Endemic Viruses of Squirrel Monkeys (Saimiri Spp.)

Overview Endemic Viruses of Squirrel Monkeys (Saimiri spp.)

Donna L Rogers,1 Gloria B McClure,1 Julio C Ruiz,2 Christian R Abee,2 and John A Vanchiere1,*

Nonhuman primates are the experimental animals of choice for the study of many human diseases. As such, it is important to understand that endemic viruses of primates can potentially affect the design, methods, and results of biomedical studies designed to model human disease. Here we review the viruses known to be endemic in squirrel monkeys (Saimiri spp.). The pathogenic potential of these viruses in squirrel monkeys that undergo experimental manipulation remains largely unexplored but may have implications regarding the use of squirrel monkeys in biomedical research.

Abbreviations: HTLV1, human T-cell leukemia virus type 1; HVS, herpesvirus saimiri; IPF, idiopathic pulmonary fibrosis; SaHV, Saimiriine herpesvirus; SFV, simian foamy virus; SM-CMV, squirrel monkey cytomegalovirus; SMPyV, squirrel monkey polyomavirus; SMRV, squirrel monkey retrovirus

The similarity between the nonhuman primate and human ment during handling, make squirrel monkeys attractive species immune systems is a key advantage in the use of nonhuman for model development and for studies of viral pathogenesis, primates compared with other mammalian models of human which cost approximately 30% to 40% less than comparable disease.13,71,88,94,103,113,125 In addition, the diversity of environmental studies in macaques.1 The likelihood of zoonotic transmission and infectious disease agents encountered by primates is similar of infectious pathogens is considerably less than that associated to that of humans, providing nonhuman primates a comparable with macaques and the risk of Macacine herpesvirus 1 (B virus) is level of biologic complexity.1 Old World primates, such as ma- nonexistent, given that neotropical primates do not harbor this caques and baboons, and New World primates, including squir- lethal virus.1 These factors are increasingly important in the cur- rel monkeys and marmosets, are commonly used in biomedical rent climate of limited grant funding for biomedical research and research. Squirrel monkeys (Saimiri spp.) are neotropical primates emphasis on safety for laboratory personnel. The limited avail- native to the forests of Central and South America. Of the 7 spe- ability of immunologic reagents with specificity for neotropi- cies of squirrel monkey, 3 (S. oerstedii, S. vanzolinii, and S. ustus) cal primates has hindered broader use of squirrel monkeys in are classified as endangered, vulnerable to extinction in the wild, biomedical research, compared with that of the more commonly or near threatened, whereas the remaining 4 (S. boliviensis, S. used Old World primates. In addition, the small size of neotropi- cassiquiarensis, S. macrodon, and S. sciureus) are not endangered, cal primates limits the volume of blood that can be collected at although the S. cassiquiarensis albigena subspecies is near threat- any one time. To abrogate these limitations, the NIH Nonhuman ened52,81 (Figure 1). In South America, where squirrel monkeys are Primate Reagent Resource (www.nhpreagents.org) provides an indigenous, breeding colonies of S. sciureus have been maintained increasing repertoire of agents that have been characterized for at the Pasteur Institute in French Guiana and at the Oswaldo Cruz immunologic studies of neotropical primates.89 Foundation in Brazil.7,12 In the United States, the Squirrel Monkey Squirrel monkeys are used in numerous aspects of biomedical Breeding and Research Resource, an NIH-sponsored national research, including studies of viral persistence, neuroendocrinol- research resource, maintains breeding colonies for S. boliviensis ogy, infectious diseases, cancer treatments, vaccine development, boliviensis, S. sciureus sciureus, and S. boliviensis peruviensis. gene expression, and reproductive physiology.117 The similarity Squirrel monkeys adapt easily to laboratory housing and can between the squirrel monkey immune system and that of hu- be housed in smaller spaces than can Old World primates.1 Unlike mans means that, as with macaques, there is a high likelihood when working with Old World primates, particularly macaques, that research outcomes will recapitulate what occurs in human no additional personnel protective equipment is necessary when diseases.13,71,87,94 This is particularly true for the study of several working with squirrel monkeys beyond that recommended for notable infectious diseases, including malaria, Creutzfeldt–Jakob