction (pcr), to detect viral sequences in cell lines known to express viral genes or particles. dop-pcr was highly sensitive for the detection of small quantities of isolated viral sequences. detected viral sequences included nodavirus, bracovirus, and endogenous retroviruses in hig ...201424309095
quantitative detection of residual porcine host cell dna by real-time pcr.all biological products are derived from complex living systems and are often mixed with large numbers of impurities. for reasons of safety, residual host-cell dna must be eliminated during processing. to assay host-cell dna content in biopharmaceutical products derived from porcine sources, this study applies the quantitative real-time polymerase chain reaction (q-pcr) method. the optimized assay in this study is based on the pol region of the porcine endogenous retrovirus (perv). assay validat ...201424394374
molecular evolution of the porcine type i interferon family: subtype-specific expression and antiviral activity.type i interferons (ifns), key antiviral cytokines, evolve to adapt with ever-changing viral threats during vertebrate speciation. due to novel pathogenic pressure associated with suidae speciation and domestication, porcine ifns evolutionarily engender both molecular and functional diversification, which have not been well addressed in pigs, an important livestock species and animal model for biomedical sciences. annotation of current swine genome assembly sscrofa10.2 reveals 57 functional gene ...201425372927
inhibition of porcine endogenous retrovirus in pk15 cell line by efficient multitargeting rna interference.to effectively suppress porcine endogenous retroviruses (perv)s, rnai technique was utilized. rnai is the up-to-date skill for gene knockdown which simultaneously multitargets both gag and pol genes critical for replication of pervs. previously, two of the most effective sirnas (gag2, pol2) were found to reduce the expression of pervs. concurrent treatment of these two sirnas (gag2+pol2) showed knockdown efficiency of up to 88% compared to negative control. however, despite the high initial knoc ...201424138389
novel neutralising antibodies targeting the n-terminal helical region of the transmembrane envelope protein p15e of the porcine endogenous retrovirus (perv).previously, immunising different species with the transmembrane envelope protein p15e of the porcine endogenous retrovirus (perv), neutralising antibodies were induced which recognised epitopes in the fusion peptide proximal region (fppr) and in the membrane-proximal external region (mper). only the mper-specific antibodies were shown to neutralise and these antibodies targeted epitopes in the mper similarly localised as the epitopes recognised by antibodies broadly neutralising hiv-1 such as 2f ...201423729215
ethical and regulatory guidelines in clinical trials of xenocorneal transplantation in korea; the korean xenocorneal transplantation consensus statement.to establish the consensus about the conditions for undertaking clinical trials in xenocorneal transplantation in korea, specific issues regarding the xenocorneal transplantation on ethical and regulatory aspects are addressed, and the guidelines to conduct clinical trial of the xenocorneal transplantation are proposed.201323683073
knockdown of porcine endogenous retroviruses by rna interference in chinese experimental miniature pig fibroblasts.the clinical application of porcine-derived xenotransplants is limited by the potential risk of infection due to the presence of porcine endogenous retrovirus (perv) in tissues, organs, and cells. the establishment of pig fibroblasts with low perv expression and without perv-c can provide a nuclear donor to generate a safer transgenic pig.201323498816
preparation of immunogen-reduced and biocompatible extracellular matrices from porcine liver.decellularized biologic matrices are plausible biomedical materials for the bioengineering in liver transplantation. however, one of the concerns for safe medical application is the lack of objective assessment of the immunogen within the materials and the in vivo immune responses to the matrices. the purpose of this study was the production of immunogen-reduced and biocompatible matrices from porcine liver. in the present study, 0.1% sds solution was effective for removing dna fragments and seq ...201323068617
long-term igg response to porcine neu5gc antigens without transmission of perv in burn patients treated with porcine skin xenografts.acellular materials of xenogenic origin are used worldwide as xenografts, and phase i trials of viable pig pancreatic islets are currently being performed. however, limited information is available on transmission of porcine endogenous retrovirus (perv) after xenotransplantation and on the long-term immune response of recipients to xenoantigens. we analyzed the blood of burn patients who had received living pig-skin dressings for up to 8 wk for the presence of perv as well as for the level and n ...201323945141
