Journal articles: 'PERVs (Porcine Endogenous Retroviruses)'

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Mang, Rui, Jolanda Maas, Xianghong Chen, Jaap Goudsmit, and Antoinette C. van der Kuyl. "Identification of a novel type C porcine endogenous retrovirus: evidence that copy number of endogenous retroviruses increases during host inbreeding." Journal of General Virology 82, no. 8 (August 1, 2001): 1829–34. http://dx.doi.org/10.1099/0022-1317-82-8-1829.

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Different classes of porcine endogenous retroviruses (PERVs), which have the potential to infect humans during xenotransplantation, have been isolated from the pig genome. Because vertebrate genomes may contain numerous endogenous retrovirus sequences, the pig genome was examined for additional endogenous retroviruses, resulting in the isolation of a novel, complete endogenous retrovirus genome, designated PERV-E. The gag, pol and env genes of PERV-E are closely related to those of human endogenous retrovirus (HERV) 4-1, which belongs to the HERV-E family. Results of studies to determine the presence and copy number of PERVs demonstrated that PERV-E and PERV-A/B-like proviruses were present in all genomes tested, but that PERV-C was not found in two of the species examined, including wild boar. Multiple copies of PERVs could be found in each pig genome. Among all of the pig genomes tested, the wild boar genome had the lowest copy number of all PERVs, suggesting that the number of integrations of complete endogenous retroviruses is increased by inbreeding.

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Lee, Jun-Heon, Graham C. Webb, Richard D. M. Allen, and Chris Moran. "Characterizing and Mapping Porcine Endogenous Retroviruses in Westran Pigs." Journal of Virology 76, no. 11 (June 1, 2002): 5548–56. http://dx.doi.org/10.1128/jvi.76.11.5548-5556.2002.

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ABSTRACT Since porcine endogenous retroviruses (PERVs) can infect cultured human cells, they are a potential hazard to xenotransplantation. For this reason, endogenous retroviruses from the Westran (Westmead Hospital transplantation) inbred line of pigs were analyzed by using consensus primers for the type A and type B viruses to amplify 1.8-kb envelope gene fragments. After preliminary analysis with restriction enzymes KpnI and MboI, 31 clones were sequenced. Between types A and B, five recombinant clones were identified. Fifty-five percent of clones (17 of 31) had premature stop codons within the envelope protein-encoding region. Endogenous retroviruses in Westran pigs were physically mapped by fluorescence in situ hybridization (FISH) using PERV-A and PERV-B envelope clones as probes to identify at least 32 integration sites (19 PERV-A sites and 13 PERV-B sites). The chromosomal sites of integration in the Westran strain are quite different from those in the European Large White pig. The recombinant clones suggest that defective PERVs could become infective through recombination and further that PERVs might recombine with human endogenous retroviruses in xenotransplants.

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Wolf, Gernot, Anders Lade Nielsen, Jacob Giehm Mikkelsen, and Finn Skou Pedersen. "Epigenetic marking and repression of porcine endogenous retroviruses." Journal of General Virology 94, no. 5 (May 1, 2013): 960–70. http://dx.doi.org/10.1099/vir.0.049288-0.

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Endogenous retroviruses (ERVs) are remnants of retroviral germ line infections and have been identified in all mammals investigated so far. Although the majority of ERVs are degenerated, some mammalian species, such as mice and pigs, carry replication-competent ERVs capable of forming infectious viral particles. In mice, ERVs are silenced by DNA methylation and histone modifications and some exogenous retroviruses were shown to be transcriptionally repressed after integration by a primer-binding site (PBS) targeting mechanism. However, epigenetic repression of porcine ERVs (PERVs) has remained largely unexplored so far. In this study, we screened the pig genome for PERVs using LTRharvest, a tool for de novo detection of ERVs, and investigated various aspects of epigenetic repression of three unrelated PERV families. We found that these PERV families are differentially up- or downregulated upon chemical inhibition of DNA methylation and histone deacetylation in cultured porcine cells. Furthermore, chromatin immunoprecipitation analysis revealed repressive histone methylation marks at PERV loci in primary porcine embryonic germ cells and immortalized embryonic kidney cells. PERV elements belonging to the PERV-γ1 family, which is the only known PERV family that has remained active up to the present, were marked by significantly higher levels of histone methylations than PERV-γ2 and PERV-β3 proviruses. Finally, we tested three PERV-associated PBS sequences for repression activity in murine and porcine cells using retroviral transduction experiments and showed that none of these PBS sequences induced immediate transcriptional silencing in the tested primary porcine cells.

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Oldmixon, Beth A., James C. Wood, Thomas A. Ericsson, Carolyn A. Wilson, Mary E. White-Scharf, Goran Andersson, Julia L. Greenstein, Henk-Jan Schuurman, and Clive Patience. "Porcine Endogenous Retrovirus Transmission Characteristics of an Inbred Herd of Miniature Swine." Journal of Virology 76, no. 6 (March 15, 2002): 3045–48. http://dx.doi.org/10.1128/jvi.76.6.3045-3048.2002.

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ABSTRACT Here we report the identification of inbred miniature swine that failed to produce human-tropic replication-competent porcine endogenous retroviruses (HTRC PERVs), using in vitro coculture assays. When HTRC PERVs were isolated from transmitting animals, all were recombinant viruses, with the receptor-binding domain of PERV-A combining with PERV-C-related sequences.

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Lavillette, Dimitri, and David Kabat. "Porcine Endogenous Retroviruses Infect Cells Lacking Cognate Receptors by an Alternative Pathway: Implications for Retrovirus Evolution and Xenotransplantation." Journal of Virology 78, no. 16 (August 15, 2004): 8868–77. http://dx.doi.org/10.1128/jvi.78.16.8868-8877.2004.

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ABSTRACT A PHQ motif near the amino termini of gammaretroviral envelope glycoprotein surface (SU) subunits is important for infectivity but not for incorporation into virions or binding to cognate receptors. The H residue of this motif is most critical, with all substitutions we tested being inactive. Interestingly, porcine endogenous retroviruses (PERVs) of all three host-range groups, A, B, and C, lack full PHQ motifs, but most members have an H residue at position 10. H10A PERV mutants are noninfectious but were efficiently transactivated by adding to the assays a PHQ-containing SU or receptor-binding subdomain (RBD) derived from a gibbon ape leukemia virus (GALV). A requirement of this transactivation was a functional GALV receptor on the cells. In contrast to this heterologous transactivation, PERV RBDs and SUs were inactive in all tested cells, including porcine ST-IOWA cells. Surprisingly, transactivation by GALV RBD enabled wild-type or H10A mutant PERVs of all three host-range groups to efficiently infect cells from humans and rodents that lack functional PERV receptors and it substantially enhanced infectivities of wild-type PERVs, even for cells with PERV receptors. Thus, PERVs can suboptimally infect cells that contain cognate receptors or they can employ a transactivation pathway to more efficiently infect all cells. This ability to infect cells lacking cognate receptors was previously demonstrated only for nontransmissible variant gammaretroviruses with recombinant and mutant envelope glycoproteins. We conclude that some endogenously inherited mammalian retroviruses also have a receptor-independent means for overcoming host-range and interference barriers, implying a need for caution in xenotransplantation, especially of porcine tissues.