working with other New World primates.92 Their small size, disease, and human T-cell leukemia virus type 1 (HTLV1) infec- combined with the reduced need for personnel protective equip- tion.19,56,128 For these diseases, squirrel monkeys are the model system of choice for studying pathogenesis, experimental treatments, and strategies for prevention. Received: 06 Oct 2014. Revision requested: 10 Nov 2014. Accepted: 25 Jan 2015. Squirrel monkeys are recognized as some of the most suscepti- 1Department of Pediatrics, Section of Infectious Diseases, Louisiana State University Health Sciences Center, Shreveport, Louisiana, and 2Keeling Center for Comparative ble nonhuman primate species for the experimental transmission Medicine, Department of Veterinary Sciences, University of Texas MD Anderson Cancer of Creutzfeldt–Jakob disease and other transmissible spongiform Center, Bastrop, Texas. encephalopathies that cause chronic wasting disease.11,72,98,130 The *Corresponding author. Email: [email protected]

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Figure 1. Taxonomy of Saimiri species with associated IUCN designations.52,81 experimental infection of squirrel monkeys with HTLV1 has led during immune suppression has been largely unexplored. As to their use in vaccine development and chemotherapy research such, the implications of these viruses regarding the interpreta- directed against HTLV1.44,57,58,82 In addition, squirrel monkeys are tion of data from studies that involve immune suppression in an important model for studying the immunology of malaria and squirrel monkeys are currently unknown. Therefore, for studies for testing vaccines against several Plasmodium species.19,20,68,114 involving an immune suppression component, it is prudent to Furthermore, squirrel monkeys have been used in pharmacologic monitor the blood, urine, and saliva for significant changes in research to raise HDL levels to prevent atherosclerosis and reduce the viral loads of the endemic viruses, particularly herpesvirus the risk of coronary heart disease.6 As the use of squirrel monkeys saimiri (HVS), which is ubiquitous in squirrel monkeys and is increases, especially for infectious disease research, accurate in- directly immunomodulatory.36,73 The salient characteristics of the formation about the endemic viral infections of squirrel monkeys known endemic squirrel monkey viruses are presented in Figure 2 is needed because of the potential for zoonotic transfer of these and reviewed here. viruses to humans (and vice versa) and to understand the potential influence these agents may have on research involving other Herpesviruses infectious pathogens diseases and immunosuppressive drugs. Herpesviruses are present in most species of animals and are classified into 3 subfamilies α( , β, and γ) on the basis of their bio- Endemic Viruses of Squirrel Monkeys logic properties and genome sequences. Eight herpesviruses have The presence of endemic squirrel monkey viruses has been been identified in humans, and 4 analogous herpesviruses have known for over 40 y, and all primates used in biomedical re- been found in squirrel monkeys. Herpesviruses share a common search are assumed to asymptomatically harbor persistent vi- evolutionary origin and establish lifelong latency in their host, ruses, including herpesviruses and polyomaviruses.53,54,61,77,124 Of with intermittent periods of lytic replication and excretion.95 the known endemic viruses of squirrel monkeys, only Saimiriine SaHV1. The squirrel monkey alphaherpesvirus SaHV1 was herpesvirus 1 (SaHV1) is occasionally pathogenic in its natural originally named ‘herpesvirus tamarinus’ because the virus host, causing orofacial ulcers and lingual plaques.61 These lesions was initially isolated and characterized from tamarins (Sa- are mild and self-limited, occurring only sporadically in the large guinas spp.).46,80 In 1964, 2 independent reports described fatal colony of animals at the Squirrel Monkey Breeding and Research generalized disease in tamarins, marmosets, rabbits, and mice Resource. Whether any of the endemic viruses remain benign infected with this novel alphaherpesvirus;46,80 owl monkeys also