susceptibility of human liver cells to porcine endogenous retrovirus.the risk of porcine endogenous retrovirus infection is a major barrier for pig-to-human xenotransplant. porcine endogenous retrovirus, present in porcine cells, can infect many human and nonhuman primate cells in vitro, but there is no evidence available about in vitro infection of human liver cells. we investigated the susceptibility of different human liver cells to porcine endogenous retrovirus.201323901808
construction and characterization of an infectious replication competent clone of porcine endogenous retrovirus from chinese miniature pigs.xenotransplantation from animals has been considered to be a preferable approach to alleviate the shortage of human allografts. pigs are the most suitable candidate because of the anatomical and physiological similarities shared with humans as well as ethical concerns. however, it may be associated with the risk of transmission of infectious porcine pathogens. porcine endogenous retroviruses (pervs) are of particular concern because they have been shown to infect human cells in vitro. to date, r ...201323837947
promoter activity analysis and methylation characterization of ltr elements of pervs in nih miniature pig.the potential risk of porcine endogenous retrovirus (perv) transmission is an important issue in xenotransplantation (pig-to-human transplantation). long terminal repeats (ltrs) in perv elements show promoter activity that could affect neighboring functional genes. the methylation status and promoter activities of 3 ltr structures (perv-ltr1, ltr2, and ltr3 elements) belonging to the perv-a family were examined using luciferase reporter genes in human liver cell lines (hepg2 and hep3b). the perv ...201323832305
neutralization of porcine endogenous retrovirus by antibodies against the membrane-proximal external region of the transmembrane envelope protein.immunization of different species including goats, rats, hamsters and guinea pigs with the recombinant ectodomain of the transmembrane envelope (tm) protein p15e of porcine endogenous retrovirus (perv) has been shown to result in the production of virus-neutralizing antibodies. the sera recognize two groups of epitopes, one located in the fusion peptide-proximal region (fppr) and the second in the membrane-proximal external region (mper) of p15e. most interestingly, the epitopes in the mper are ...201323223617
immunising with the transmembrane envelope proteins of different retroviruses including hiv-1: a comparative study.the induction of neutralizing antibodies is a promising way to prevent retrovirus infections. neutralizing antibodies are mainly directed against the envelope proteins, which consist of two molecules, the surface envelope (su) protein and the transmembrane envelope (tm) protein. antibodies broadly neutralizing the human immunodeficiencvy virus-1 (hiv-1) and binding to the tm protein gp41 of the virus have been isolated from infected individuals. their epitopes are located in the membrane proxima ...201323249763
koala retroviruses: characterization and impact on the life of koalas.koala retroviruses (korv) have been isolated from wild and captive koalas in australia as well as from koala populations held in zoos in other countries. they are members of the genus gammaretrovirus, are most closely related to gibbon ape leukemia virus (galv), feline leukemia virus (felv) and porcine endogenous retrovirus (perv) and are likely the result of a relatively recent trans-species transmission from rodents or bats. the first korv to be isolated, korv-a, is widely distributed in the k ...201324148555
porcine endogenous retrovirus infection changes the expression of inflammation-related genes in lipopolysaccharide-stimulated human dermal fibroblasts.the present study focuses on explaining the interaction between porcine endogenous retroviruses (pervs) and human cells in inflammatory conditions. the differences in expression of selected inflammation-related genes in human dermal fibroblasts (nhdf) infected with pervs with and without lipopolysaccharide stimulation were identified.201324157628
improved pig donor screening including newly identified variants of porcine endogenous retrovirus-c (perv-c).porcine endogenous retroviruses (perv) are widely distributed in the genomes of pigs. perv-a and perv-b are present in all pigs. they infect human cells in vitro and therefore represent a risk for xenotransplantation when pig cells, tissues or organs are used. perv-c infects only pig cells and is not present in the genomes of all pigs. however, perv-a/c recombinants infecting human cells and characterized by high replication titers were found in pigs. to select perv-c-free animals that cannot ge ...201323053520
characterization of molecular clones of porcine endogenous retrovirus-a containing different numbers of u3 repeat boxes in the long terminal repeat region.when full-length molecular clones of porcine endogenous retrovirus (perv)-a and porcine endogenous retrovirus (perv)-b were passaged on human cells, an increase in the length of the long terminal repeat (ltr) was reported. a 39-bp repeat box in the ltr u3 region was multimerized dynamically upon replication, acting as a viral enhancer element that contains binding sites for nuclear transcription factor nf-y. to analyze the optimum number of 39-bp repeats for viral replication, molecular clones o ...201222343070
