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[PMID]:27412414
[Au] Autor:Jagessar SA; Holtman IR; Hofman S; Morandi E; Heijmans N; Laman JD; Gran B; Faber BW; van Kasteren SI; Eggen BJ; 't Hart BA
[Ad] Endereço:Department of Immunobiology, Biomedical Primate Research Centre, 2288GJ Rijswijk, the Netherlands; Department of Immunology, Erasmus University Medical Center, 3015CE Rotterdam, the Netherlands; MS Centre ErasMS, 3015CE Rotterdam, the Netherlands;
[Ti] Título:Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein.
[So] Source:J Immunol;197(4):1074-88, 2016 Aug 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:EBV is the major infectious environmental risk factor for multiple sclerosis (MS), but the underlying mechanisms remain obscure. Patient studies do not allow manipulation in vivo. We used the experimental autoimmune encephalomyelitis (EAE) models in the common marmoset and rhesus monkey to model the association of EBV and MS. We report that B cells infected with EBV-related lymphocryptovirus (LCV) are requisite APCs for MHC-E-restricted autoaggressive effector memory CTLs specific for the immunodominant epitope 40-48 of myelin oligodendrocyte glycoprotein (MOG). These T cells drive the EAE pathogenesis to irreversible neurologic deficit. The aim of this study was to determine why LCV infection is important for this pathogenic role of B cells. Transcriptome comparison of LCV-infected B cells and CD20(+) spleen cells from rhesus monkeys shows increased expression of genes encoding elements of the Ag cross-presentation machinery (i.e., of proteasome maturation protein and immunoproteasome subunits) and enhanced expression of MHC-E and of costimulatory molecules (CD70 and CD80, but not CD86). It was also shown that altered expression of endolysosomal proteases (cathepsins) mitigates the fast endolysosomal degradation of the MOG40-48 core epitope. Finally, LCV infection also induced expression of LC3-II(+) cytosolic structures resembling autophagosomes, which seem to form an intracellular compartment where the MOG40-48 epitope is protected against proteolytic degradation by the endolysosomal serine protease cathepsin G. In conclusion, LCV infection induces a variety of changes in B cells that underlies the conversion of destructive processing of the immunodominant MOG40-48 epitope into productive processing and cross-presentation to strongly autoaggressive CTLs.
[Mh] Termos MeSH primário: Linfócitos B/imunologia
Linfócitos T CD8-Positivos/imunologia
Apresentação Cruzada/imunologia
Encefalomielite Autoimune Experimental/virologia
Infecções por Herpesviridae/imunologia
Glicoproteína Mielina-Oligodendrócito/imunologia
[Mh] Termos MeSH secundário: Animais
Apresentação do Antígeno/imunologia
Células Apresentadoras de Antígenos/imunologia
Linfócitos B/virologia
Western Blotting
Callithrix
Separação Celular
Encefalomielite Autoimune Experimental/imunologia
Epitopos de Linfócito T/imunologia
Imunofluorescência
Lymphocryptovirus
Ativação Linfocitária/imunologia
Macaca mulatta
Reação em Cadeia da Polimerase
Infecções Tumorais por Vírus/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Epitopes, T-Lymphocyte); 0 (Myelin-Oligodendrocyte Glycoprotein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170802
[Lr] Data última revisão:
170802
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160715
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1600124


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[PMID]:26590795
[Au] Autor:Kamperschroer C; Gosink MM; Kumpf SW; O'Donnell LM; Tartaro KR
[Ad] Endereço:Drug Safety Research and Development, Pfizer Global Research and Development, Pfizer, Inc., Groton, CT, USA. Electronic address: cris.kamperschroer@pfizer.com.
[Ti] Título:The genomic sequence of lymphocryptovirus from cynomolgus macaque.
[So] Source:Virology;488:28-36, 2016 Jan 15.
