an animal model for acute and persistent epstein-barr virus infection.epstein-barr virus (ebv) is a human lymphocryptovirus that causes infectious mononucleosis, persists asymptomatically for life in nearly all adults, and is associated with the development of b cell lymphomas and nasopharyngeal carcinomas. a highly similar rhesus lymphocryptovirus naturally endemic in rhesus monkeys was used to orally infect naïve animals from a pathogen-free colony. this animal model reproduced key aspects of human ebv infection, including oral transmission, atypical lymphocytos ...19979197263
infection of human b lymphocytes with lymphocryptoviruses related to epstein-barr virus.lymphocryptoviruses (lcvs) naturally infecting old world nonhuman primates are closely related to the human lcv, epstein-barr virus (ebv), and share similar genome organization and sequences, biologic properties, epidemiology, and pathogenesis. lcvs can efficiently immortalize b lymphocytes from the autologous species, but the ability of a given lcv to immortalize b cells from other old world primate species is variable. we found that lcv from rhesus monkeys did not immortalize human b cells, an ...19989525646
transcriptional activation signals found in the epstein-barr virus (ebv) latency c promoter are conserved in the latency c promoter sequences from baboon and rhesus monkey ebv-like lymphocryptoviruses (cercopithicine herpesviruses 12 and 15).the epstein-barr virus (ebv) ebna2 protein is a transcriptional activator that controls viral latent gene expression and is essential for ebv-driven b-cell immortalization. ebna2 is expressed from the viral c promoter (cp) and regulates its own expression by activating cp through interaction with the cellular dna binding protein cbf1. through regulation of cp and ebna2 expression, ebv controls the pattern of latent protein expression and the type of latency established. to gain further insight i ...19999847397
mechanisms that regulate epstein-barr virus ebna-1 gene transcription during restricted latency are conserved among lymphocryptoviruses of old world primates.epstein-barr virus (ebv), the only known human lymphocryptovirus (lcv), displays a remarkable degree of genetic and biologic identity to lcvs that infect old world primates. within their natural hosts, infection by these viruses recapitulates many key aspects of ebv infection, including the establishment of long-term latency within b lymphocytes, and is therefore a potentially valuable animal model of ebv infection. however, it is unclear whether these lcvs have adopted or maintained the same me ...19999971778
inhibition of antigen presentation by the glycine/alanine repeat domain is not conserved in simian homologues of epstein-barr virus nuclear antigen 1.most humans and old world nonhuman primates are infected for life with epstein-barr virus (ebv) or closely related gammaherpesviruses in the same lymphocryptovirus (lcv) subgroup. several potential strategies for immune evasion and persistence have been proposed based on studies of ebv infection in humans, but it has been difficult to test their actual contribution experimentally. interest has focused on the ebv nuclear antigen 1 (ebna1) because of its essential role in the maintenance and repli ...199910438828
a novel epstein-barr virus-like virus, hv(mne), in a macaca nemestrina with mycosis fungoides.epstein-barr virus (ebv) infection of humans has been associated with the development of lymphoid malignancies mainly of b-cell lineage, although occasionally t-cell lymphomas have been reported. we describe here the characterization of a novel ebv-like virus (hv(mne)) isolated from a simian t-cell lymphotropic virus type i/ii (stlv-i/ii) seronegative pigtailed macaque (macaca nemestrina) with a cutaneous t-cell lymphoma. immunohistochemistry studies on the skin lesions demonstrated that the inf ...199910477739
strong selective pressure for evolution of an epstein-barr virus lmp2b homologue in the rhesus lymphocryptovirus.latent membrane protein 2b (lmp2b) is expressed during latent epstein-barr virus (ebv) infection, but little is known about its role. the goal of this study was to determine whether an lmp2b homologue is conserved in the rhesus monkey lymphocryptovirus (lcv). both rhesus lcv lmp2a and lmp2b genes were cloned and sequenced. the rhesus lcv lmp2b gene is positionally conserved, and the ebna-2 responsiveness and the bidirectional nature of the lmp1-lmp2b promoter have also been functionally conserve ...199910482645
evolution of two types of rhesus lymphocryptovirus similar to type 1 and type 2 epstein-barr virus.rhesus monkeys and other nonhuman old world primates are naturally infected with lymphocryptoviruses (lcv) that are closely related to epstein-barr virus (ebv). a rhesus lcv isolate (208-95) was derived from a b-cell lymphoma in a simian immunodeficiency virus-infected rhesus macaque. the ebna-2 homologues from 208-95 and a previous rhesus lcv isolate (lcl8664) were polymorphic on immunoblotting, so the ebna-2 genes from these two rhesus lcv were cloned, sequenced, and compared. the ebna-2 genes ...199910516028
sequence and functional analysis of ebna-lp and ebna2 proteins from nonhuman primate lymphocryptoviruses.the epstein-barr virus (ebv) ebna-lp and ebna2 proteins are the first to be synthesized during establishment of latent infection in b lymphocytes. ebna2 is a key transcriptional regulator of both viral and cellular gene expression and is essential for ebv-induced immortalization of b lymphocytes. ebna-lp is also important for ebv-induced immortalization of b lymphocytes, but far less is known about the functional domains and cellular cofactors that mediate ebna-lp function. while recent studies ...200010590127