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Denner, Joachim. "How Active Are Porcine Endogenous Retroviruses (PERVs)?" Viruses 8, no. 8 (August 3, 2016): 215. http://dx.doi.org/10.3390/v8080215.

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Denner, Joachim. "The origin of porcine endogenous retroviruses (PERVs)." Archives of Virology 166, no. 4 (February 6, 2021): 1007–13. http://dx.doi.org/10.1007/s00705-020-04925-8.

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Krüger, Luise, Milena Stillfried, Carolin Prinz, Vanessa Schröder, Lena Katharina Neubert, and Joachim Denner. "Copy Number and Prevalence of Porcine Endogenous Retroviruses (PERVs) in German Wild Boars." Viruses 12, no. 4 (April 8, 2020): 419. http://dx.doi.org/10.3390/v12040419.

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Porcine endogenous retroviruses (PERVs) are integrated in the genome of pigs and are transmitted like cellular genes from parents to the offspring. Whereas PERV-A and PERV-B are present in all pigs, PERV-C was found to be in many, but not all pigs. When PERV-C is present, recombination with PERV-A may happen and the PERV-A/C recombinants are characterized by a high replication rate. Until now, nothing has been known about the copy number of PERVs in wild boars and little is known about the prevalence of the phylogenetically youngest PERV-C in ancient wild boars. Here we investigated for the first time the copy number of PERVs in different populations of wild boars in and around Berlin using droplet digital PCR. Copy numbers between 3 and 69 per genome have been measured. A lower number but a higher variability was found compared to domestic pigs, including minipigs reported earlier (Fiebig et al., Xenotransplantation, 2018). The wild boar populations differed genetically and had been isolated during the existence of the Berlin wall. Despite this, the variations in copy number were larger in a single population compared to the differences between the populations. PERV-C was found in all 92 analyzed animals. Differences in the copy number of PERV in different organs of a single wild boar indicate that PERVs are also active in wild boars, replicating and infecting new cells as has been shown in domestic pigs.

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Takeuchi, Yasuhiro, Clive Patience, Saema Magre, Robin A. Weiss, Papia T. Banerjee, Paul Le Tissier, and Jonathan P. Stoye. "Host Range and Interference Studies of Three Classes of Pig Endogenous Retrovirus." Journal of Virology 72, no. 12 (December 1, 1998): 9986–91. http://dx.doi.org/10.1128/jvi.72.12.9986-9991.1998.

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ABSTRACT Recent interest in the use of porcine organs, tissues, and cells for xenotransplantation to humans has highlighted the need to characterize the properties of pig endogenous retroviruses (PERVs). Analysis of a variety of pig cells allowed us to isolate and identify three classes of infectious type C endogenous retrovirus (PERV-A, PERV-B, and PERV-C) which have distinct env genes but have highly homologous sequences in the rest of the genome. To study the properties of these env genes, expression plasmids for the three env genes were constructed and used to generate retrovirus vectors bearing corresponding Env proteins. Host range analyses by the vector transduction assay showed that PERV-A and PERV-B Envs have wider host ranges, including several human cell lines, compared with PERV-C Env, which infected only two pig cell lines and one human cell line. All PERVs could infect pig cells, indicating that the PERVs have a potential to replicate in pig transplants in immunosuppressed patients. Receptors for PERV-A and PERV-B were present on cells of some other species, including mink, rat, mouse, and dog, suggesting that such species may provide useful model systems to study infection and pathogenicity of PERV. In contrast, no vector transduction was observed on nonhuman primate cell lines, casting doubt on the utility of nonhuman primates as models for PERV zoonosis. Interference studies showed that the three PERV strains use receptors distinct from each other and from a number of other type C mammalian retroviruses.

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Yang, L., M. Guell, D. Niu, H. George, E. Lesha, D. Grishin, J. Aach, et al. "Genome-wide inactivation of porcine endogenous retroviruses (PERVs)." Science 350, no. 6264 (October 11, 2015): 1101–4. http://dx.doi.org/10.1126/science.aad1191.

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11

Yu, Seong-Lan, Woo-Young Jung, Kie-Chul Jung, In-Cheol Cho, Hyun-Tae Lim, Dong-Il Jin, and Jun-Heon Lee. "Characterization of Porcine Endogenous Retrovirus Clones from the NIH Miniature Pig BAC Library." Journal of Biomedicine and Biotechnology 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/482568.

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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 repeat (LTR) region, identified the expected of open reading frame length, an indicative of active PERV, in all five PERV-C clones and one of the four PERV-B clones. Premature stop codons were observed in only three PERV-A clones. Also, eleven PERV integration sites were mapped using a 5000-rad IMpRH panel. The map locations of PERV-C clones have not been reported before, thus they are novel PERV clones identified in this study. The results could provide basic information for the elimination of site-specific PERVs in selection of pigs for xenotransplantation.

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Harrison, Ian, Yasuhiro Takeuchi, Birke Bartosch, and Jonathan P. Stoye. "Determinants of High Titer in Recombinant Porcine Endogenous Retroviruses." Journal of Virology 78, no. 24 (December 15, 2004): 13871–79. http://dx.doi.org/10.1128/jvi.78.24.13871-13879.2004.

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ABSTRACT Porcine endogenous retroviruses (PERVs) pose a potential stumbling block for therapeutic xenotransplantation, with the greatest threat coming from viruses generated by recombination between members of the PERV subgroup A (PERV-A) and PERV-C families (PERV-A/C recombinants). PERV-A and PERV-B have been shown to infect human cells in culture, albeit with low titers. PERV-C has a more restricted host range and cannot infect human cells. A recombinant PERV-A/C virus (PERV-A14/220) contains the PERV-A sequence between the end of pol and the middle of the SU region in env. The remaining sequence is derived from PERV-C. PERV-A14/220 is approximately 500-fold more infectious than PERV-A. To determine the molecular basis for the increased infectivity of PERV-A14/220, we have made a series of vector constructs. The primary determinant for the enhanced replicative potential of the recombinant virus appeared to be the env gene. Using a series of chimeric env genes, we could identify two determinants of high infectivity; one was an isoleucine to valine substitution at position 140 between variable regions A and B, and the other lies within the proline rich region. Taken together, these results show that the novel juxtaposition of env gene sequences enhanced the infectivity of PERV-A14/220 for human cells, perhaps by stabilization of the envelope glycoprotein or increased receptor binding.

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Kaulitz, Danny, Uwe Fiebig, Magdalena Eschricht, Christian Wurzbacher, Reinhard Kurth, and Joachim Denner. "Generation of neutralising antibodies against porcine endogenous retroviruses (PERVs)." Virology 411, no. 1 (March 2011): 78–86. http://dx.doi.org/10.1016/j.virol.2010.12.032.

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Takefman, Daniel M., Susan Wong, Thomas Maudru, Keith Peden, and Carolyn A. Wilson. "Detection and Characterization of Porcine Endogenous Retrovirus in Porcine Plasma and Porcine Factor VIII." Journal of Virology 75, no. 10 (May 15, 2001): 4551–57. http://dx.doi.org/10.1128/jvi.75.10.4551-4557.2001.