[Is] ISSN:1096-0341
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lymphocryptoviruses such as Epstein-Barr virus (EBV) cause persistent infections in human and non-human primates, and suppression of the immune system can increase the risk of lymphocryptovirus (LCV)-associated tumor development in both human and non-human primates. To enable LCV infection as a non-clinical model to study effects of therapeutics on EBV immunity, we determined the genomic DNA sequence of the LCV from cynomolgus macaque, a species commonly used for non-clinical testing. Comparison to rhesus macaque LCV and human EBV sequences indicates that LCV from the cynomolgus macaque has the same genomic arrangement and a high degree of similarity in most genes, especially with rhesus macaque LCV. Genes showing lower similarity were those encoding proteins involved in latency and/or tumor promotion or immune evasion. The genomic sequence of LCV from cynomolgus macaque should aid the development of non-clinical tools for identifying therapeutics that impact LCV immunity and carry potential lymphoma risk.
[Mh] Termos MeSH primário: DNA Viral/química
DNA Viral/genética
Genoma Viral
Lymphocryptovirus/genética
Lymphocryptovirus/isolamento & purificação
Macaca fascicularis/virologia
[Mh] Termos MeSH secundário: Animais
Ordem dos Genes
Dados de Sequência Molecular
Análise de Sequência de DNA
Homologia de Sequência de Aminoácidos
Sintenia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (DNA, Viral)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:160206
[Lr] Data última revisão:
160206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151123
[St] Status:MEDLINE


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[PMID]:26559839
[Au] Autor:Herrman M; Mühe J; Quink C; Wang F
[Ad] Endereço:Department of Medicine, Brigham and Women's Hospital, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
[Ti] Título:Epstein-Barr Virus gp350 Can Functionally Replace the Rhesus Lymphocryptovirus Major Membrane Glycoprotein and Does Not Restrict Infection of Rhesus Macaques.
[So] Source:J Virol;90(3):1222-30, 2015 Nov 11.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: Primary Epstein-Barr virus (EBV) infection is the most common cause of infectious mononucleosis, and persistent infection is associated with multiple cancers. EBV vaccine development has focused on the major membrane glycoprotein, gp350, since it is the major target for antibodies that neutralize infection of B cells. However, EBV has tropism for both B cells and epithelial cells, and it is unknown whether serum neutralizing antibodies against B cell infection will provide sufficient protection against virus infection initiated at the oral mucosa. This could be stringently tested by passive antibody transfer and oral virus challenge in the rhesus macaque model for EBV infection. However, only neutralizing monoclonal antibodies (MAbs) against EBV are available, and EBV is unable to infect rhesus macaques because of a host range restriction with an unknown mechanism. We cloned the prototypic EBV-neutralizing antibody, 72A1, and found that recombinant 72A1 did not neutralize rhesus lymphocryptovirus (rhLCV) infection of macaque B cells. Therefore, we constructed a chimeric rhLCV in which the native major membrane glycoprotein was replaced with EBV gp350. This chimeric rhLCV became sensitive to neutralization by the 72A1 MAb, efficiently immortalized macaque B cells in vitro, and successfully established acute and persistent infection after oral inoculation of rhesus macaques. Thus, EBV gp350 can functionally replace rhLCV gp350 and does not restrict rhLCV infection in vitro or in vivo. The chimeric rhLCV enables direct use of an EBV-specific MAb to investigate the effects of serum neutralizing antibodies against B cell infection on oral viral challenge in rhesus macaques. IMPORTANCE: This study asked whether the EBV major membrane glycoprotein could functionally replace the rhLCV major membrane glycoprotein. We found that an rhLCV humanized with EBV gp350 is capable of efficiently immortalizing monkey B cells in vitro and reproduces acute and persistent infection after oral inoculation of macaques. These results advance our understanding of why EBV cannot infect rhesus macaques by proving that viral attachment through gp350 is not the mechanism for EBV host range restriction. Humanization of rhLCV with EBV gp350 also confers susceptibility to a potent EBV-neutralizing MAb and provides a novel and significant enhancement to the rhesus macaque animal model where both the clinical utility and biological role of neutralizing MAbs against B cell or epithelial cell infection can now be directly tested in the most accurate animal model for EBV infection.