persistent infection of bovine herpesvirus type 4 in bovine endothelial cell cultures.herpesviruses can establish a persistent infection in the cells and tissues of their natural hosts and thus may produce diseases due to cytolytic infections. we have isolated a herpesvirus from a bovine vascular endothelial cell culture after continuous subculturing. typical cytopathic changes were observed in bovine endothelial cell cultures 2 days after inoculation of the virus. the virus had an icosahedral nucleocapsid of 100-150 nm in diameter and an envelope. the sequences of some dna fragm ...199910591496
rhesus lymphocryptovirus infection during the progression of saids and saids-associated lymphoma in the rhesus macaque.saids-associated lymphoma (sal) represents a monoclonal expansion of b-cell origin in which simian immunodeficiency virus (siv) infection is not detected. however, tumor cells are frequently infected with rhesus lymphocryptovirus (rhlcv), a rhesus homologue of epstein-barr virus (ebv). in previous studies, the incidence of rhlcv infection in sal was determined to be 89% as measured by polymerase chain reaction (pcr) and/or in situ hybridization. the main objective of the present study was to asc ...200010659055
epidemiology of herpesvirus papio infection in a large captive baboon colony: similarities to epstein-barr virus infection in humans.the epidemiology of herpesvirus papio, a lymphocryptovirus similar to epstein-barr virus (ebv), was studied in a captive colony of >1900 baboons. herpesvirus papio igg antibody titers were measured by ifa. in total, 438 specimens from 296 baboons were assessed, including 116 serial specimens from 52 juveniles and 6 infants studied monthly for 1 year following birth and at age 18 months. maternally derived antibody reached a nadir at 4 months of age. about 75% of animals at 12 months of age and > ...200010762578
structural, functional, and genetic comparisons of epstein-barr virus nuclear antigen 3a, 3b, and 3c homologues encoded by the rhesus lymphocryptovirus.ebna-3a, -3b, and -3c are three latent infection nuclear proteins important for epstein-barr virus (ebv)-induced b-cell immortalization and the immune response to ebv infection. all three are hypothesized to function as transcriptional transactivators, but little is known about their precise mechanism of action or their role in ebv pathogenesis. we have cloned and studied the three ebna-3 homologues from a closely related lymphocryptovirus (lcv) which naturally infects rhesus monkeys. the rhesus ...200010846073
cloning of the rhesus lymphocryptovirus viral capsid antigen and epstein-barr virus-encoded small rna homologues and use in diagnosis of acute and persistent infections.epstein-barr virus (ebv) is the most common cause of infectious mononucleosis and is associated with the development of several human malignancies. a closely related herpesvirus in the same lymphocryptovirus (lcv) genera as ebv naturally infects rhesus monkeys and provides an important animal model for studying ebv pathogenesis. we cloned the small viral capsid antigen (svca) homologue from the rhesus lcv and developed a peptide enzyme-linked immunosorbent assay (elisa) to determine whether epit ...200010970361
sequence analysis and variation of ebna-1 in epstein-barr virus-related herpesvirus of cynomolgus monkey.the epstein-barr virus (ebv) nuclear antigen 1 (ebna-1) is an important protein for immortalization and tumorigenesis of infected cells. ebna-1 gene variants may play a role in tumorigenesis. we determined the nucleotide and amino acid (aa) sequences of ebna-1 in ebv-related herpesviruses from cynomolgus monkeys (cynomolgus-ebv) which induced malignant lymphomas in its natural host and in rabbits, and compared them with sequences of ebv and other lymphocryptoviruses (lcvs).200010971128
fatal lymphoproliferative disease associated with a novel gammaherpesvirus in a captive population of common marmosets.callitrichids (marmosets and tamarins) are extremely susceptible to experimental tumor induction by herpesviruses native to other primate species. a colony of common marmosets developed a syndrome of weight loss, inappetence, diarrhea, and in several animals, palpable abdominal masses.200010987671
comparative analysis of the transforming mechanisms of epstein-barr virus, kaposi's sarcoma-associated herpesvirus, and herpesvirus saimiri.members of the gamma herpesvirus family include the lymphocryptoviruses (gamma-1 herpesviruses) and the rhadinoviruses (gamma-2 herpesviruses). gammaherpesvirinae uniformly establish long-term, latent, reactivatable infection of lymphocytes, and several members of the gamma herpesviruses are associated with lymphoproliferative diseases. epstein-barr virus is a lymphocryptovirus, whereas kaposi sarcoma-associated herpesvirus and herpesvirus saimiri are members of the rhadinovirus family. genes en ...200111034540
b-cell leukemia in a rhesus macaque (macaca mulatta) infected with simian immunodeficiency virus.conditions associated with abnormal b-cell proliferation have an increased incidence in the hiv-infected population. a longitudinal study conducted at the tulane regional primate research center has followed more than 1,000 rhesus macaques infected with simian-immunodeficiency virus (siv) since 1984. while spontaneous b-cell malignancy in siv-negative macaques has not been reported, 42 cases of siv-associated-lymphoma (sal) have been documented in this cohort. recently we identified a single cas ...200011042530