comparison of the convergent receptor utilization of a retargeted feline leukemia virus envelope with a naturally-occurring porcine endogenous retrovirus a.in vitro screening of randomized felv envelope libraries identified the cp isolate, which enters cells through hupar-1, one of two human receptors utilized by porcine endogenous retrovirus-a (perv-a), a distantly related gammaretrovirus. the cp and perv-a envs however, share little amino acid homology. their receptor utilization was examined to define the common receptor usage of these disparate viral envs. we demonstrate that the receptor usage of cp extends to hupar-2 but not to the porcine re ...201222405627
Characterization of porcine endogenous retrovirus clones from the NIH miniature pig BAC library.Pigs have been considered as donors for xenotransplantation in the replacement of human organs and tissues. However, porcine endogenous retroviruses (PERVs) might transmit new infectious disease to humans during xenotransplantation. To investigate PERV integration sites, 45 PERV-positive BAC clones, including 12 PERV-A, 16 PERV-B, and 17 PERV-C clones, were identified from the NIH miniature pig BAC library. The analysis of 12 selected full-length sequences of PERVs, including the long terminal r ...201221912484
emerging and re-emerging swine viruses.in the past two decades or so, a number of viruses have emerged in the global swine population. some, such as porcine reproductive and respiratory syndrome virus (prrsv) and porcine circovirus type 2 (pcv2), cause economically important diseases in pigs, whereas others such as porcine torque teno virus (ttv), now known as torque teno sus virus (ttsuv), porcine bocavirus (pbov) and related novel parvoviruses, porcine kobuvirus, porcine toroviruses (ptov) and porcine lymphotropic herpesviruses (pl ...201222225855
carbohydrate antigens.purpose of review: to summarize the current knowledge of carbohydrate antigens as related to xenotransplantation. the emphasis is on non-gal carbohydrate antigens identified in many institutes. in addition, several topics such as glycosyltransferase-transgenic pigs, innate cell receptors and porcine endogenous retrovirus (perv) will be discussed. recent findings: studies related to igb3 and neoantigens after knocking out galt (ggta1) were reviewed. available data do not support the conclusion th ...201222262104
transmission of zoonoses in xenotransplantation: porcine endogenous retroviruses from an immunological and molecular point of view.background and objectives: pigs offer an unlimited source of xenografts for humans. the use of transplants from animal origin offers a potential solution to the limited supply of human organs and tissues. however, like many other mammalian species, pigs harbor porcine endogenous retrovirus (perv), which are encoded in their genomic dna and are assumed to have been integrated into the porcine germ line more than 7.6 × 106 years ago and showing that the age correlates with the time of separation b ...201223897566
xenotransplantation-associated infectious risk: a who consultation.xenotransplantation carries the potential risk of the transmission of infection with the cells or tissues of the graft. the degree of risk is unknown in the absence of clinical trials. the clinical application of xenotransplantation has important implications for infectious disease surveillance, both at the national and international levels. preclinical data indicate that infectious disease events associated with clinical xenotransplantation from swine, should they occur, will be rare; data in h ...201222497509
viral metagenomic analysis of bushpigs (potamochoerus larvatus) in uganda identifies novel variants of porcine parvovirus 4 and torque teno sus virus 1 and 2.as a result of rapidly growing human populations, intensification of livestock production and increasing exploitation of wildlife habitats for animal agriculture, the interface between wildlife, livestock and humans is expanding, with potential impacts on both domestic animal and human health. wild animals serve as reservoirs for many viruses, which may occasionally result in novel infections of domestic animals and/or the human population. given this background, we used metagenomics to investig ...201222967311
evaluation of a novel hybrid bioartificial liver based on a multi-layer flat-plate bioreactor.to evaluate the efficacy and safety of a hybrid bioartificial liver (hbal) system in the treatment of acute liver failure.201222851870
binding of transcription factor activating protein 2 γ on the 5'-proximal promoter region of human porcine endogenous retrovirus subgroup a receptor 2/gpr172b.xenotransplantation is one of the solutions for the shortage of organ donors, and pigs have been considered to be the most suitable animal donors. specific pathogen-free pigs are utilized in the xenotransplantation; however, pigs have infectious gammaretroviruses, named porcine endogenous retroviruses (pervs) in their genome. of them, perv-a and perv-b can infect human cells in vitro and potentially induce diseases like other gammaretroviruses. the human cellular receptors for perv-a were identi ...201222702469