[Mh] Termos MeSH primário: Infecções por Herpesviridae/veterinária
Herpesvirus Humano 4/genética
Lymphocryptovirus/fisiologia
Glicoproteínas de Membrana/metabolismo
Doenças dos Primatas/virologia
Recombinação Genética
Infecções Tumorais por Vírus/veterinária
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/administração & dosagem
Anticorpos Monoclonais/imunologia
Anticorpos Neutralizantes/administração & dosagem
Anticorpos Neutralizantes/imunologia
Anticorpos Antivirais/administração & dosagem
Anticorpos Antivirais/imunologia
Infecções por Herpesviridae/virologia
Imunização Passiva
Lymphocryptovirus/genética
Macaca mulatta
Glicoproteínas de Membrana/genética
Infecções Tumorais por Vírus/virologia
Virulência
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antibodies, Neutralizing); 0 (Antibodies, Viral); 0 (Membrane Glycoproteins)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151113
[St] Status:MEDLINE
[do] DOI:10.1128/JVI.02531-15


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[PMID]:26428382
[Au] Autor:Mühe J; Wang F
[Ad] Endereço:Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, 181 Longwood Ave, Boston, MA, 02115.
[Ti] Título:Non-human Primate Lymphocryptoviruses: Past, Present, and Future.
[So] Source:Curr Top Microbiol Immunol;391:385-405, 2015.
[Is] ISSN:0070-217X
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Epstein-Barr virus (EBV) orthologues from non-human primates (NHPs) have been studied for nearly as long as EBV itself. Cross-reactive sera and DNA hybridization studies provided the first glimpses of the closely related herpesviruses that belonged to the same gamma-1 herpesvirus, or lymphocryptovirus, genus, as EBV. Over the years, detailed molecular and sequence analyses of LCVs that infect humans and other NHPs revealed similar colinear genome structures and homologous viral proteins expressed during latent and lytic infection. Despite these similarities, experimental infection of NHPs with EBV did not result in acute symptoms or persistent infection as observed in humans, suggesting some degree of host species restriction. Genome sequencing and a molecular clone of an LCV isolate from naturally infected rhesus macaques combined with domestic colonies of LCV-naïve rhesus macaques have opened the door to a unique experimental animal model that accurately reproduces the normal transmission, acute viremia, lifelong persistence, and immune responses found in EBV-infected humans. This chapter will summarize the advances made over the last 50 years in our understanding of LCVs that naturally infect both Old and New World NHPs, the recent, groundbreaking developments in the use of rhesus macaques as an animal model for EBV infection, and how NHP LCVs and the rhLCV animal model can advance future EBV research and the development of an EBV vaccine.
[Mh] Termos MeSH primário: Modelos Animais de Doenças
Infecções por Vírus Epstein-Barr/virologia
Infecções por Herpesviridae/veterinária
Herpesvirus Humano 4/fisiologia
Lymphocryptovirus/fisiologia
Doenças dos Primatas/virologia
[Mh] Termos MeSH secundário: Animais
Infecções por Vírus Epstein-Barr/imunologia
Infecções por Herpesviridae/imunologia
Infecções por Herpesviridae/virologia
Herpesvirus Humano 4/genética
Seres Humanos
Lymphocryptovirus/genética
Macaca mulatta
Doenças dos Primatas/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Em] Mês de entrada:1512
[Cu] Atualização por classe:161026
[Lr] Data última revisão:
161026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151003
[St] Status:MEDLINE
[do] DOI:10.1007/978-3-319-22834-1_13


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[PMID]:26085168
[Au] Autor:Mühe J; Wang F
[Ad] Endereço:Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, and Department of Molecular Biology & Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
[Ti] Título:Host Range Restriction of Epstein-Barr Virus and Related Lymphocryptoviruses.
[So] Source:J Virol;89(17):9133-6, 2015 Sep.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Epstein-Barr-related herpesviruses, or lymphocryptoviruses (LCV), naturally infect humans and nonhuman primates (NHP), but their host range is not well characterized. Using LCV and B cells from multiple species of Hominidae and Cercopithecidae, we show that LCV can immortalize B cells from some nonnative species but that growth transformation is restricted to B cells from their own family of hominoids or Old World NHP, suggesting a high degree of LCV adaptation to their natural primate host.