sequences of cytotoxic t-lymphocyte epitopes in the epstein-barr virus (ebv) nuclear antigen-3b gene in a japanese population with or without ebv-positive lymphoid malignancies.latent infection antigens of ebv, including ebv nuclear antigens (ebnas) and latent membrane proteins, are expressed in latently infected and immortalized b cells but work as target antigens for host cytotoxic t-lymphocyte (ctl) responses in an hla class i-restricted manner. among these latent antigens, the immunodominant ctl epitopes in ebna3b (ebna3b 399-408 and ebna3b 416-424) are well characterized. mutations and strain differences in these sequences, compared to the prototype a sequence, re ...200011058881
amino acids of epstein-barr virus nuclear antigen 3a essential for repression of jkappa-mediated transcription and their evolutionary conservation.epstein-barr virus (ebv) nuclear antigen 3a (ebna-3a) is essential for virus-mediated immortalization of b lymphocytes in vitro and is believed to regulate transcription of cellular and/or viral genes. one known mechanism of regulation is through its interaction with the cellular transcription factor jkappa. this interaction downregulates transcription mediated by ebna-2 and jkappa. to identify the amino acids that play a role in this interaction, we have generated mutant ebna-3a proteins. a mut ...200111119577
simian homologues of epstein-barr virus.gamma-herpesviruses closely related to the epstein-barr virus (ebv) are known to naturally infect old world non-human primates and are classified in the same lymphocryptovirus (lcv) genera. lcv infecting humans and old world primates share similar biology, and recent studies have demonstrated that these viruses share a similar repertoire of viral genes. surprisingly, the latent infection genes associated with cell growth transformation demonstrate the most striking sequence divergence, but the f ...200111313007
simian homologues of human herpesvirus 8.gamma-herpesviruses can be found in most primates including old world an new world monkeys. the gamma-herpesvirinae are grouped into two classes: lymphocryptoviruses (gamma1) and rhadinoviruses (gamma2). the lymphocryptoviruses include epstein-barr virus, lymphocryptovirus of rhesus monkeys, and herpesvirus papio of baboons. rhadinoviruses that infect new world monkeys include herpesvirus saimiri, whose natural host is the squirrel monkey, and herpesvirus ateles, which infects spider monkeys. rh ...200111313010
comparative pathobiology of hiv- and siv-associated lymphoma. 200111429114
a new animal model for epstein-barr virus pathogenesis. 200111443863
hv(mne), a novel lymphocryptovirus related to epstein-barr virus, induces lymphoma in new zealand white rabbits.hv(mne) is a novel epstein-barr (ebv)-like virus isolated from a macaca nemestrina with cd8(+) t-cell mycosis fungoides-cutaneous t-cell lymphoma. here it is demonstrated that intravenous inoculation of irradiated hv(mne)-infected t cells or cell-free virus from the j94356(pbmc) cell line in new zealand white rabbits results in seroconversion to the viral capsid antigen (vca) of ebv; all animals that seroconverted to vca developed malignant lymphoma within months of inoculation. in contrast, con ...200111568007
genetic analysis of the epstein-barr virus-coded leader protein ebna-lp as a co-activator of ebna2 between the epstein-barr virus (ebv)-coded leader protein ebna-lp and the nuclear antigen ebna2 appears to be critical for efficient virus-induced b cell transformation. here we report the genetic analysis of ebna-lp function using two transient co-transfection assays of co-operativity, activation of latent membrane protein 1 (lmp1) expression from a resident ebv genome in akata-bl cells and activation of an ebna2-responsive reporter construct. small deletions were introduced into e ...200111714985
complete nucleotide sequence of the rhesus lymphocryptovirus: genetic validation for an epstein-barr virus animal model.we sequenced the rhesus lymphocryptovirus (lcv) genome in order to determine its genetic similarity to epstein-barr virus (ebv). the rhesus lcv encodes a repertoire identical to that of ebv, with 80 open reading frames, including cellular interleukin-10, bcl-2, and colony-stimulating factor 1 receptor homologues and an equivalent set of viral glycoproteins. the highly conserved rhesus lcv gene repertoire provides a unique animal model for the study of ebv pathogenesis.200211739708
characterization of an epstein-barr virus-related gammaherpesvirus from common marmoset (callithrix jacchus).a gammaherpesvirus related to epstein-barr virus (ebv; human herpesvirus 4) infects otherwise healthy common marmosets (callithrix jacchus). long-term culture of common marmoset peripheral blood lymphocytes resulted in outgrowth of spontaneously immortalized lymphoblastoid cell lines, primarily of b cell lineage. electron microscopy of cells and supernatants showed herpesvirus particles. there were high rates of serological cross-reactivity to other herpesviruses (68-86%), but with very low geom ...200212075080
siv-associated lymphomas in rhesus monkeys (macaca mulatta) in comparison with hiv-associated lymphomas.a retrospective study was performed to characterize malignant lymphomas of 16 simian immunodeficiency virus (siv)-infected rhesus monkeys (macaca mulatta), 2-9 years of age, on the basis of clinical data, histologic and immunophenotypic results, and cell death indices compiled with the tdt-mediated x-dutp nick end labeling method. we particularly focused on providing immunohistochemical evidence of expression products of ebna2, bc12, c-myc, p21, p53, and bc16. results were compared with data fro ...200212102218