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Figure 2. Characteristics of known endemic squirrel monkey viruses. SaHV3 has been proposed as the designation, but the International Committee on Taxonomy of Viruses has not yet assigned it. HSV, herpes simplex virus; HHV8, human herpesvirus 8; EBV, Epstein–Barr virus; HCMV, human cytomegalovirus. were found to be susceptible to fatal disease after infection with genomic organization and DNA sequence, HVS is most closely SaHV1.31 Subsequent studies revealed that squirrel monkeys are related to human herpesvirus 8, also known as Kaposi sarcoma- the natural host for this virus.24,47,61 The prevalence of SaHV1 in associated herpesvirus.5,23,65 Squirrel monkeys are naturally in- squirrel monkeys is high, with seropositivity greater than 90%.120 fected with HVS through saliva, usually within the first 2 y of Biologically and genetically, SaHV1 is most closely related to life.37 Early studies determined that the virus is nonpathogenic other primate herpes simplex viruses, including human simplex in squirrel monkeys after establishing lifelong persistence, pri- viruses 1 and 2.27,120 SaHV1 can be propagated in a variety of cell marily in T lymphocytes.22 However, HVS has a potent ability lines, including human cells, where it induces cytopathic effects to induce T-cell leukemia and lymphomas in other neotropical that are indistinguishable from those caused by human simplex primate species.22,33,50,77,78 Three subtypes of HVS are known, each virus 1.46 In addition, like the cold sores caused by human simplex with slightly different transforming abilities. All 3 subtypes cause virus 1 in humans, SaHV1 infection can cause ulcerative oral le- T-cell lymphoma in cotton-top tamarins, whereas subtypes A and sions and lingual plaques in squirrel monkeys (Figure 3). SaHV1 C also can induce these tumors in marmosets, and subtype C vi- lacks homologs for several genes that are found in all other pri- ruses can induce tumors in macaques.26,36,74 In addition, HVS can mate simplex viruses, including genes that code for type 1, type 2, cause malignant lymphoma after inoculation into marmosets, and type 3 membrane proteins; a dsRNA binding protein; and an owl, and howler and spider monkeys and in incidentally infected inhibitor of antigen presentation.120 The overall genomic organiza- owl monkeys.3,17,34,40,48-50,100 tion of SaHV1 differs from that of the type E genomes found in Immune suppression of squirrel monkeys acutely infected with other simplexviruses.120 Specifically, SaHV1 has a type D genome HVS results in prolonged oropharyngeal shedding of HVS and like that of the varicelloviruses, another alphaherpesvirus sub- a significant decrease in the proportion of latently infected lym- group that includes human varicella zoster virus.120 phocytes in peripheral blood.73 Notably, tumor development has Although the herpes simplex viruses of nonhuman primates not been observed in studies of immunosuppression.73 Seminal collectively are considered a zoonotic threat, in the 50 y since the studies in the field of viral oncogenesis revealed that neotropi- first description of SaHV1, there have been no known cases of cal primates vaccinated with heat-killed, formaldehyde-treated SaHV1 infection in humans.119,120 In contrast, the herpes B virus, HVS were protected against tumor formation.79 This protection a neurotropic alphaherpesvirus endemic in macaques, is highly can be passively transferred in serum, suggesting that the an- virulent in humans.90 Transmission of the herpes B virus to hu- tibody response provides the antitumor effect.66,67 More recent mans can occur through bites or scratches from infected mon- investigations of HVS have focused on molecular studies of viral keys, leading to an encephalomyelitis that has a mortality rate immunomodulatory elements and the viral genes involved in of greater than 80% without prompt treatment.90 The lethality of oncogenesis, cell signaling, and the maintenance of episomal viral herpes B virus in humans remains a sobering reminder of the im- elements.22,41,62 portance of safety precautions for the protection of both humans A notable caution in working with squirrel monkeys comes and research animals. from the ability of HVS subgroup C strains to transform human T SaHV2. Discovered in 1968, Saimiriine herpesvirus 2 (SaHV2), lymphocytes to stable growth in vitro and yield continuously pro- commonly known as herpesvirus saimiri (HVS), is now classi- liferating T-cell lines with the phenotype of mature CD4+ or CD8+ fied as aγ 2 herpesvirus, or rhadinovirus, and is the most-stud- cells.8 The recognition of this unique feature opened the possibil- ied of the endemic squirrel monkey viruses.75,76 According to its ity of generating human T-cell lines for a variety of immunologic