[Mh] Termos MeSH primário: Cercopithecidae/virologia
Herpesvirus Humano 4/patogenicidade
Especificidade de Hospedeiro
Lymphocryptovirus/patogenicidade
Doenças dos Macacos/virologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Linfócitos B/imunologia
Linfócitos B/virologia
Sequência de Bases
Cercopithecidae/imunologia
Antígenos Nucleares do Vírus Epstein-Barr/genética
Infecções por Herpesviridae/patologia
Infecções por Herpesviridae/virologia
Seres Humanos
Dados de Sequência Molecular
Alinhamento de Sequência
Análise de Sequência de DNA
Proteínas Virais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (EBNA-2 protein, Human herpesvirus 4); 0 (Epstein-Barr Virus Nuclear Antigens); 0 (Viral Proteins)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150619
[St] Status:MEDLINE
[do] DOI:10.1128/JVI.01235-15


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[PMID]:25505061
[Au] Autor:Spiess K; Fares S; Sparre-Ulrich AH; Hilgenberg E; Jarvis MA; Ehlers B; Rosenkilde MM
[Ad] Endereço:Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Division 12, Measles, Mumps, Rubella, and Viruses Affecting Immunocompromised Patients, Robert Koch Institute, Berlin, Germany.
[Ti] Título:Identification and functional comparison of seven-transmembrane G-protein-coupled BILF1 receptors in recently discovered nonhuman primate lymphocryptoviruses.
[So] Source:J Virol;89(4):2253-67, 2015 Feb.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: Coevolution of herpesviruses with their respective host has resulted in a delicate balance between virus-encoded immune evasion mechanisms and host antiviral immunity. BILF1 encoded by human Epstein-Barr virus (EBV) is a 7-transmembrane (7TM) G-protein-coupled receptor (GPCR) with multiple immunomodulatory functions, including attenuation of PKR phosphorylation, activation of G-protein signaling, and downregulation of major histocompatibility complex (MHC) class I surface expression. In this study, we explored the evolutionary and functional relationships between BILF1 receptor family members from EBV and 12 previously uncharacterized nonhuman primate (NHP) lymphocryptoviruses (LCVs). Phylogenetic analysis defined 3 BILF1 clades, corresponding to LCVs of New World monkeys (clade A) or Old World monkeys and great apes (clades B and C). Common functional properties were suggested by a high degree of sequence conservation in functionally important regions of the BILF1 molecules. A subset of BILF1 receptors from EBV and LCVs from NHPs (chimpanzee, orangutan, marmoset, and siamang) were selected for multifunctional analysis. All receptors exhibited constitutive signaling activity via G protein Gαi and induced activation of the NF-κB transcription factor. In contrast, only 3 of 5 were able to activate NFAT (nuclear factor of activated T cells); chimpanzee and orangutan BILF1 molecules were unable to activate NFAT. Similarly, although all receptors were internalized, BILF1 from the chimpanzee and orangutan displayed an altered cellular localization pattern with predominant cell surface expression. This study shows how biochemical characterization of functionally important orthologous viral proteins can be used to complement phylogenetic analysis to provide further insight into diverse microbial evolutionary relationships and immune evasion function. IMPORTANCE: Epstein-Barr virus (EBV), known as an oncovirus, is the only human herpesvirus in the genus Lymphocryptovirus (LCV). EBV uses multiple strategies to hijack infected host cells, establish persistent infection in B cells, and evade antiviral immune responses. As part of EBV's immune evasion strategy, the virus encodes a multifunctional 7-transmembrane (7TM) G-protein-coupled receptor (GPCR), EBV BILF1. In addition to multiple immune evasion-associated functions, EBV BILF1 has transforming properties, which are linked to its high constitutive activity. We identified BILF1 receptor orthologues in 12 previously uncharacterized LCVs from nonhuman primates (NHPs) of Old and New World origin. As 7TM receptors are excellent drug targets, our unique insight into the molecular mechanism of action of the BILF1 family and into the evolution of primate LCVs may enable validation of EBV BILF1 as a drug target for EBV-mediated diseases, as well as facilitating the design of drugs targeting EBV BILF1.