two nonconsensus sites in the epstein-barr virus oncoprotein ebna3a cooperate to bind the co-repressor carboxyl-terminal-binding protein (ctbp).ctbp (carboxyl-terminal binding protein) has been shown to be a highly conserved co-repressor of transcription that is important in development, cell cycle regulation, and transformation. viral proteins e1a and ebna3c and all the various drosophila and vertebrate transcription factors to which ctbp has been reported to bind contain a conserved "pxdls" ctbp-interaction domain. here we show that ebna3a binds ctbp both in vitro and in vivo but that this interaction does not require a near consensus ...200212372828
the structure of hla-b8 complexed to an immunodominant viral determinant: peptide-induced conformational changes and a mode of mhc class i dimerization.ebv is a ubiquitous human pathogen that chronically infects up to 90% of the population. persistent viral infection is characterized by latency and periods of viral replication that are kept in check by a strong antiviral ctl response. despite the size of the ebv genome, ctl immunity focuses on only a few viral determinants but expands a large primary and memory response toward these epitopes. in unrelated hla-b8(+) individuals, the response to the immunodominant latent ag flrgraygl from epstein ...200212391232
complete genomic sequence of an epstein-barr virus-related herpesvirus naturally infecting a new world primate: a defining point in the evolution of oncogenic lymphocryptoviruses.callitrichine herpesvirus 3 (calhv-3) was isolated from a b-cell lymphoma arising spontaneously in the new world primate callithrix jacchus, the common marmoset. partial genomic sequence analysis definitively identified calhv-3 as a member of the epstein-barr virus (ebv)-related lymphocryptovirus (lcv) genus and extended the known host range of lcvs beyond humans and old world nonhuman primates. we have now completed the first genomic sequence of an lcv infecting a new world primate by describin ...200212414947
transcriptional regulatory properties of epstein-barr virus nuclear antigen 3c are conserved in simian lymphocryptoviruses.epstein-barr virus (ebv) nuclear antigen 3c (ebna-3c) is a large transcriptional regulator essential for ebv-mediated immortalization of b lymphocytes. we previously identified interactions between ebna-3c and two cellular transcription factors, j kappa and spi proteins, through which ebna-3c regulates transcription. to better understand the contribution of these interactions to ebna-3c function and ebv latency, we examined whether they are conserved in the homologous proteins of nonhuman primat ...200312719556
novel gamma-1 herpesviruses identified in free-ranging new world monkeys (golden-handed tamarin [saguinus midas], squirrel monkey [saimiri sciureus], and white-faced saki [pithecia pithecia]) in french guiana.the recent finding of a novel epstein-barr virus-related lymphocryptovirus (calhv-3) in a captive colony of common marmoset (callithrix jacchus) in the united states modifies the view that the host range of lymphocryptovirus is restricted to humans and old world primates. we investigated the presence of epstein-barr virus-related viruses in 79 samples of new world monkeys caught in the wild, including six species of the cebidae family and one of the callitrichidae, living in the rain forest of f ...200312885928
novel simian homologues of epstein-barr virus.thirty different lymphocryptoviruses (lcv), 26 of them novel, were detected in primates by a panherpesvirus pcr assay. nineteen lcv from chimpanzees, bonobos, gorillas, and other old world primates were closely related to epstein-barr virus (ebv), the type species of the genus lymphocryptovirus. seven lcv originating from new world primates were related to callitrichine herpesvirus 3 (calhv-3), the first recognized new world lcv. importantly, a second lcv from gorillas and three lcv from orangut ...200312970457
species-specific transformation of t cells by hv(mne).hv(mne) is an epstein-barr virus (ebv)-like lymphocryptovirus (lcv) originally isolated from a macaca nemestrina with cd8(+) t cell mycosis fungoides/cutaneous t cell lymphoma (blood 98 (2001), 2193). hv(mne) transforms rabbit t cells in vitro and causes t cell lymphoma in new zealand white rabbits. here we demonstrate that hv(mne) also immortalizes t cells from mustached tamarins but not those from owl monkeys, common marmosets, squirrel monkeys, black-capped capuchins, and humans. cytogenetic ...200314698668
phylogenetic relationships in the lymphocryptovirus genus of the gammaherpesvirinae.complete dna sequences were determined for the glycoprotein b (gb) genes of four viruses from the genus lymphocryptovirus, whose hosts had been assigned as baboon, orangutan, chimpanzee and gorilla. together with published sequences for the gb genes of three lymphocryptoviruses, namely the human pathogen epstein-barr virus (ebv), a rhesus monkey virus and a marmoset virus, the sequences were used to investigate evolutionary relationships in the genus. the chimpanzee and orangutan viruses' sequen ...200414749184