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ABSTRACT The pig genome contains porcine endogenous retroviruses (PERVs) capable of infecting human cells. Detection of infectious retrovirus in porcine peripheral blood mononuclear cells and endothelial cells suggested to us that pig plasma is likely to contain PERV. Both PERV env sequences and viral reverse transcriptase (RT) activity were detected in all plasma samples isolated from four NIH minipigs. To detect infectious virus from plasma, we performed a culture assay using three cell lines of feline, swine, and human origin that had previously been shown to be permissive for PERV. Infectious virus was successfully cultured from all four NIH minipig plasmas on the swine cell line ST-IOWA. Using RT-PCR with env-specific primers, we could detect expression of PERV class C envelope in the supernatant of ST-IOWA cells that had been exposed to each pig plasma. We next examined a pig plasma derivative, Hyate:C (porcine factor VIII), and found evidence of PERV particles, since all six lots examined were positive for PERV RNA and RT activity. However, infectious virus could not be detected in clinical lots of Hyate:C, suggesting that the manufacturing process might reduce the load of infectious virus to levels below detectable limits of the assay. Detection of infectious virus in porcine plasma confirms and extends the previous findings that certain porcine cells express PERV when manipulated in vitro and clearly demonstrates that there are porcine cells that express infectious PERV constitutively in vivo.

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Specke, Volker, Stefan J. Tacke, Klaus Boller, Jochen Schwendemann, and Joachim Denner. "Porcine endogenous retroviruses: in vitro host range and attempts to establish small animal models." Journal of General Virology 82, no. 4 (April 1, 2001): 837–44. http://dx.doi.org/10.1099/0022-1317-82-4-837.

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Using transgenic pigs as the source of cells or organs for xenotransplantation is associated with the risk of porcine endogenous retrovirus (PERV) transmission. Multiple proviruses are integrated into the genome of all pigs, and virus particles, some of which are able to infect human cells, are released from normal pig cells. In order to evaluate the potential risk posed by the transmission of PERVs, in vitro infection studies were performed as a basis for small animal as well as non-human primate models. In vitro infectivity was demonstrated for permanent cell lines and primary cells from a wide range of species. Productive infection was shown using reverse transcriptase (RT) assays and RT–PCR for mink, feline and human kidney cell lines, primary rhesus peripheral blood mononuclear cells (PBMCs), and baboon spleen cells and PBMCs as well as for different human lymphoid and monocyte cell lines and PBMCs. In an attempt to establish a small animal model, naive guinea pigs, non-immunosuppressed rats, rats immunosuppressed by cyclosporin-A and immunosuppressed rats treated with cobra venom factor were inoculated with PERVs produced from porcine kidney PK-15 cells, infected human 293 kidney cells and mitogen-stimulated porcine PBMCs. Animals were also inoculated with PERV-producing PK-15 and 293 cells. No antibodies against PERV and no provirus integration were observed in any of the treated animals. This suggests that productive infection of these animals did not occur in this experimental setting.

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Denner, Joachim, and Hendrik Jan Schuurman. "High Prevalence of Recombinant Porcine Endogenous Retroviruses (PERV-A/Cs) in Minipigs: A Review on Origin and Presence." Viruses 13, no. 9 (September 18, 2021): 1869. http://dx.doi.org/10.3390/v13091869.

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Minipigs play an important role in biomedical research and they have also been used as donor animals for preclinical xenotransplantations. Since zoonotic microorganisms including viruses can be transmitted when pig cells, tissues or organs are transplanted, virus safety is an important feature in xenotransplantation. Whereas most porcine viruses can be eliminated from pig herds by different strategies, this is not possible for porcine endogenous retroviruses (PERVs). PERVs are integrated in the genome of pigs and some of them release infectious particles able to infect human cells. Whereas PERV-A and PERV-B are present in all pigs and can infect cells from humans and other species, PERV-C is present in most, but not all pigs and infects only pig cells. Recombinant viruses between PERV-A and PERV-C have been found in some pigs; these recombinants infect human cells and are characterized by high replication rates. PERV-A/C recombinants have been found mainly in minipigs of different origin. The possible reasons of this high prevalence of PERV-A/C in minipigs, including inbreeding and higher numbers and expression of replication-competent PERV-C in these animals, are discussed in this review. Based on these data, it is highly recommended to use only pig donors in clinical xenotransplantation that are negative for PERV-C.

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Ericsson, Thomas, Beth Oldmixon, Jonas Blomberg, Margaret Rosa, Clive Patience, and Göran Andersson. "Identification of Novel Porcine Endogenous Betaretrovirus Sequences in Miniature Swine." Journal of Virology 75, no. 6 (March 15, 2001): 2765–70. http://dx.doi.org/10.1128/jvi.75.6.2765-2770.2001.

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ABSTRACT PCR amplification of genomic DNA from miniature swine peripheral blood lymphocytes, using primers corresponding to highly conserved regions of the polymerase (pol) gene, allowed the identification of two novel porcine endogenous retrovirus (PERV) sequences, PMSN-1 and PMSN-4. Phylogenetic analyses of the nucleotide sequences of PMSN-1 and PMSN-4 revealed them to be most closely related to betaretroviruses. The identification of PERVs belonging to theBetaretrovirus genus shows that endogenous retroviruses of this family are more broadly represented in mammalian species than previously appreciated. Both sequences contained inactivating mutations, implying that these particular loci are defective. However, Southern blot analysis showed additional copies of closely related proviruses in the miniature swine genome. Analyses of fetal and adult miniature swine tissues revealed a broad mRNA expression pattern of both PMSN-1 and PMSN-4. The most abundant expression was detected in whole bone marrow c-kit +(CD117+) progenitor bone marrow cells, fetal liver, salivary gland, and thymus. It appears unlikely that functional loci encoding these novel PERV sequences exist, but this remains to be established. The betaretrovirus sequences described in this report will allow such investigations to be actively pursued.

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Wood, Andrew, Benjamin L. J. Webb, Birke Bartosch, Torsten Schaller, Yasuhiro Takeuchi, and Greg J. Towers. "Porcine endogenous retroviruses PERV A and A/C recombinant are insensitive to a range of divergent mammalian TRIM5α proteins including human TRIM5α." Journal of General Virology 90, no. 3 (March 1, 2009): 702–9. http://dx.doi.org/10.1099/vir.0.007377-0.

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The potential risk of cross-species transmission of porcine endogenous retroviruses (PERV) to humans has slowed the development of xenotransplantation, using pigs as organ donors. Here, we show that PERVs are insensitive to restriction by divergent TRIM5α molecules despite the fact that they strongly restrict a variety of divergent lentiviruses. We also show that the human PERV A/C recombinant clone 14/220 reverse transcribes with increased efficiency in human cells, leading to significantly higher infectivity. We conclude that xenotransplantation studies should consider the danger of highly infectious TRIM5α-insensitive human-tropic PERV recombinants.

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Heo, Yoonki, Yeondong Cho, Keon Bong Oh, Ki Hoon Park, Hansam Cho, Hanul Choi, Minjee Kim, Ik Jin Yun, Hee Jung Lee, and Young Bong Kim. "Detection of Pig Cells Harboring Porcine Endogenous Retroviruses in Non-Human Primate Bladder After Renal Xenotransplantation." Viruses 11, no. 9 (August 29, 2019): 801. http://dx.doi.org/10.3390/v11090801.