[Mh] Termos MeSH primário: Variação Genética
Lymphocryptovirus/genética
Lymphocryptovirus/fisiologia
Receptores Acoplados a Proteínas-G/genética
Receptores Acoplados a Proteínas-G/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Análise por Conglomerados
Genótipo
Seres Humanos
Lymphocryptovirus/isolamento & purificação
NF-kappa B/metabolismo
Fatores de Transcrição NFATC/metabolismo
Filogenia
Primatas
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (NF-kappa B); 0 (NFATC Transcription Factors); 0 (Receptors, G-Protein-Coupled)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141216
[St] Status:MEDLINE
[do] DOI:10.1128/JVI.02716-14


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[PMID]:25248517
[Au] Autor:Hirata A; Hashimoto K; Katoh Y; Sakai H; Bruce AG; Rose TM; Kaneko A; Suzuki J; Nikami H; Yanai T
[Ad] Endereço:Division of Animal Experiment, Life Science Research Center, Gifu University, Gifu City, Gifu, Japan akatsuki@gifu-u.ac.jp.
[Ti] Título:Characterization of spontaneous malignant lymphomas in Japanese macaques (Macaca fuscata).
[So] Source:Vet Pathol;52(3):566-72, 2015 May.
[Is] ISSN:1544-2217
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lymphomas are common spontaneous tumors in nonhuman primates but remain poorly characterized in Japanese macaques (Macaca fuscata). This study examined 5 cases of spontaneous malignant lymphoma in Japanese macaques, focusing on the immunophenotypes and presence of simian lymphocryptoviruses, which are Epstein-Barr virus-related herpesviruses in nonhuman primates. The macaques with lymphoma were 5 to 28 years old, indicating that lymphomas develop over a wide age range. The common macroscopic findings were splenomegaly and enlargement of lymph nodes. Histologic and immunohistochemical analyses revealed that all cases were non-Hodgkin type and exhibited a T-cell phenotype, positive for CD3 but negative for CD20 and CD79α. The lymphomas exhibited diverse cellular morphologies and were subdivided into 3 types according to the World Health Organization classification. These included 3 cases of peripheral T-cell lymphoma, not otherwise specified; 1 case of T-cell prolymphocytic leukemia; and 1 case of an unclassifiable T-cell lymphoma. Positive signals were detected by in situ hybridization in 2 of the 4 examined cases using probes for the Epstein-Barr virus-encoded small RNA (EBER). Furthermore, the presence of M. fuscata lymphocryptovirus 2, a macaque homolog of Epstein-Barr virus, was demonstrated in EBER-positive cases by polymerase chain reaction amplification followed by direct sequencing. Immunohistochemistry using antibody to the Epstein-Barr virus-encoded nuclear antigen 2 was negative, even in the EBER-positive cases. The present study suggests that T-cell lymphoma is more common than B-cell lymphoma in Japanese macaques and that M. fuscata lymphocryptovirus 2 is present in some cases.
[Mh] Termos MeSH primário: Linfoma/veterinária
Doenças dos Macacos/patologia
[Mh] Termos MeSH secundário: Animais
Feminino
Infecções por Herpesviridae/diagnóstico
Infecções por Herpesviridae/patologia
Infecções por Herpesviridae/veterinária
Hibridização In Situ/veterinária
Leucemia Prolinfocítica de Células T/diagnóstico
Leucemia Prolinfocítica de Células T/patologia
Leucemia Prolinfocítica de Células T/veterinária
Leucemia Prolinfocítica de Células T/virologia
Linfonodos/patologia
Lymphocryptovirus
Linfoma/complicações
Linfoma/patologia
Linfoma/virologia
Linfoma de Células T/diagnóstico
Linfoma de Células T/patologia
Linfoma de Células T/veterinária
Linfoma de Células T/virologia
Linfoma de Células T Periférico/diagnóstico
Linfoma de Células T Periférico/patologia
Linfoma de Células T Periférico/veterinária
Linfoma de Células T Periférico/virologia
Macaca
Masculino
Doenças dos Macacos/diagnóstico
Doenças dos Macacos/virologia
Reação em Cadeia da Polimerase em Tempo Real/veterinária
Esplenomegalia/etiologia
Esplenomegalia/patologia
Esplenomegalia/veterinária
Infecções Tumorais por Vírus/diagnóstico
Infecções Tumorais por Vírus/patologia
Infecções Tumorais por Vírus/veterinária
Infecções Tumorais por Vírus/virologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1604
[Cu] Atualização por classe:150423
[Lr] Data última revisão:
150423
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140925
[St] Status:MEDLINE
[do] DOI:10.1177/0300985814547389


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[PMID]:25064358
[Au] Autor:Kamperschroer C; Tartaro K; Kumpf SW
[Ad] Endereço:Drug Safety Research and Development, Pfizer Global Research and Development, Pfizer, Inc., Groton, CT United States. Electronic address: cris.kamperschroer@pfizer.com.