detailed mapping of determinants within the porcine endogenous retrovirus envelope surface unit identifies critical residues for human cell infection within the proline-rich region.replication-competent porcine endogenous retroviruses (pervs) are either human cell tropic (perv-a and perv-b) or non-human cell tropic (perv-c). we previously demonstrated that perv in vitro cell tropism is modulated by 2 residues within the c terminus of su and that the perv receptor binding domain (rbd) extends beyond the variable regions a and b (vra and vrb, respectively), to include the proline rich-region (prr) of su (m. gemeniano et al., virology 346:108-117, 2000; t. argaw et al., j. vi ...201222696659
potential zoonotic infection of porcine endogenous retrovirus in xenotransplantation.porcine endogenous retrovirus (perv) is considered the major biosafety issue in xenotransplantation. several techniques have been employed for the analysis of the perv status in the animal donor and for the assessment of perv transmission/infection in the xenograft recipient. in this chapter, methods to assess the expression of perv and the potential for perv transmission from a donor animal are described in addition to the identification of relevant loci within the porcine genome.perv detection ...201222566002
[new evidence of porcine endogenous retrovirus transmission with new bio-artificial liver system: a experimental study].to investigate the potential transmissibility of porcine endogenous retrovirus (perv) from a newly-developed porcine hepatocyte bioartificial liver (bal) system prior to human clinical trial by using a live canine model.201222464706
porcine endogenous retrovirus copy number in different pig breeds is not related to genetic diversity.the risk of zoonoses is a major obstacle to xenotransplantation. porcine endogenous retrovirus (perv) poses a potential risk of zoonotic infection, and its control is a prerequisite for the development of clinical xenotransplantation. the copy number of perv varies among different breeds, and it has been suggested that the perv integrations number is increased by inbreeding. the purpose of this study was (i) to examine the copy number of perv in different spanish pig breeds, spanish wild boar an ...201222348392
degradation effect of diepoxide fixation on porcine endogenous retrovirus dna in heart valves: molecular aspects.xenotransplantations of porcine cells, tissues, and organs involve a risk of zoonotic viral infections in recipients, including by porcine endogenous retroviruses (pervs), which are embedded the genome of all pigs. an appropriate preparation of porcine heart valves for transplantation can prevent retroviral infection. therefore, the present study focuses on the effect of epoxy compounds and glutaraldehyde on the perv presence in porcine heart valves prepared for clinical use.201222307333
the sequence and analysis of a chinese pig genome.the pig is an economically important food source, amounting to approximately 40% of all meat consumed worldwide. pigs also serve as an important model organism because of their similarity to humans at the anatomical, physiological and genetic level, making them very useful for studying a variety of human diseases. a pig strain of particular interest is the miniature pig, specifically the wuzhishan pig (wzsp), as it has been extensively inbred. its high level of homozygosity offers increased ease ...201223587058
a clinical trial of xenotransplantation of neonatal pig islets for diabetic patients.to ascertain the safety and function of the transplantation of neonatal pig islets (npis) for diabetic patients.201122246351
genetic prevalence of porcine endogenous retrovirus in chinese experimental miniature pigs.pig-to-human xenotransplantation poses the potential risk of interspecies transmission of porcine endogenous retrovirus (perv). the chinese experimental miniature pig may be used as a pig-to-human xenograft donor. however, data for the distribution of perv provirus in genomic dna and perv expression at the rna level for the chinese experimental miniature pig population are lacking. in this study, perv was investigated in this regard using polymerase chain reaction (pcr), real-time quantitative p ...201121911159
increased neutralizing antibody response after simultaneous immunization with leucogen and the feline leukemia virus transmembrane protein.to develop improved vaccination strategies against feline leukemia virus (felv), rats were immunized with the transmembrane envelope protein p15e of felv alone or in combination with the commercial vaccine leucogen® comprising the nonglycosylated felv surface envelope protein. binding and neutralizing antibodies were induced in both groups and in the group immunized with leucogen alone. higher titers of antibodies neutralizing felv were induced by simultaneous immunization with leucogen and p15e ...201120829603