molecular evidence for rhesus lymphocryptovirus infection of epithelial cells in immunosuppressed rhesus macaques.epstein-barr virus (ebv) is a human oncogenic herpesvirus associated with epithelial cell and b-cell malignancies. ebv infection of b lymphocytes is essential for acute and persistent ebv infection in humans; however, the role of epithelial cell infection in the normal ebv life cycle remains controversial. the rhesus lymphocryptovirus (lcv) is an ebv-related herpesvirus that naturally infects rhesus macaques and can be used experimentally to model persistent b-cell infection and b-cell lymphomag ...200415016868
retrospective analysis of clinical and laboratory factors associated with lymphoma in simian aids.a nonhuman primate model for aids-associated non-hodgkin's lymphoma (aids-nhl) has been described in which animals inoculated with simian immunodeficiency virus (siv) develop simian aids (saids) and saids-nhl. the objective of the present study was to describe statistically the major trends observed in clinical and laboratory data collected longitudinally on a large cohort of nonhuman primates that developed saids-nhl. clinical and laboratory data were collected longitudinally on each animal fro ...200415061214
orangutan herpesvirus.a male orangutan suffered from ulcers at the buccal mucosa. we obtained swab fluid from the base of both vesicles and ulcers and collected blood for further separation into serum, plasma and peripheral blood mononuclear cells (pbmc) for detection of antibody to herpesvirus by serology and herpesvirus dna by polymerase chain reaction (pcr) using consensus degenerate primers. serology was positive for human ebv igg but negative for epstein-barr virus (ebv) immunoglobulin (igm), as well as for both ...200415061729
experimental rhesus lymphocryptovirus infection in immunosuppressed macaques: an animal model for epstein-barr virus pathogenesis in the immunosuppressed develop a model for epstein-barr virus (ebv) pathogenesis in immunosuppressed hosts, we studied experimental infections of immunocompetent versus shiv 89.6p-infected, immunosuppressed rhesus macaques with the ebv-related rhesus lymphocryptovirus (lcv). primary lcv infection after oral inoculation of 4 immunocompetent animals was characterized by an acute viremia and seroconversion followed by asymptomatic lcv persistence. four immunosuppressed macaques infected orally with lcv failed to devel ...200415150077
de novo generation of cd4 t cells against viruses present in the host during immune reconstitution.t cells recognizing self-peptides are typically deleted in the thymus by negative selection. it is not known whether t cells against persistent viruses (eg, herpesviruses) are generated by the thymus (de novo) after the onset of the infection. peptides from such viruses might be considered by the thymus as self-peptides, and t cells specific for these peptides might be deleted (negatively selected). here we demonstrate in baboons infected with baboon cytomegalovirus and baboon lymphocryptovirus ...200515479725
the epstein-barr virus bilf1 gene encodes a g protein-coupled receptor that inhibits phosphorylation of rna-dependent protein kinase.epstein-barr virus (ebv) infection is associated with many lymphoproliferative diseases, such as infectious mononucleosis and burkitt's lymphoma. consequently, ebv is one of the most extensively studied herpesviruses. surprisingly, a putative g protein-coupled receptor (gpcr) gene of ebv, bilf1, has hitherto escaped attention, yet bilf1-like genes are conserved among all known lymphocryptovirus species, suggesting that they play a pivotal role in viral infection. to determine the function of ebv ...200515596837
on phylogenetic relationships among major lineages of the gammaherpesvirinae.phylogenetic relationships within the subfamily gammaherpesvirinae of the family herpesviridae were investigated for three species in the genus lymphocryptovirus (or gamma1 group) and nine in the genus rhadinovirus (or gamma2 group). alignments of amino acid sequences from up to 28 genes were used to derive trees by maximum-likelihood and bayesian monte carlo markov chain methods. two problem areas were identified involving an unresolvable multifurcation for a clade within the gamma2 group, and ...200515659749
comparative transmission of multiple herpesviruses and simian virus 40 in a baboon breeding colony.little is known about the natural history of herpesviruses indigenous in baboons. here, we describe the development of elisas for five herpesviruses. these assays were used to test more than 950 serum samples collected from approximately 210 infant/juvenile and 130 adult baboons in a captive breeding colony over a period of seven years. results indicated that baboon cytomegalovirus, lymphocryptovirus, and rhadinovirus are transmitted efficiently within the colony and are acquired at an early age ...200415679269
epstein-barr virus ebna3 proteins bind to the c8/alpha7 subunit of the 20s proteasome and are degraded by 20s proteasomes in vitro, but are very stable in latently infected b cells.a yeast two-hybrid screen using ebna3c as bait revealed an interaction between this epstein-barr virus (ebv)-encoded nuclear protein and the c8 (alpha7) subunit of the human 20s proteasome. the interaction was confirmed by glutathione s-transferase (gst) pull-down experiments and these also revealed that the related proteins ebna3a and ebna3b can bind similarly to c8/alpha7. the interaction between these viral proteins and gst-c8/alpha7 was shown to be significantly more robust than the previous ...200515831937