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Figure 3. Ulcerative orofacial lesions (left, black arrow) and lingual plaques (right, white arrows) in squirrel monkeys are associated with active SaHV1 infection. Photographs by Julio C Ruiz, DVM (Keeling Center for Comparative Medicine, MD Anderson Cancer Center). studies.8 Since then, HVS-transformed T-cell lines have been used epithelia of IPF tissue.38,129 An initial screen of 13 cases of IPF by to study primary human immunodeficiencies, including defects using in situ hybridization revealed that all cases were negative involving CD3γ, IL2Rγ, IL12R, MHC class II, CD43, CD95, and for human herpesviruses and positive for HVS.38 In a comparison CD18/LFA1.36 HVS-transformed human T cells have also been of 21 IPF cases and 21 cases of age-matched pulmonary fibrosis used in studies of HIV, which have led to the identification and cases of known etiology, all 21 IPF cases were positive for mul- increasing understanding of numerous factors involved in the tiple HVS DNA targets by in situ hybridization, whereas none of inhibition of HIV1 replication.21,64,83,84,105 the 21 control cases was positive.38 Further investigation through HVS is appealing as a potential gene-delivery vector because it a prospective study is needed to validate this finding and deter- can package a large amount of heterologous DNA and establish mine its significance. To date, HVS has not been associated with a persistent infection while its genome remains as a nonintegrat- pulmonary fibrosis in squirrel monkeys or any other nonhuman ed episome.42 Because studies of HVS deletion mutants showed primate species. that saimiri transforming protein C and the tyrosine-kinase–in- A second γ2 herpesvirus has been detected in both free-ranging teracting protein are essential for transformation in cell culture, and captive squirrel monkeys, but little is known about this agent all HVS-based vectors contain deletions in these 2 genes and are at present.29 thought to be nonpathogenic.28,42 The HVS-based vectors infect SaHV3 and other squirrel monkey lymphocryptoviruses. Infec- and persist in a wide range of human cell lines, including lung, tion of Old World primates with lymphocryptoviruses (γ1 her- colorectal, pancreatic, breast, gastric, and esophageal carcinoma pesviruses) has been recognized for 40 y, whereas the discovery and human hematopoietic cell lines.42 Intravenous and intraperi- of lymphocryptoviruses in New World primates is relatively re- toneal inoculation with an HVS vector construct led to the per- cent.126 One of the first lymphocryptoviruses discovered among sistent expression of the delivered genes in mice, as did vector neotropical primates was first identified in 2001 in captive squir- injection into human tumor xenografts.109,110 For HVS-based vec- rel monkeys in the United States and was called SaHV3.15 Sub- tors to become useful as therapeutics, biosafety concerns need to sequently, 2 independent research groups identified another be addressed, particularly with regard to preventing viral repli- lymphocryptovirus (Saimiri sciureus LHV1 or Saimiri sciureus cation and (when desired) eliminating the vector after delivery. LCV2) in wild squirrel monkeys in French Guyana and captive Although HVS can transform human T cells and cause lym- squirrel monkeys in Germany.25,30 In addition, one of the captive phomas in other neotropical primates, infection with HVS is not squirrel monkeys was coinfected with a second lymphocryptovi- associated with human lymphomas, and the risk that HVS poses rus that had 95% homology with SaHV3.30 On the basis of their to humans has long been thought to be very low.2,36 However, genomic organization and DNA sequences, these lymphocryp- human herpesviruses, and particularly gammaherpesviruses, toviruses are most closely related to Epstein–Barr virus in hu- have previously been associated with idiopathic pulmonary fi- mans.15,25,30 These discoveries could potentially be the basis for an brosis (IPF), and equine and asinine gammaherpesviruses cause animal model to study the pathogenesis of Epstein–Barr virus- pulmonary fibrosis in horses and donkeys.116,127 A recent study of induced lymphomas in humans. IPF specifically associated this fatal disease with HVS infection.38 SaHV4. The squirrel monkey cytomegalovirus (SM-CMV) is a The association between HVS and IPF was revealed when the betaherpesvirus that was initially isolated from the salivary gland inflammatory cytokine IL17 (a pirated mammalian gene found in of a Guyanese squirrel monkey in 1980 and is now designated the HVS genome) was shown to be expressed in the regenerating Saimiriine herpesvirus 4.51,99 No clinical disease has been attributed