mapping of a neutralizing epitope in the surface envelope protein of porcine endogenous retrovirus subgroup b.pigs are thought to be the most suitable donor animal for xenotransplantation. however, pigs harbour potentially hazardous infectious agents, termed porcine endogenous retroviruses (pervs), in their genome. in this study, we generated a mab against perv-b surface (su) envelope protein (env), designated krt1. krt1 binding was detected by an indirect immunofluorescence assay and flow cytometric analysis on cells infected with perv-b. krt1 neutralized perv-b pseudotype virus and specifically recogn ...201121228129
generation of neutralising antibodies against porcine endogenous retroviruses (pervs).antibodies neutralising porcine endogenous retroviruses (pervs) were induced in different animal species by immunisation with the transmembrane envelope protein p15e. these antibodies recognised epitopes, designated e1, in the fusion peptide proximal region (fppr) of p15e, and e2 in the membrane proximal external region (mper). e2 is localised in a position similar to that of an epitope in the transmembrane envelope protein gp41 of the human immunodeficiency virus-1 (hiv-1), recognised by the mo ...201121237477
restriction of porcine endogenous retrovirus by porcine apobec3 cytidine deaminases.xenotransplantation of porcine cells, tissues, and organs shows promise to surmount the shortage of human donor materials. among the barriers to pig-to-human xenotransplantation are porcine endogenous retroviruses (perv) since functional representatives of the two polytropic classes, perv-a and perv-b, are able to infect human embryonic kidney cells in vitro, suggesting that a xenozoonosis in vivo could occur. to assess the capacity of human and porcine cells to counteract perv infections, we an ...201121307203
detection of porcine endogenous retrovirus (perv) viremia in diseased versus healthy us pigs by qualitative and quantitative real-time rt-pcr.previous studies have linked levels of porcine endogenous retroviruses (perv) with poor health and disease in pigs. to determine the levels of expression of pervs and their potential association with disease expression, real-time reverse transcriptase (rt) pcr assays were used to assess perv-abc, perv-c and perv-a/c levels in three commercial swine operations in the united states. pigs (n = 204) aged 3-25 weeks were screened, and all 369 serum samples collected were found to be positive for perv ...201121396084
repression of porcine endogenous retrovirus infection by human apobec3 proteins.it has been shown that porcine endogenous retrovirus (perv) can infect human cells, indicating that perv transmission poses a serious concern in pig-to-human xenotransplantation. a number of recent studies have reported on retrovirus interference by antiviral proteins. the most potent antiviral proteins are members of the apobec family of cytidine deaminases, which are involved in defense against retroviral attack. these proteins are present in the cytoplasm of mammalian cells and inhibit retrov ...201121396348
evaluation of the potential risk of porcine endogenous retrovirus (perv) infection in nude mice.nude mice (balb/c) were grafted with human 293 cells and perv (porcine endogenous retrovirus)-ires-egfp (a packageable retroviral vector plasmid containing an internal ribosome entry site-enhanced green fluorescent protein)-producing pig pk15 cells in order to determine whether the pig cells could transmit perv-ires-egfp to mice and human 293 cells in vivo. none of the transplanted human 293 cell lines were infected by perv, but pcr analysis identified perv-b provirus integration into both the h ...201121532322
development of sensitive methods for detection of porcine endogenous retrovirus-c (perv-c) in the genome of pigs.porcine endogenous retroviruses (perv) represent a risk for xenotransplantation using pig cells, tissues or organs. perv-a and perv-b are present in the genome of all pigs and both infect human cells in vitro. perv-c infects only pig cells and it is integrated in the genome of most, but not all pigs. recombinants between perv-a and perv-c were described that infect human cells and replicate at high titres. to avoid such recombinations, perv-c positive animals should not be used for breeding anim ...201121539860
multiplex high resolution melting assay for estimation of porcine endogenous retrovirus (perv) relative gene dosage in pigs and detection of perv infection in xenograft recipients.porcine endogenous retrovirus (perv) poses an infectious risk in the field of xenotransplantation. this risk may be mitigated by breeding selectively animals bearing favorable perv genetic characteristics including pigs with low levels of perv integrated in the genome. a real-time quantitative polymerase chain reaction (pcr) assay employing the roche high resolution melting (hrm) master was used to estimate the relative gene dosage of perv pol integrated within the pig genome. when assessed acro ...201121545811