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Pigs are used as potential donor animals for xenotransplantation. However, porcine endogenous retrovirus (PERV), shown to infect both human and non-human primate (NHP) cells in vitro, presents a risk of transmission to humans in xenotransplantation. In this study, we analyzed PERV transmission in various organs after pig-to-NHP xenotransplantation. We utilized pig-to-NHP xenotransplant tissue samples obtained using two types of transgenic pigs from the National Institute of Animal Science (NIAS, Republic of Korea), and examined them for the existence of PERV genes in different organs via PCR and RT-PCR with specific primers. To determine PERV insertion into chromosomes, inverse PCR using PERV long terminal repeat (LTR) region-specific primers was conducted. The PERV gene was not detected in NHP organs in cardiac xenotransplantation but detected in NHP bladders in renal xenotransplantation. The insertion experiment confirmed that PERVs originate from porcine donor cells rather than integrated provirus in the NHP chromosome. We also demonstrate the presence of pig cells in the NHP bladder after renal xenotransplantation using specific-porcine mitochondrial DNA gene PCR. The PERV sequence was detected in the bladder of NHPs after renal xenotransplantation by porcine cell-microchimerism but did not integrate into the NHP chromosome.

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Scobie, Linda, Samantha Taylor, James C. Wood, Kristen M. Suling, Gary Quinn, Sharon Meikle, Clive Patience, Henk-Jan Schuurman, and David E. Onions. "Absence of Replication-Competent Human-Tropic Porcine Endogenous Retroviruses in the Germ Line DNA of Inbred Miniature Swine." Journal of Virology 78, no. 5 (March 1, 2004): 2502–9. http://dx.doi.org/10.1128/jvi.78.5.2502-2509.2004.

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ABSTRACT The potential transmission of porcine endogenous retroviruses (PERVs) has raised concern in the development of porcine xenotransplantation products. Our previous studies have resulted in the identification of animals within a research herd of inbred miniature swine that lack the capacity to transmit PERV to human cells in vitro. In contrast, other animals were capable of PERV transmission. The PERVs that were transmitted to human cells are recombinants between PERV-A and PERV-C in the post-VRA region of the envelope (B. A. Oldmixon, J. C. Wood, T. A. Ericsson, C. A. Wilson, M. E. White-Scharf, G. Andersson, J. L. Greenstein, H. J. Schuurman, and C. Patience, J. Virol. 76:3045-3048, 2002); these viruses we term PERV-A/C. This observation prompted us to determine whether these human-tropic replication-competent (HTRC) PERV-A/C recombinants were present in the genomic DNA of these miniature swine. Genomic DNA libraries were generated from one miniature swine that transmitted HTRC PERV as well as from one miniature swine that did not transmit HTRC PERV. HTRC PERV-A/C proviruses were not identified in the germ line DNAs of these pigs by using genomic mapping. Similarly, although PERV-A loci were identified in both libraries that possessed long env open reading frames, the Env proteins encoded by these loci were nonfunctional according to pseudotype assays. In the absence of a germ line source for HTRC PERV, further studies are warranted to assess the mechanisms by which HTRC PERV can be generated. Once identified, it may prove possible to generate animals with further reduced potential to produce HTRC PERV.

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MAZUREK, URSZULA, MALGORZATA W. KIMSA, BARBARA STRZALKA-MROZIK, MAGDALENA C. KIMSA, CELINA KRUSZNIEWSKA-RAJS, JOANNA GOLA, JOLANTA ADAMSKA, and MAGDALENA TWARDOCH. "Microarray Analysis of Retroviral Restriction Factor Gene Expression in Response to Porcine Endogenous Retrovirus Infection." Polish Journal of Microbiology 63, no. 2 (2014): 183–90. http://dx.doi.org/10.33073/pjm-2014-024.

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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 infectivity was analyzed using a co-culture system of NHDFs and porcine kidney epithelial cells (PK15 cell line). Detection of the copy number of PERV A, PERV B DNA and PERV A, PERV B RNA was performed using real-time Q-PCR and QRT-PCR. The expression of retroviral restriction factor genes was compared between PERV-infected and uninfected NHDF cells using oligonucleotide microarray. The up-regulated transcripts were recorded for two differentially expressed genes (TRIM1, TRIM16) with the use of GeneSpring platform and Significance Analysis of Microarrays. In conclusion, our results suggest that the TRIM family may play an important role in innate immunity to PERV infection. These results can allow a better understanding of restriction mechanism of PERV infection and probably design molecularly targeted therapies in the future. Moreover, knowledge of retroviral restriction factor gene expression in human cells may help to uncover strategies for determining their exact function. Microarray analyses seem to be promising in biological and biomedical studies, however, these results should be further confirmed by research conducted at the protein level.

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Wilson, Carolyn A., Sabahat Laeeq, Armin Ritzhaupt, Winston Colon-Moran, and Fayth K. Yoshimura. "Sequence Analysis of Porcine Endogenous Retrovirus Long Terminal Repeats and Identification of Transcriptional Regulatory Regions." Journal of Virology 77, no. 1 (January 1, 2003): 142–49. http://dx.doi.org/10.1128/jvi.77.1.142-149.2003.

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ABSTRACT Porcine cells express endogenous retroviruses, some of which are infectious for human cells. To better understand the replication of these porcine endogenous retroviruses (PERVs) in cells of different types and animal species, we have performed studies of the long terminal repeat (LTR) region of known gammaretroviral isolates of PERV. Nucleotide sequence determination of the LTRs of PERV-NIH, PERV-C, PERV-A, and PERV-B revealed that the PERV-A and PERV-B LTRs are identical, whereas the PERV-NIH and PERV-C LTRs have significant sequence differences in the U3 region between each other and with the LTRs of PERV-A and PERV-B. Sequence analysis revealed a similar organization of basal promoter elements compared with other gammaretroviruses, including the presence of enhancer-like repeat elements. The sequences of the PERV-NIH and PERV-C repeat element are similar to that of the PERV-A and PERV-B element with some differences in the organization of these repeats. The sequence of the PERV enhancer-like repeat elements differs significantly from those of other known gammaretroviral enhancers. The transcriptional activities of the PERV-A, PERV-B, and PERV-C LTRs relative to each other were similar in different cell types of different animal species as determined by transient expression assays. On the other hand, the PERV-NIH LTR was considerably weaker in these cell types. The transcriptional activity of all PERV LTRs was considerably lower in porcine ST-IOWA cells than in cell lines from other species. Deletion mutant analysis of the LTR of a PERV-NIH isolate identified regions that transactivate or repress transcription depending on the cell type.

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Pakhomov, Oleg, Lionel Martignat, Jiri Honiger, Béatrice Clémenceau, Pierre Säi, and Sylviane Darquy. "AN69 Hollow Fiber Membrane will Reduce but Not Abolish the Risk of Transmission of Porcine Endogenous Retroviruses." Cell Transplantation 14, no. 10 (November 2005): 749–56. http://dx.doi.org/10.3727/000000005783982468.