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to this virus that is considered ubiquitous in squirrel monkey been considered to be an oncogenic retrovirus;118 SMRV has yet to colonies.99 SM-CMV-free animals were nursery-reared from birth demonstrate oncogenic properties. The identification of a type D and maintained for more than 6 y but quickly seroconverted retrovirus with close homology to Mason–Pfizer monkey virus when housed with seropositive monkeys.99 According to pro- in the B cell lymphomas of a patient with AIDS indicates that posed primate cytomegalovirus phylogenetic trees, primate cy- similar viruses may infect humans in various circumstances.9,39 tomegaloviruses may not be exclusively species-specific and may Unlike human endogenous retroviruses, SMRV produces infec- have the potential to be transmitted horizontally to phylogeneti- tious virions that are believed to be capable of infecting human cally related hosts (for example, among neotropical primates).69 cells.111,121 The coexistence of HVS and SMRV in a single permis- Although this virus has garnered little attention for more than 30 sive cell supports the idea of herpesvirus–retrovirus interactions y, a recent investigation of 3 free-ranging black howler monkeys in lymphoproliferative diseases such as Burkitt lymphoma and found dead from yellow fever reported the detection of SM-CMV Marek disease.63,96,108 It has been theorized that one virus may up- antibodies, a finding of unclear significance.35 From a global per- regulate the expression of the other virus, but data to support this spective, human cytomegalovirus is the most common cause of hypothesis are unavailable as yet. PCR-based studies have de- congenital viral infections. Additional study of SM-CMV likely tected SMRV in the LCL-HO human lymphoblastoid cell line and will advance our knowledge of the pathogenesis of cytomegalo- in 5 subclones of the Namalwa human lymphoblastoid cell line, virus, and squirrel monkeys might serve as a useful model in the including several used to produce interferon for human use.97,121 development of a cytomegalovirus vaccine.106 By using nested PCR analysis, SMRV DNA was detected in some commercially available interferon preparations, but no untoward 97 Squirrel monkey polyomavirus (SMPyV) effect of this contamination have been documented. Retrovi- ruses are responsible for diverse human diseases, including AIDS Initially described in 2007, SMPyV was the first polyomavi- (HIV) and T-cell leukemias, lymphomas, and spastic parapare- rus detected in New World primates.124 The complete SMPyV sis (HTLV1). SMRV is of recent interest due to its similarity to a genome was amplified from archived Bolivian squirrel monkey simian retrovirus that causes simian AIDS in macaques; whether spleen DNA, and SMPyV DNA sequences subsequently were de- SMRV causes an equivalent syndrome in squirrel monkeys is un- tected in 5 of 10 available squirrel monkey specimens.124 SMPyV known.70,118 Additional study of SMRV may offer new insights is not known to be pathogenic in the host species.124 The mode of into human retroviruses and yield a useful model for the develop- transmission of SMPyV remains unclear.123 The human analogs of ment of antiretroviral drugs. SMPyV are BK virus and JC virus, which exist as persistent infec- Simian foamy virus (SFV) of squirrel monkeys. Evolutionary tions, with seroprevalences of 82% and 39%, respectively.59 Infec- comparisons suggest that foamy viruses are the oldest known tions with BK virus and JC virus are asymptomatic in healthy retroviruses and that they coevolved with their hosts beginning people, but reactivation can occur in immunocompromised more than 100 million years ago.55,102,115 These unusual retrovi- persons, such as AIDS patients and organ-transplant recipients, ruses are endemic in diverse mammals, including bovines, fe- and lead to severe complications. Reactivation of BK virus can lines, equines, and nonhuman primates.101 Nonhuman primate irreversibly damage the kidneys due to polyomavirus-associated foamy viruses currently are grouped together as simian foamy nephropathy, and JC virus can cause progressive multifocal leu- viruses within the spumavirus genus.86 SFV are widespread in koencephalopathy, a fatal, demyelinating neurologic disease.122 both Old and New World primates and were first described in Discovery of a New World polyomavirus in squirrel monkeys 1954 in human tissue culture after what was later determined to has opened a door for research on the human polyomaviruses, be zoonotic transmission from a chimpanzee.32,60,86 SFV infections and studies on SMPyV at the Squirrel Monkey Breeding and in