identification of developmental competence-related genes in mature porcine oocytes.oocyte competence is a key factor limiting female fertility, yet the underlying molecular mechanisms that contribute to oocyte competence remain unclear. the objective of this study was to elucidate specific genes whose function contributes to oocyte competence. we observed that 6 of 20 target genes examined were differentially expressed between adult (more competent) and prepubertal (less competent) porcine in vitro matured (ivm) oocytes. these genes were the cholesterol synthesis-related gene ...201121774025
no enhanced expression and infectivity of porcine endogenous retrovirus in primary porcine hepatocytes with chitosan nanofiber scaffold.our previous report suggested that chitosan nanofiber scaffold may find application in bioartificial livers for it could enhance the function of hepatocytes. this study was focused on its microbiological safety, that is, its influence on the expression and infectivity of porcine endogenous retrovirus (perv) in primary porcine hepatocytes. freshly isolated porcine hepatocytes were cultured with or without chitosan nanofiber scaffold (defined as exp group and ctr group) and porcine kidney 15 (pk15 ...201121830478
influence of chitosan nanofiber scaffold on porcine endogenous retroviral expression and infectivity in pig hepatocytes.to investigate the influence of chitosan nanofiber scaffold on the production and infectivity of porcine endogenous retrovirus (perv) expressed by porcine hepatocytes.201121734784
Rapid determination of perv copy number from porcine genomic DNA by real-time polymerase chain reaction.Here, we report the quantification of porcine endogenous retrovirus (PERV) copy numbers using real time PCR. After generating standard curves using plasmid DNA, copy numbers were determined for PERV pol and for a housekeeping gene, porcine estrogen receptor2 (ER2) with the same amount of genomic DNA. Using this method, we examined 6 pig breeds in Korea including two breeds of miniature pig, one domestic pig from Jeju, and imported pig breeds, Duroc, Landrace, and Yorkshire. All breeds showed PER ...201122132811
xenotransplantation of galactosyl-transferase knockout, cd55, cd59, cd39, and fucosyl-transferase transgenic pig kidneys into baboons.galactosyl-transferase knockout (gt-ko) pigs represent the latest major progress to reduce immune reactions in xenotransplantation. however, their organs are still subject to rapid humoral rejection involving complement activation requiring the ongoing development of further genetic modifications in the pig. in a pig-to-baboon renal transplantation setting, we have used donor pigs that are not only gt-ko, but also transgenic for human cd55 (hcd55), hcd59, hcd39, and fucosyl-transferase (hht). we ...201122099813
reduction of n-tropic mutant porcine endogenous retrovirus infectivity by human tripartite motif-containing 5-isoform alpha.in cases of retroviral infection, the host cell deploys antiviral proteins as a type of innate immunity. tripartite motif-containing 5-isoform alpha (trim5α) is a potent antiviral protein. trim5α has been reported to restrict human immunodeficiency virus (hiv) 1 infection in rhesus monkey cells by targeting the incoming viral capsid at the postentry or preintegration stage of the viral life cycle. as a consequence, virus replication and reverse transcription are interrupted. trim5α of human orig ...201121911161
fluidized-bed bioartificial liver assist devices (blads) based on microencapsulated primary porcine hepatocytes have risk of porcine endogenous retroviruses transmission.bioartificial liver assist devices (blads) are expected to bridge liver failure patients to liver transplantation, but porcine endogenous retroviruses (pervs) still pose a potential risk in pig-to-human xenotransplantation and thereby limit the use of bioartificial liver therapy. in our lab, fluidized-bed blads based on microencapsulated primary porcine hepatocytes have been successfully used to treat liver failure pigs. we detected the risk of pervs transmission of microencapsulated primary por ...201021286347
islet cell transplantation for type 1 diabetes.islet transplantation is an attractive concept for the treatment of type 1 diabetes because of its potential high efficacy and minimal invasion to patients. the treatment may effectively control blood glucose for brittle type 1 diabetes, resulting in a marked reduction in hypoglycemic episodes and improvements in hba1c. in addition, approximately 70% of transplanted type 1 diabetic patients have achieved insulin independence. however, there are still important issues to be addressed before this ...201020923470
the rapid production of high-titer porcine endogenous retrovirus(perv)-b env pseudotype and construction of an egfp-expressing replication competent perv-a vector.porcine endogenous retroviruses (pervs) present a unique concern associated with xenotransplantation because they have been shown to infect certain human cells in vitro and it is also difficult to generate herds of pigs free of pervs. a simple system for the production of high-titer momlv-perv pseudotypes is reported; an egfp-expressing replication-competent molecular clone that allows direct measurement of titer was also constructed. to improve the mlv-based retroviral vector system, a 2.1-kb p ...201020933542
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