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As the risk of porcine endogenous retrovirus (PERV) infection is a major obstacle to the xenotransplantation of porcine tissue, we investigated whether an AN69 hollow fibre membrane, used for islets of Langerhans transplantation, could prevent the transfer of PERVs and thus reduce the risk of PERV infection. PK15 cells were used as a PERV source. A specific and highly sensitive RCR was used for detection of a PERV provirus DNA (gag region) and a porcine mtDNA. Human U293 cells were incubated in vitro with encapsulated PK15 cells, concentrated encapsulated PK15 supernatant, or concentrated PK15 supernatant as a control. CD1 mice were implanted in vivo with encapsulated PK15 cells or injected with PK15 supernatant. We found no infection in human cells incubated with either encapsulated PK15 supernatant or in 10 out of 11 samples after coincubation with encapsulated PK15 cells. Infection of human cells was, however, detected in 1 out of 11 samples after coincubation with encapsulated PK15 cells. The presence of PERV provirus DNA and porcine mtDNA was detected in all the investigated tissues of the mice injected with PK15 supernatant and in various tissues of the mice implanted with encapsulated PK15 cells. Four weeks after the last injection of PK15 supernatant or a fiber explantation, no mouse showed any presence of PERV provirus DNA or porcine mtDNA. Our results demonstrate that AN69 hollow fiber membrane will reduce but not abolish the risk of PERV infection. Because the real risk of PERV infection still remains unknown, it is necessary to investigate further the real protection that could be provided by hollow fibers to ensure the safety of clinical xenotransplantation.

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Krüger, Luise, Monika Nowak-Imialek, Yannick Kristiansen, Doris Herrmann, Björn Petersen, and Joachim Denner. "Unexpected low expression of porcine endogenous retroviruses (PERVs) in porcine expanded potential stem cells (EPSCs)." Virus Research 294 (March 2021): 198295. http://dx.doi.org/10.1016/j.virusres.2021.198295.

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Dieckhoff, Britta, Alexander Karlas, Björn Petersen, Wilfried A. Kues, Reinhard Kurth, Heiner Niemann, and Joachim Denner. "Transmission of porcine endogenous retroviruses (PERVs): Animal models and inhibition by RNA interference." Xenotransplantation 14, no. 4 (July 2007): 372–73. http://dx.doi.org/10.1111/j.1399-3089.2007.00418_16.x.

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Dieckhoff, B., A. Karlas, A. Hofmann, W. A. Kues, B. Petersen, A. Pfeifer, H. Niemann, R. Kurth, and J. Denner. "Inhibition of porcine endogenous retroviruses (PERVs) in primary porcine cells by RNA interference using lentiviral vectors." Archives of Virology 152, no. 3 (November 16, 2006): 629–34. http://dx.doi.org/10.1007/s00705-006-0868-y.

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Akiyoshi, Donna E., Maria Denaro, Haihong Zhu, Julia L. Greenstein, Papia Banerjee, and Jay A. Fishman. "Identification of a Full-Length cDNA for an Endogenous Retrovirus of Miniature Swine." Journal of Virology 72, no. 5 (May 1, 1998): 4503–7. http://dx.doi.org/10.1128/jvi.72.5.4503-4507.1998.

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ABSTRACT Endogenous retroviruses of swine are a concern in the use of pig-derived tissues for xenotransplantation into humans. The nucleotide sequence of porcine endogenous retrovirus taken from lymphocytes of miniature swine (PERV-MSL) has been characterized. PERV-MSL is a type C retrovirus of 8,132 bp with the greatest nucleic acid sequence identity to gibbon ape leukemia virus and murine leukemia virus. Constitutive production of PERV-MSL RNA has been detected in normal leukocytes and in multiple organs of swine. The copy numbers of full-length PERV sequences per genome (approximately 8 to 15) vary among swine strains. The open reading frames for gag, pol, andenv in PERV-MSL have over 99% amino acid sequence identity to those of Tsukuba-1 retrovirus and are highly homologous to those of endogenous retrovirus of cell line PK15 (PK15-ERV). Most of the differences in the predicted amino acid sequences of PK15-ERV and PERV-MSL are in the SU (cell attach- ment) region ofenv. The existence of these PERV clones will enable studies of infection by endogenous retroviruses in xenotransplantation.

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Bösch, Steffi, Claire Arnauld, and André Jestin. "Study of Full-Length Porcine Endogenous Retrovirus Genomes with Envelope Gene Polymorphism in a Specific-Pathogen-Free Large White Swine Herd." Journal of Virology 74, no. 18 (September 15, 2000): 8575–81. http://dx.doi.org/10.1128/jvi.74.18.8575-8581.2000.

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ABSTRACT Specific-pathogen-free (SPF) swine appear to be the most appropriate candidate for pig to human xenotransplantation. Still, the risk of endogenous retrovirus transmission represents a major obstacle, since two human-tropic porcine endogenous retroviruses (PERVs) had been characterized in vitro (P. Le Tissier, J. P. Stoye, Y. Takeuchi, C. Patience, and R. A. Weiss, Nature 389:681–682, 1997). Here we addressed the question of PERV distribution in a French Large White SPF pig herd in vivo. First, PCR screening for previously described PERV envelope genes envA, envB, and envC(D. E. Akiyoshi, M. Denaro, H. Zhu, J. L. Greenstein, P. Banerjee, and J. A. Fishman, J. Virol. 72:4503–4507, 1998; Le Tissier et al., op. cit.). demonstrated ubiquity of envAand envB sequences, whereas envC genes were absent in some animals. On this basis, selective out-breeding of pigs of remote origin might be a means to reduce proviral load in organ donors. Second, we investigated PERV genome carriage inenvC negative swine. Eleven distinct full-length PERV transcripts were isolated. The sequence of the complete envelope open reading frame was determined. The deduced amino acid sequences revealed the existence of four clones with functional and five clones with defective PERV PK-15 A- and B-like envelope sequences. The occurrence of easily detectable levels of PERV variants in different pig tissues in vivo heightens the need to assess PERV transmission in xenotransplantation animal models.

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Dieckhoff, Britta, Jenny Puhlmann, Kristina Büscher, Angela Hafner-Marx, Nadja Herbach, Norbert Bannert, Mathias Büttner, Rüdiger Wanke, Reinhard Kurth, and Joachim Denner. "Expression of porcine endogenous retroviruses (PERVs) in melanomas of Munich miniature swine (MMS) Troll." Veterinary Microbiology 123, no. 1-3 (July 20, 2007): 53–68. http://dx.doi.org/10.1016/j.vetmic.2007.02.024.

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Klymiuk, Nikolai, Mathias Müller, Gottfried Brem, and Bernhard Aigner. "Recombination analysis of human-tropic porcine endogenous retroviruses." Journal of General Virology 84, no. 10 (October 1, 2003): 2729–34. http://dx.doi.org/10.1099/vir.0.19284-0.

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Prevention of cross-species infection of porcine endogenous retroviruses (PERV) is crucial for xenotransplantation. The potential risk of infection is caused by replication-competent PERV as well as by hybrid viruses derived from recombination events of distinct PERV genomes. Recently, human-tropic, replication-competent PERV genomes obtaining hybrid sequences have been observed. Here, complete polymorphism pattern analysis was performed on the full-length PERV γ1 clones and on the complete envelope (env) gene sequences published to date. Several recombined full-length clones and a high number of different recombination patterns in the env gene were identified. In addition, recombinations with retroviral genomes not yet known were found. Thus, the potential risk of infection also exists for recombination products, including defective PERV loci.