humans are uncommon, with zoonotic transmission to 1% to Research Resource have already yielded new insights into the 4% of the people exposed occupationally in zoos, primate centers, natural history of this virus.117 Additional research is needed to and laboratories.85 SFV replicate in oral mucosa and are thought develop SMPyV-infected squirrel monkeys as a model of human to be transmitted to humans primarily through bites from infect- polyomavirus disease and to understand the epidemiology and ed animals.85,104 SFV infections have developed in people bitten clinical implications of SMPyV in its natural host. by Old World primates, including mandrills, gorillas, and chim- panzees, and latent infections can persist for years in the periph- Retroviruses eral blood mononuclear cells and saliva of those infected.10,85,104 Squirrel monkey retrovirus (SMRV). SMRV initially was iso- Zoonotic transmission of SFV from New World primates is be- lated from squirrel monkey lung tissue and described in 1977;18,43 lieved to occur as well, given that several people with exposure to SMRV has also been detected in squirrel monkey placenta.108 A New World primates have been seropositive for an SFV acquired member of the betaretrovirus genus, SMRV is characterized as a from spider monkeys.112 However, because none of the spider type D retrovirus.51,91 Endogenous retroviruses are unique among monkey SFV-seropositive persons had detectable levels of spider animal viruses in that they are transmitted genetically: SMRV is monkey SFV DNA in their blood, to date there is no evidence transmitted among squirrel monkeys from parent to offspring, of long-term SFV persistence in humans after exposure to New and multiple copies occur in the squirrel monkey genome.14,107 World primates.112 The potential for secondary transmission of Two type D retroviruses, SMRV and Mason–Pfizer monkey virus, SFV between humans is unclear but appears to be low: a limited which affects rhesus monkeys, are related evolutionarily, sug- longitudinal study of 7 men with documented SFV infections did gesting that a progenitor of type D retroviruses became geneti- not reveal any secondary transmissions, and no other human-to- cally associated with primates at a very early time during their human transmissions have been reported.10 evolution.45 Mason–Pfizer monkey virus was recovered from a Among New World primates, 8 distinct lineages of SFV have rhesus monkey with spontaneous breast adenocarcinoma and has been described in 23 different species.86 Cross-species trans-

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mission of SFV in New World primates has been documented ase in nonhuman primates leads to an antiatherogenic lipoprotein to occur in captive animals but is not believed to be a common phenotype by increasing high-density lipoprotein and lowering occurrence.86 A recent study of SFV from New World primates low-density lipoprotein. Metabolism 58:568–575. revealed that TRIM5α may function as a species-specificity fac- 7. Andrade MCR, Coelho JMCdO, Amendoeira MRR, Vicente RT, Cardoso CVP, Ferreira PCB, Marchevsky RS. 2007. Toxoplasmosis tor that is responsible for the species-specific restriction of SFV in squirrel monkeys: histological and immunohistochemical analysis. 93 among New World primates. This finding suggests that the Cienc Rural 37:1724–1727. TRIM5α protein and SFV may have exerted evolutionary pres- 8. Biesinger B, Müller-Fleckenstein I, Simmer B, Lang G, Wittmann sure on each other. S, Platzer E, Desrosiers RC, Fleckenstein B. 1992. Stable growth SFV are cytotoxic in cell culture, causing the formation of large transformation of human T lymphocytes by herpesvirus saimiri. syncytium and characteristic vacuoles that give foamy viruses Proc Natl Acad Sci USA 89:3116–3119. their name. As yet, no specific disease is attributed to infection 9. Bohannon RC, Donehower LA, Ford RJ. 1991. Isolation of a type with squirrel monkey foamy virus or any other foamy virus.4,85 D retrovirus from B-cell lymphomas of a patient with AIDS. J Virol 65:5663–5672. In a recent study of the influence of SFV on SIV disease in rhesus 10. Boneva RS, Switzer WM, Spira TJ, Bhullar VB, Shanmugam macaques, preexisting SFV infection was associated with an in- V, Cong ME, Lam L, Heneine W, Folks TM, Chapman LE. 2007. + creased SIV plasma viral load, increased loss of CD4 T cells, and Clinical and virological characterization of persistent human in- a decreased survival rate.16 This observation may have important fection with simian foamy viruses. 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