[Ti] Título:Quantitative PCR assays reveal high prevalence of lymphocryptovirus as well as lytic phase gene expression in peripheral blood cells of cynomolgus macaques.
[So] Source:J Virol Methods;207:220-5, 2014 Oct.
[Is] ISSN:1879-0984
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Lymphocryptoviruses such as Epstein-Barr virus (EBV) are important pathogens in both human and non-human primates, particularly during immunosuppression. Immunomodulatory molecules that may suppress antiviral immunity are commonly tested in the cynomolgus macaque. To enable the study of lymphocryptovirus (LCV) in this non-clinical model, PCR-based assays were developed to measure LCV viral load, as well as transcripts for the lytic phase LCV gene, BALF-2. Results from studies employing these assays showed that LCV genome was detected in the oropharyngeal epithelium of all cynomolgus monkeys tested, and the majority had viral genome in peripheral blood mononuclear cells (PBMCs). The results also revealed LCV lytic phase gene expression not only in the oropharynx of most monkeys, but also in PBMCs of approximately one half of monkeys tested. This unexpected finding suggests that initiation of the lytic gene expression cascade occurs often in the peripheral blood cells of healthy monkeys.
[Mh] Termos MeSH primário: Expressão Gênica
Infecções por Herpesviridae/veterinária
Leucócitos Mononucleares/virologia
Lymphocryptovirus/isolamento & purificação
Doenças dos Primatas/virologia
[Mh] Termos MeSH secundário: Animais
Epitélio/virologia
Genes Virais
Infecções por Herpesviridae/virologia
Lymphocryptovirus/genética
Macaca fascicularis
Orofaringe/virologia
Prevalência
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1505
[Cu] Atualização por classe:140827
[Lr] Data última revisão:
140827
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140728
[St] Status:MEDLINE


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[PMID]:24945689
[Au] Autor:Aswad A; Katzourakis A
[Ad] Endereço:Department of Zoology, University of Oxford, Oxford, Oxfordshire, United Kingdom.
[Ti] Título:The first endogenous herpesvirus, identified in the tarsier genome, and novel sequences from primate rhadinoviruses and lymphocryptoviruses.
[So] Source:PLoS Genet;10(6):e1004332, 2014 Jun.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Herpesviridae is a diverse family of large and complex pathogens whose genomes are extremely difficult to sequence. This is particularly true for clinical samples, and if the virus, host, or both genomes are being sequenced for the first time. Although herpesviruses are known to occasionally integrate in host genomes, and can also be inherited in a Mendelian fashion, they are notably absent from the genomic fossil record comprised of endogenous viral elements (EVEs). Here, we combine paleovirological and metagenomic approaches to both explore the constituent viral diversity of mammalian genomes and search for endogenous herpesviruses. We describe the first endogenous herpesvirus from the genome of the Philippine tarsier, belonging to the Roseolovirus genus, and characterize its highly defective genome that is integrated and flanked by unambiguous host DNA. From a draft assembly of the aye-aye genome, we use bioinformatic tools to reveal over 100,000 bp of a novel rhadinovirus that is the first lemur gammaherpesvirus, closely related to Kaposi's sarcoma-associated virus. We also identify 58 genes of Pan paniscus lymphocryptovirus 1, the bonobo equivalent of human Epstein-Barr virus. For each of the viruses, we postulate gene function via comparative analysis to known viral relatives. Most notably, the evidence from gene content and phylogenetics suggests that the aye-aye sequences represent the most basal known rhadinovirus, and indicates that tumorigenic herpesviruses have been infecting primates since their emergence in the late Cretaceous. Overall, these data show that a genomic fossil record of herpesviruses exists despite their extremely large genomes, and expands the known diversity of Herpesviridae, which will aid the characterization of pathogenesis. Our analytical approach illustrates the benefit of intersecting evolutionary approaches with metagenomics, genetics and paleovirology.