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Klymiuk, Nikolai, Mathias Müller, Gottfried Brem, and Bernhard Aigner. "Phylogeny, recombination and expression of porcine endogenous retrovirus γ2 nucleotide sequences." Journal of General Virology 87, no. 4 (April 1, 2006): 977–86. http://dx.doi.org/10.1099/vir.0.81552-0.

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Endogenous retroviral sequences in the pig genome represent a potential infectious risk in xenotransplantation. Porcine endogenous retrovirus (PERV) γ sequences described to date have been classified into several families. The known infectious, human-tropic PERVs have been assigned to the PERV γ1 subfamilies A, B and C. High copy numbers and full-length clones have also been observed for an additional family, designated PERV γ2. The aim of this study was to examine the PERV γ2 family by analysis of retroviral pro/pol gene sequences. The proviral load was observed to be similar among various pig breeds. Although clones harbouring an open reading frame in the examined region were found, analysis of published large PERV γ2 clones revealed multiple deleterious mutations in each of the retroviral genes. Various recombination events between γ2 genomes were revealed. In contrast to PERV γ1, phylogenetic analyses did not distinguish defined subfamilies, but indicated the independent evolution of the proviruses after a single event of retroviral amplification. Expression analysis showed large PERV γ2 transcripts and variable transcription in several tissues. Analysis of the two published γ2 env gene sequences observed the partial lack of the receptor-binding domain. Overall, this study indicated the low infectious potential for PERV γ2.

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Hirata, Maki, Manita Wittayarat, Takayuki Hirano, Nhien Thi Nguyen, Quynh Anh Le, Zhao Namula, Mokhamad Fahrudin, Fuminori Tanihara, and Takeshige Otoi. "The Relationship between Embryonic Development and the Efficiency of Target Mutations in Porcine Endogenous Retroviruses (PERVs) Pol Genes in Porcine Embryos." Animals 9, no. 9 (August 22, 2019): 593. http://dx.doi.org/10.3390/ani9090593.

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Porcine endogenous retrovirus (PERV) is a provirus found in the pig genome that may act as an infectious pathogen in humans who receive pig organ xenotransplantation. Inactivation of the PERV pol gene in porcine cells reportedly affects cell growth. Therefore, the mutation of PERV pol gene in porcine embryos using genome editing may affect the embryonic development. The present study was carried out to investigate the relationship between the mutation of the PERV pol gene in porcine embryos and their development. We introduced, either alone or in combination, three different gRNAs (gRNA1, 2, and 3) into porcine zygotes by genome editing using electroporation of the Cas9 protein (GEEP) system. All three gRNAs targeted the PERV pol gene, and we assessed their effects on porcine embryonic development. Our results showed that the blastocyst formation rates of zygotes electroporated with gRNA3—alone and in combination—were significantly lower (p < 0.05) than those of zygotes electroporated with gRNA1. The mutation rates assessed by the PERV pol gene target site sequencing in individual blastocysts and pooled embryos at the 2-to-8-cell stage did not differ among the three gRNAs. However, the frequency of indel mutations in mutant embryos at the 2-to-8-cell stage trended higher in the embryos electroporated with gRNA3 alone and in combination. Embryonic development may be affected by gRNAs that induce high-frequency indel mutations.

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Krüger, Luise, Yannick Kristiansen, Emelie Reuber, Lars Möller, Michael Laue, Christian Reimer, and Joachim Denner. "A Comprehensive Strategy for Screening for Xenotransplantation-Relevant Viruses in a Second Isolated Population of Göttingen Minipigs." Viruses 12, no. 1 (December 29, 2019): 38. http://dx.doi.org/10.3390/v12010038.

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Xenotransplantation using pig tissues and organs is under development in order to alleviate the increasing shortage of human transplants. Since xenotransplantation may be associated with the transmission of porcine microorganisms to the human recipient, the donor pigs should be carefully analyzed, especially for the presence of potentially zoonotic viruses. Göttingen Minipigs (GöMP) are potential donors of islet cells for the treatment of diabetes. Despite the fact that all animals produced at Ellegaard Göttingen Minipigs A/S carry porcine endogenous retroviruses (PERVs) in their genome and that very few animals were infected with porcine cytomegalovirus (PCMV), hepatitis E virus (HEV) and porcine lymphotropic herpesvirus (PLHV), no transmission of these viruses was observed in a preclinical trial transplanting GöMP islet cells into cynomolgus monkeys. Using a new comprehensive strategy, we then analyzed an isolated subpopulation of Göttingen Minipigs which remained at the University of Göttingen. We concentrated on 11 xenotransplantation-relevant viruses and combined co-incubation assays with susceptible human target cells and molecular biological methods to evaluate the risk posed by PERV. All animals in Göttingen carry PERV-A, PERV-B, and PERV-C in their genome but they are not infected with PCMV, PLHV and HEV. The difference may be explained by selection of negative animals and/or de novo infection. The PERV copy number was established using ddPCR (93 copies) and a human-tropic PERV-A/C was found released from PBMCs of one animal with a high expression of PERV-C.

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Keller, Martina, Björn Petersen, Heiner Niemann, and Joachim Denner. "Lack of antibody response in pigs immunized with the transmembrane envelope protein of porcine endogenous retroviruses." Journal of General Virology 95, no. 8 (August 1, 2014): 1827–31. http://dx.doi.org/10.1099/vir.0.064857-0.

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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 can be used to study the involvement of the TM protein in placental development (as was shown for endogenous retroviruses of other species), German landrace pigs were immunized with PERV p15E. No binding and neutralizing antibodies were produced as shown in three Western blot analyses and in a neutralization assay, indicating that pigs are tolerant to their endogenous retroviruses, at least for the ectodomain of the TM protein.

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Jung, K. C., S. L. Yu, T. H. Kim, J. T. Jeon, C. Rogel-Gaillard, C. S. Park, D. I. Jin, C. Moran, and J. H. Lee. "Insertional Variations of Two Porcine Endogenous Retroviruses (PERVs) in Korean Native Pigs and Asian Wild Boars." Asian-Australasian Journal of Animal Sciences 20, no. 4 (January 24, 2007): 461–65. http://dx.doi.org/10.5713/ajas.2007.461.

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Schmidt, Peter, Göran Andersson, Jonas Blomberg, Anders Malmsten, and Olle Korsgren. "Possible Transmission of Zoonoses in Xenotransplantation: Porcine Endogenous Retroviruses (PERVs) from an Immunological Point of View." Acta Veterinaria Scandinavica 45, Suppl 1 (2004): S27. http://dx.doi.org/10.1186/1751-0147-45-s1-s27.

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37

Scobie, Linda, Samantha Taylor, Nicola A. Logan, Sharon Meikle, David Onions, Clive Patience, and Gary Quinn. "Characterization of germline porcine endogenous retroviruses from Large White pig." Journal of General Virology 85, no. 8 (August 1, 2004): 2421–28. http://dx.doi.org/10.1099/vir.0.79970-0.