reduced prevalence of epstein-barr virus-related lymphocryptovirus infection in sera from a new world primate.the recent discovery of an epstein-barr virus (ebv)-related lymphocryptovirus (lcv) naturally infecting common marmosets demonstrated that gamma-1 herpesviruses are not limited to human and old world nonhuman primate hosts. we developed serologic assays to detect serum antibodies against lytic- and latent-infection marmoset lcv antigens in order to perform the first seroepidemiologic study of lcv infection in new world primates. in three different domestic colonies and in animals recently captur ...200516014968
mutations of epstein-barr virus gh that are differentially able to support fusion with b cells or epithelial cells.the core fusion machinery of all herpesviruses consists of three conserved glycoproteins, gb and ghgl, suggesting a common mechanism for virus cell fusion, but fusion of epstein-barr virus (ebv) with b cells and epithelial cells is initiated differently. fusion with b cells requires a fourth protein, gp42, which complexes with ghgl and interacts with hla class ii, the b-cell coreceptor. fusion with an epithelial cell does not require gp42 but requires interaction of ghgl with a novel epithelial ...200516103144
the cd8+ t-cell response to an epstein-barr virus-related gammaherpesvirus infecting rhesus macaques provides evidence for immune evasion by the ebna-1 homologue.epstein-barr virus (ebv) infection persists for life in humans, similar to other gammaherpesviruses in the same lymphocryptovirus (lcv) genus that naturally infect old world nonhuman primates. the specific immune elements required for control of ebv infection and potential immune evasion strategies essential for persistent ebv infection are not well defined. we evaluated the cellular immune response to latent infection proteins in rhesus macaques with naturally and experimentally acquired rhesus ...200516188971
pathogenesis of gammaherpesvirus infections.gammaherpesviruses are members of an emerging subfamily among the herpesviridae. two genera are discriminated: (i) lymphocryptovirus, including its type species epstein-barr virus (ebv), and (ii) rhadinovirus, including viruses of interest for medicine, veterinary medicine, and biomedical research, i.e. alcelaphine herpesvirus 1, bovine herpesvirus 4, equine herpesvirus 2, human herpesvirus 8, mouse herpesvirus 68, and ovine herpesvirus 2 (ovhv-2). the perception that these viruses have a narrow ...200616332416
conserved cell cycle regulatory properties within the amino terminal domain of the epstein-barr virus nuclear antigen 3c.the gammaherpesviruses rhesus lymphocryptovirus (lcv) and epstein-barr virus (ebv) are closely related phylogenetically. rhesus lcv efficiently immortalizes rhesus b cells in vitro. however, despite a high degree of conservation between the rhesus lcv and ebv genomes, rhesus lcv fails to immortalize human b cells in vitro. this species restriction may, at least in part, be linked to the ebv nuclear antigens (ebnas) and latent membrane proteins (lmps), known to be essential for b cell transformat ...200616364389
the bzlf1 homolog of an epstein-barr-related gamma-herpesvirus is a frequent target of the ctl response in persistently infected rhesus macaques.although cd8(+) t lymphocytes targeting lytic infection proteins dominate the immune response to acute and persistent ebv infection, their role in immune control of ebv replication is not known. rhesus lymphocryptovirus (rhlcv) is a gamma-herpesvirus closely related to ebv, which establishes persistent infection in rhesus macaques. in this study, we investigated cellular immune responses to the rhlcv bzlf1 (rhbzlf1) homolog in a cohort of rhlcv-seropositive rhesus macaques. rhbzlf1-specific ifn- ...200616517707
epstein-barr virus micrornas are evolutionarily conserved and differentially expressed.the pathogenic lymphocryptovirus epstein-barr virus (ebv) is shown to express at least 17 distinct micrornas (mirnas) in latently infected cells. these are arranged in two clusters: 14 mirnas are located in the introns of the viral bart gene while three are located adjacent to bhrf1. the bart mirnas are expressed at high levels in latently infected epithelial cells and at lower, albeit detectable, levels in b cells. in contrast to the tissue-specific expression pattern of the bart mirnas, the bh ...200616557291
prevalence and molecular characterization of the polymerase gene of gibbon lymphocryptovirus.lymphocryptovirus (lcv) is found in various non-human primates. as a herpesvirus naturally infecting gibbons it is closely related to human epstein-barr virus (ebv) with which it shares considerable genetic, biological and epidemiologic features.200616764671
ebna-3b- and ebna-3c-regulated cellular genes in epstein-barr virus-immortalized lymphoblastoid cell lines.the cellular pathways that epstein-barr virus (ebv) manipulates in order to effect its lifelong persistence within hosts and facilitate its transmission between hosts are not well understood. the ebv nuclear antigen 3 (ebna-3) family of latent infection proteins consists of transcriptional regulators that influence viral and cellular gene expression in ebv-infected cells. to identify ebna-3b- and ebna-3c-regulated cellular genes potentially important for virus infection in vivo, we studied a lym ...200617005691
translation efficiency of ebna1 encoded by lymphocryptoviruses influences endogenous presentation of cd8+ t cell epitopes.lymphocryptoviruses (lcv) that infect humans and old world primates display a significant degree of genetic identity. these viruses use b lymphocytes as primary host cells to establish a long-term latent infection and express highly homologous latent viral proteins. of particular interest is the expression of the ebv-encoded nuclear antigen-1 (ebna1), which plays a crucial role in maintaining the viral genome in b cells. using human and old world primate homologues of ebna1, we show that the int ...200717236233