[Mh] Termos MeSH primário: Retrovirus Endógenos/genética
Lymphocryptovirus/genética
Rhadinovirus/genética
Tarsiidae/genética
Tarsiidae/virologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Mapeamento Cromossômico
Evolução Molecular
Genoma/genética
Filogenia
Roseolovirus/genética
Alinhamento de Sequência
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1506
[Cu] Atualização por classe:150805
[Lr] Data última revisão:
150805
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140620
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1004332


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[PMID]:24522914
[Au] Autor:Leskowitz R; Fogg MH; Zhou XY; Kaur A; Silveira EL; Villinger F; Lieberman PM; Wang F; Ertl HC
[Ad] Endereço:The Wistar Institute, Philadelphia, Pennsylvania, USA.
[Ti] Título:Adenovirus-based vaccines against rhesus lymphocryptovirus EBNA-1 induce expansion of specific CD8+ and CD4+ T cells in persistently infected rhesus macaques.
[So] Source:J Virol;88(9):4721-35, 2014 May.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: The impact of Epstein-Barr virus (EBV) on human health is substantial, but vaccines that prevent primary EBV infections or treat EBV-associated diseases are not yet available. The Epstein-Barr nuclear antigen 1 (EBNA-1) is an important target for vaccination because it is the only protein expressed in all EBV-associated malignancies. We have designed and tested two therapeutic EBV vaccines that target the rhesus (rh) lymphocryptovirus (LCV) EBNA-1 to determine if ongoing T cell responses during persistent rhLCV infection in rhesus macaques can be expanded upon vaccination. Vaccines were based on two serotypes of E1-deleted simian adenovirus and were administered in a prime-boost regimen. To further modulate the response, rhEBNA-1 was fused to herpes simplex virus glycoprotein D (HSV-gD), which acts to block an inhibitory signaling pathway during T cell activation. We found that vaccines expressing rhEBNA-1 with or without functional HSV-gD led to expansion of rhEBNA-1-specific CD8(+) and CD4(+) T cells in 33% and 83% of the vaccinated animals, respectively. Additional animals developed significant changes within T cell subsets without changes in total numbers. Vaccination did not increase T cell responses to rhBZLF-1, an immediate early lytic phase antigen of rhLCV, thus indicating that increases of rhEBNA-1-specific responses were a direct result of vaccination. Vaccine-induced rhEBNA-1-specific T cells were highly functional and produced various combinations of cytokines as well as the cytolytic molecule granzyme B. These results serve as an important proof of principle that functional EBNA-1-specific T cells can be expanded by vaccination. IMPORTANCE: EBV is a common human pathogen that establishes a persistent infection through latency in B cells, where it occasionally reactivates. EBV infection is typically benign and is well controlled by the host adaptive immune system; however, it is considered carcinogenic due to its strong association with lymphoid and epithelial cell malignancies. Latent EBNA-1 is a promising target for a therapeutic vaccine, as it is the only antigen expressed in all EBV-associated malignancies. The goal was to determine if rhEBNA-1-specific T cells could be expanded upon vaccination of infected animals. Results were obtained with vaccines that target EBNA-1 of rhLCV, a virus closely related to EBV. We found that vaccination led to expansion of rhEBNA-1 immune cells that exhibited functions fit for controlling viral infection. This confirms that rhEBNA-1 is a suitable target for therapeutic vaccines. Future work should aim to generate more-robust T cell responses through modified vaccines.
[Mh] Termos MeSH primário: Linfócitos T CD4-Positivos/imunologia
Linfócitos T CD8-Positivos/imunologia
Infecções por Herpesviridae/veterinária
Vacinas contra Herpesvirus/imunologia
Lymphocryptovirus/imunologia
Proteínas Virais/imunologia
[Mh] Termos MeSH secundário: Adenovirus dos Símios/genética
Animais
Portadores de Fármacos
Feminino
Vetores Genéticos
Infecções por Herpesviridae/imunologia
Vacinas contra Herpesvirus/administração & dosagem
Vacinas contra Herpesvirus/genética
Lymphocryptovirus/genética
Macaca mulatta
Vacinação/métodos
Proteínas Virais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Drug Carriers); 0 (Herpesvirus Vaccines); 0 (Viral Proteins)
[Em] Mês de entrada:1406
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140214
[St] Status:MEDLINE
[do] DOI:10.1128/JVI.03744-13



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