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Porcine endogenous retroviruses (PERV) are of concern when the microbiological safety aspects of xenotransplantation are considered. Four unique isolates of PERV B have been identified previously from a lambda library constructed from genomic DNA from a Large White pig. This study shows that none of these isolates are replication competent when transfected into permissive human or pig cells in vitro, and the removal of flanking genomic sequences does not confer a human tropic replication competent (HTRC) phenotype on these PERV proviruses. Analysis of the envelope sequences revealed that PERV B demonstrated high similarity to the envelope sequences derived from replication-competent PERV, indicating that lack of replication competence does not appear to be attributable to this region of the provirus. These data complement recent findings that HTRC PERV are recombinants between the PERV A and PERV C subgroups, and that these recombinants are not present in the germline of miniature swine. Together, these results indicate that these individual PERV B proviruses are unlikely to give rise to HTRC PERV.

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38

Powell, S. K., M. E. Gates, G. Langford, M. L. Gu, C. Lockey, Z. Long, and E. Otto. "Antiretroviral Agents Inhibit Infection of Human Cells by Porcine Endogenous Retroviruses." Antimicrobial Agents and Chemotherapy 44, no. 12 (December 1, 2000): 3432–33. http://dx.doi.org/10.1128/aac.44.12.3432-3433.2000.

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ABSTRACT The efficacy of antiretroviral drugs against porcine endogenous retroviruses (PERV) that may be harbored in pig organs intended for transplantation was examined in human cells in vitro. The nucleoside analogs zidovudine and dideoxyinosine were found to effectively inhibit PERV replication.

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39

Morgan, Doris A., John Fitzsimmons, Takele Argaw, and Carolyn Wilson. "Productive Infection of Human Cord Blood Stem Cells and Lineage Progenitors by Porcine Endogenous Retrovirus (PERV)." Blood 108, no. 11 (November 16, 2006): 4178. http://dx.doi.org/10.1182/blood.v108.11.4178.4178.

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Abstract Endogenous retroviruses were once considered “junk DNA” and merely residual evolutionary genetic material. In the human system, recent reports have suggested a link between activation of human endogenous retroviruses (HERV) and certain diseases. Activation may be restricted to an up-regulation of viral specific transcripts or may involve gene translation with the assembly of virus-like particles (Morgan, Exp.Hem., 2004). Against this background of a possible link between activated endogenous retroviruses and disease, the potential risks of porcine to human transmission in the context of xenotransplantation becomes more plausible. The principal focus of this report was to determine the susceptibility of human primary cells to porcine endogenous retroviruses (PERV). Expression of a receptor for PERV has been described to be widespread in human tissues (Ericsson,PNAS,2003) and was expressed in hematopoietic stem cells and progenitors of our study. We exposed human umbilical cord blood (UCB) stem cells and cytokine-induced erythroid, myeloid and megakaryocytic progenitors to retroviral pseudotypes composed of replication competent wildtype PERV-NIH virions that also carry an MLV-based retroviral vector genome encoding β-galactosidase (β-gal) (Wilson, J. Vir., 2000; Harrison, J. Vir., 2004). Three days after exposure to PERV, cells were washed in order to remove unbound virus and assayed for viral RNA and DNA using quantitative PCR and RT-PCR (Argaw, J. Gen. Vir. 2002). Cell pellets from stem cells as well as lineage-induced cells were consistently positive for viral DNA and RNA and persisted during a kinetic study 3,5,6,and 7 days post-exposure to PERV. Control cells that were not exposed to PERV were negative in all parameters. There were no detectable adverse effects of PERV infection on cell proliferation or on terminal maturation of the progenitors of all three lineages. PERV infection does not require lineage commitment and provides a mechanism by which self-renewing stem cells may serve as an in vivo reservoir of virus in human bone marrow. Of note, the natural course of disease (anemia) of a related retrovirus, feline leukemia virus, also relies upon infection of hematopoietic progenitors in the bone marrow.

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Wood, James C., Gary Quinn, Kristen M. Suling, Beth A. Oldmixon, Brian A. Van Tine, Robert Cina, Scott Arn, et al. "Identification of Exogenous Forms of Human-Tropic Porcine Endogenous Retrovirus in Miniature Swine." Journal of Virology 78, no. 5 (March 1, 2004): 2494–501. http://dx.doi.org/10.1128/jvi.78.5.2494-2501.2004.

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ABSTRACT The replication of porcine endogenous retrovirus subgroup A (PERV-A) and PERV-B in certain human cell lines indicates that PERV may pose an infectious risk in clinical xenotransplantation. We have previously reported that human-tropic PERVs isolated from infected human cells following cocultivation with miniature swine peripheral blood mononuclear cells (PBMC) are recombinants of PERV-A with PERV-C. Here, we report that these recombinants are exogenous viruses in miniature swine; i.e., they are not present in the germ line DNA. These viruses were invariably present in miniature swine that transmitted PERV to human cells and were also identified in some miniature swine that lacked this ability. These data, together with the demonstration of the absence of both replication-competent PERV-A and recombinant PERV-A/C loci in the genome of miniature swine (L. Scobie, S. Taylor, J. C. Wood, K. M. Suling, G. Quinn, C. Patience, H.-J. Schuurman, and D. E. Onions, J. Virol. 78:2502-2509, 2004), indicate that exogenous PERV is the principal source of human-tropic virus in these animals. Interestingly, strong expression of PERV-C in PBMC correlated with an ability of the PBMC to transmit PERV-A/C recombinants in vitro, indicating that PERV-C may be an important factor affecting the production of human-tropic PERV. In light of these observations, the safety of clinical xenotransplantation from miniature swine will be most enhanced by the utilization of source animals that do not transmit PERV to either human or porcine cells. Such animals were identified within the miniature swine herd and may further enhance the safety of clinical xenotransplantation.

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Niebert, Marcus, and Ralf R. Tönjes. "Evolutionary Spread and Recombination of Porcine Endogenous Retroviruses in the Suiformes." Journal of Virology 79, no. 1 (January 1, 2005): 649–54. http://dx.doi.org/10.1128/jvi.79.1.649-654.2005.

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ABSTRACT Different Suiformes with increasing phylogenetic distance to the common pig (Sus scrofa) were assayed for the presence of porcine endogenous retroviruses (PERV) in general (pol gene), while the distribution of long terminal repeat (LTR) types (with or without repeats in U3) and env genes (classes A, B, and C) were determined in detail. PERV was not detectable in the most distantly related species, while classes PERV-A and PERV-B are present in Suiformes originating in the Pliocene epoch, and class PERV-C was detectable only in S. scrofa and in closely related species originating in the Holocene epoch. This distribution pattern of PERV classes is in line with our previous study on the age of PERV (45) and suggests an African origin of about 7.5 million years ago (MYA) and a gradual spread of PERV through the Suiformes. It seems likely that PERV-C originated more recently (1.5 to 3.5 MYA) by recombination with a homologue of unknown descent, while the origin of the repeatless LTR was a separate event approximately 3.5 MYA.

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Quinn, Gary, James Wood, Kristen Suling, Scott Arn, David H. Sachs, Henk-Jan Schuurman, and Clive Patience. "Genotyping of Porcine Endogenous Retroviruses from a Family of Miniature Swine." Journal of Virology 78, no. 1 (January 1, 2004): 314–19. http://dx.doi.org/10.1128/jvi.78.1.314-319.2004.