de novo svm classification of precursor micrornas from genomic pseudo hairpins using global and intrinsic folding measures.micrornas (mirnas) are small ncrnas participating in diverse cellular and physiological processes through the post-transcriptional gene regulatory pathway. critically associated with the mirnas biogenesis, the hairpin structure is a necessary feature for the computational classification of novel precursor mirnas (pre-mirs). though many of the abundant genomic inverted repeats (pseudo hairpins) can be filtered computationally, novel species-specific pre-mirs are likely to remain elusive.200717267435
epstein-barr virus thymidine kinase is a centrosomal resident precisely localized to the periphery of centrioles.the thymidine kinase (tk) encoded by epstein-barr virus (ebv) differs not only from that of the alphaherpesviruses but also from that of the gamma-2 herpesvirus subfamily. because cellular location is frequently a determinant of regulatory function, to gain insight into additional role(s) of ebv tk and to uncover how the lymphocryptovirus and rhadinovirus enzymes differ, the subcellular localizations of ebv tk and the related cercopithecine herpesvirus-15 tk were investigated. we show that in co ...200717428875
compatibility of the gh homologues of epstein-barr virus and related lymphocryptoviruses.glycoprotein gh, together with its chaperone gl and a third glycoprotein gb, is essential for cell-cell fusion and virus-cell fusion mediated by herpesviruses. epstein-barr virus (ebv), the prototype human lymphocryptovirus, requires a fourth glycoprotein gp42 to support fusion with b cells in addition to epithelial cells. two other lymphocryptoviruses, the rhesus lymphocryptovirus (rh-lcv) and the common marmoset lymphocryptovirus (calhv3), have been sequenced in their entirety and each has a g ...200717622614
molecular biology of ebv in relationship to aids-associated oncogenesis.epstein-barr virus (ebv) is a gammaherpesvirus of the lymphocryptovirus genus, which infects greater than 90% of the world's population. infection is nonsymptomatic in healthy individuals, but has been associated with a number of lymphoproliferative disorders when accompanied by immunosuppression. like all herpesviruses, ebv has both latent and lytic replication programs, which allows it to evade immune clearance and persist for the lifetime of the host. latent infection is characterized by repl ...200717672040
discovery of herpesviruses in multi-infected primates using locked nucleic acids (lna) and a bigenic pcr approach.targeting the highly conserved herpes dna polymerase (dpol) gene with pcr using panherpes degenerate primers is a powerful tool to universally detect unknown herpesviruses. however, vertebrate hosts are often infected with more than one herpesvirus in the same tissue, and pan-herpes dpol pcr often favors the amplification of one viral sequence at the expense of the others. here we present two different technical approaches that overcome this obstacle: (i) pan-herpes dpol pcr is carried out in th ...200717822523
impact of infections and normal flora in nonhuman primates on drug development.preclinical safety studies that are required for the marketing approval of a pharmaceutical include single and repeat dose studies in rodent and nonrodent species. the use of nonhuman primates (nhps), primarily macaques, as the nonrodent species has increased in recent years, in part due to the increase in development of biopharmaceuticals and immunomodulatory agents. depending on the source of the macaques, they may vary in genetic background, normal flora, and/or the incidence of preexisting p ...200818323580
rhesus lymphocryptovirus latent membrane protein 2a activates beta-catenin signaling and inhibits differentiation in epithelial cells.rhesus lymphocryptovirus (lcv) is a gamma-herpesvirus closely related to epstein-barr virus (ebv). the rhesus latent membrane protein 2a (lmp2a) is highly homologous to ebv lmp2a. ebv lmp2a activates the phosphatidylinositol 3-kinase (pi3k) and beta-catenin signaling pathways in epithelial cells and affects differentiation. in the present study, the biochemical and biological properties of rhesus lmp2a in epithelial cells were investigated. the expression of rhesus lmp2a in epithelial cells indu ...200818570966
rhesus lymphocryptovirus type 1-associated b-cell nasal lymphoma in siv-infected rhesus macaques.epstein-barr virus (ebv) is a worldwide endemic gamma herpesvirus of the genus lymphocryptovirus (lcv) that infects more than 90% of the world's population. ebv has been associated with a variety of malignancies, but it has a demonstrated role in lymphomas, especially in immunosuppressed individuals. lymphomas of the nasal cavity, paranasal sinuses, and nasopharynx are uncommon and constitute less than 5% of all extranodal lymphomas. sinonasal non-hodgkin's lymphomas have been reported in patien ...200818984796
cd8+ t cell immunity to epstein-barr virus and kaposi's sarcoma-associated herpes virus.gammaherpesviruses are agents which have evolved to persist within the lymphoid system and many have oncogenic potential; studying gammaherpesvirus infections therefore has the potential to reveal much about the workings of the immune system and the control over viral oncogenesis. the lymphocryptovirus epstein-barr virus (ebv) and the rhadinovirus kaposi's sarcoma-associated herpesvirus (kshv, also known as human herpesvirus 8) are the two human gammaherpesviruses. analysis of the t cell respons ...200819007888