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ABSTRACT The identification of animals in an inbred miniature swine herd that consistently fail to produce replication- competent humantropic porcine endogenous retrovirus (PERV) has prompted studies on the biology of PERV in transmitter and nontransmitter animals. We analyzed PERV RNA transcript profiles in a family of inbred miniature swine (SLAd/d haplotype) in which individual members differed in their capacity to generate humantropic and ecotropic (i.e., pigtropic) virus. We identified unique HaeIII and HpaII gag restriction fragment length polymorphism (RFLP) profiles resulting from single nucleotide polymorphisms in blood cells; these were found only in animals that produced humantropic PERV. These HaeIII and HpaII gag RFLP profiles proved to be components of humantropic PERV as they were transmitted to 293 human target cells in vitro. The humantropic HaeIII and HpaII gag RFLP genotypes in the family of study were not present in other miniature swine in the herd that produced humantropic PERV, indicating that these RFLP profiles relate specifically to this family's lineage.

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43

Stephan, Oliver, Jochen Schwendemann, Volker Specke, Stefan J. Tacke, Klaus Boller, and Joachim Denner. "Porcine endogenous retroviruses (PERVs): Generation of specific antibodies, development of an immunoperoxidase assay (IPA) and inhibition by AZT." Xenotransplantation 8, no. 4 (November 2001): 310–16. http://dx.doi.org/10.1034/j.1399-3089.2001.00098.x.

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44

Bartosch, Birke, Dimitrios Stefanidis, Richard Myers, Robin Weiss, Clive Patience, and Yasuhiro Takeuchi. "Evidence and Consequence of Porcine Endogenous Retrovirus Recombination." Journal of Virology 78, no. 24 (December 15, 2004): 13880–90. http://dx.doi.org/10.1128/jvi.78.24.13880-13890.2004.

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ABSTRACT The genetic nature and biological effects of recombination between porcine endogenous retroviruses (PERV) were studied. An infectious molecular clone was generated from a high-titer, human-tropic PERV isolate, PERV-A 14/220 (B. A. Oldmixon, et al. J. Virol. 76:3045-3048, 2002; T. A. Ericsson et al. Proc. Natl. Acad. Sci. USA 100:6759-6764, 2003). To analyze this sequence and 15 available full-length PERV nucleotide sequences, we developed a sequence comparison program, LOHATM to calculate local sequence homology between two sequences. This analysis determined that PERV-A 14/220 arose by homologous recombination of a PERV-C genome replacing an 850-bp region around the pol-env junction with that of a PERV-A sequence. This 850-bp PERV-A sequence encompasses the env receptor binding domain, thereby conferring a wide host range including human cells. In addition, we determined that multiple regions derived from PERV-C are responsible for the increased infectious titer of PERV-A 14/220. Thus, a single recombination event may be a fast and effective way to generate high-titer, potentially harmful PERV. Further, local homology and phylogenetic analyses between 16 full-length sequences revealed evidence for other recombination events in the past that give rise to other PERV genomes that possess the PERV-A, but not the PERV-B, env gene. These results indicate that PERV-A env is more prone to recombination with heterogeneous backbone genomes than PERV-B env. Such recombination events that generate more active PERV-A appear to occur in pigs rather frequently, which increases the potential risk of zoonotic PERV transmission. In this context, pigs lacking non-human-tropic PERV-C would be more suitable as donor animals for clinical xenotransplantation.

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45

Herring, C., G. Quinn, R. Bower, N. Parsons, N. A. Logan, A. Brawley, K. Elsome, et al. "Mapping Full-Length Porcine Endogenous Retroviruses in a Large White Pig." Journal of Virology 75, no. 24 (December 15, 2001): 12252–65. http://dx.doi.org/10.1128/jvi.75.24.12252-12265.2001.

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ABSTRACT Xenotransplantation may bridge the widening gap between the shortage of donor organs and the increasing number of patients waiting for transplantation. However, a major safety issue is the potential cross-species transmission of porcine endogenous retroviruses (PERV). This problem could be resolved if it is possible to produce pigs that do not contain replication-competent copies of this virus. In order to determine the feasibility of this, we have determined the number of potentially replication-competent full-length PERV proviruses and obtained data on their integration sites within the porcine genome. We have screened genomic DNA libraries from a Large White pig for potentially intact proviruses. We identified six unique PERV B proviruses that were apparently intact in all three genes, while the majority of isolated proviruses were defective in one or more genes. No intact PERV A proviruses were found in this pig, despite the identification of multiple defective A proviruses. Genotyping of 30 unrelated pigs for these unique proviruses showed a heterogeneous distribution. Two proviruses were uncommon, present in 7 of 30 and 3 of 30 pigs, while three were each present in 24 of 30 pigs, and one was present in 30 of 30 animals examined. Our data indicate that fewPERV proviruses in Large White pigs are capable of productive infection and suggest that many could be removed by selective breeding. Further studies are required to determine if all potentially functional proviruses could be removed by breeding or whether gene knockout techniques will be required to remove the residuum.

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46

Nowak, Ewa. "Modulation of Porcine Endogenous Retroviruses (PERVs) expression in vitro by shRNA in the presence of cyclosporine A and dexamethasone." Annals of Transplantation 17, no. 4 (2012): 92–107. http://dx.doi.org/10.12659/aot.883699.

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47

SHI, M., X. WANG, E. DECLERCQ, S. TAKAO, and M. BABA. "Antiviral Activity of Reverse Transcriptase Inhibitors against Porcine Endogenous Retroviruses (PERV)." Antiviral Research 74, no. 3 (June 2007): A62. http://dx.doi.org/10.1016/j.antiviral.2007.01.093.

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48

Li, Zhang, Yu Ping, Li Shengfu, Bu Hong, Li Youping, Zeng Yangzhi, and Cheng Jingqiu. "Phylogenetic relationship of porcine endogenous retrovirus (PERV) in Chinese pigs with some type C retroviruses." Virus Research 105, no. 2 (October 2004): 167–73. http://dx.doi.org/10.1016/j.virusres.2004.05.007.

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Preuss, Thomas, Nicole Fischer, Klaus Boller, and Ralf R. Tönjes. "Isolation and Characterization of an Infectious Replication-Competent Molecular Clone of Ecotropic Porcine Endogenous Retrovirus Class C." Journal of Virology 80, no. 20 (October 15, 2006): 10258–61. http://dx.doi.org/10.1128/jvi.01140-06.

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ABSTRACT Xenotransplantation of pig organs is complicated by the existence of polytropic replication-competent porcine endogenous retroviruses (PERV) capable of infecting human cells. The potential for recombination between ecotropic PERV-C and human-tropic PERV-A and PERV-B adds another level of infectious risk. Proviral PERV-C were characterized in MAX-T cells derived from d/d haplotype miniature swine. Three proviruses were cloned from a genomic library. Clone PERV-C(1312) generated infectious particles after transfection into porcine ST-IOWA cells. Electron microscopy revealed the same morphologies of virions in MAX-T cells and in ST-IOWA cells infected with cell-free PERV-C(1312) particles, indicating that MAX-T cells harbor one functional PERV-C provirus.

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Specke, V., R. Plesker, C. Coulibaly, K. Boller, and J. Denner. "Productive infection of a mink cell line with porcine endogenous retroviruses (PERVs) but lack of transmission to minks in vivo." Archives of Virology 147, no. 2 (February 1, 2002): 305–19. http://dx.doi.org/10.1007/s705-002-8321-z.

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Journal articles on the topic 'PERVs (Porcine Endogenous Retroviruses)'

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