self-assembly of epstein-barr virus capsids.epstein-barr virus (ebv), a member of the gammaherpesvirus family, primarily infects b lymphocytes and is responsible for a number of lymphoproliferative diseases. the molecular genetics of the assembly pathway and high-resolution structural analysis of the capsid have not been determined for this lymphocryptovirus. as a first step in studying ebv capsid assembly, the baculovirus expression vector (bev) system was used to express the capsid shell proteins bclf1 (major capsid protein), borf1 (tri ...200919158247
functional analysis of glycoprotein l (gl) from rhesus lymphocryptovirus in epstein-barr virus-mediated cell fusion indicates a direct role of gl in gb-induced membrane fusion.glycoprotein l (gl), which complexes with gh, is a conserved herpesvirus protein that is essential for epstein-barr virus (ebv) entry into host cells. the gh/gl complex has a conserved role in entry among herpesviruses, yet the mechanism is not clear. to gain a better understanding of the role of gl in ebv-mediated fusion, chimeric proteins were made using rhesus lymphocryptovirus (rh-lcv) gl (rh gl), which shares a high sequence homology with ebv gl but does not complement ebv gl in mediating f ...200919457993
expression and processing of a small nucleolar rna from the epstein-barr virus genome.small nucleolar rnas (snornas) are localized within the nucleolus, a sub-nuclear compartment, in which they guide ribosomal or spliceosomal rna modifications, respectively. up until now, snornas have only been identified in eukaryal and archaeal genomes, but are notably absent in bacteria. by screening b lymphocytes for expression of non-coding rnas (ncrnas) induced by the epstein-barr virus (ebv), we here report, for the first time, the identification of a snorna gene within a viral genome, des ...200919680535
comparative pathobiology of macaque lymphocryptoviruses.lymphocryptoviruses (lcvs) have been identified as naturally occurring infections of both old and new world nonhuman primates. these viruses are closely related to epstein-barr virus (ebv, human herpesvirus 4) and share similar genomic organization and biological properties. nonhuman primate lcvs have the ability to immortalize host cells and express a similar complement of viral lytic and latent genes as those found in ebv. recent evidence indicates that nonhuman primate lcvs can immortalize b ...200819793458
genetic diversity and molecular evolution of human and non-human primate gammaherpesvirinae.the gammaherpesvirinae sub-family is divided into two genera: lymphocryptovirus and rhadinovirus. until the middle of the 1990s, the rhadinovirus genus was only represented by herpesvirus saimiri and herpesvirus ateles, which infect new world monkey species. until the year 2000, epstein-barr virus (ebv), the human prototype of the lymphocryptovirus, and simian homologues had only been detected in humans and old world non-human primates. it was thought, therefore, that the separation of the conti ...201019879975
a global analysis of evolutionary conservation among known and predicted gammaherpesvirus micrornas.micrornas (mirnas) are small, noncoding rnas which posttranscriptionally regulate gene expression. the current release of the mirna registry lists 16 viruses which encode a total of 146 mirna hairpins. strikingly, 139 of these are encoded by members of the herpesvirus family, suggesting an important role for mirnas in the herpesvirus life cycle. however, with the exception of 7 mirna hairpins known to be shared by epstein-barr virus (ebv) and the closely related rhesus lymphocryptovirus (rlcv), ...201019889779
lymphocryptovirus phylogeny and the origins of epstein-barr virus.specimens from wild and captive primates were collected and novel members of the genus lymphocryptovirus (subfamily gammaherpesvirinae) were searched for utilizing pcr for the dna polymerase gene. twenty-one novel viruses were detected. together with previous findings, more than 50 distinct lymphocryptoviruses (lcvs) are now known, with hosts from six primate families (hominidae, hylobatidae, cercopithecidae, atelidae, cebidae and pitheciidae). further work extended genomic sequences for 25 lcvs ...201019923263
viral host resistance studies.a foremost objective of preclinical immunotoxicity testing is to address whether or not a drug or environmental toxicant causes adverse effects on net immune health, expressly the host's ability to mount an appropriate immune response to clear infectious organisms. given the complex interactions, diverse molecular signaling events, and redundancies of immunity that has itself been subdivided into interdependent arms, namely innate, adaptive, and humoral, the results of single immune parameter te ...201019967509
tap-inhibitors from old world primate 1-herpesviruses and their use: wo2009008713.cytotoxic t lymphocytes (ctls) recognize peptide antigens in the context of major histocompatibility complex (mhc) class i molecules. ctl-mediated immunity is important for defense against cancers and virus infections, and thus viruses and tumors have evolved ctl-evasion mechanisms. the transporter associated with antigen processing (tap) is a key factor for mhc class i assembly, and tap is a frequent target of immune evasion by viruses and tumors. wo2009008713 discloses potential therapeutic us ...201020100007
episomal replication timing of gamma-herpesviruses in latently infected cells.this study addresses the timing of gammaherpesviral episomal dna replication with respect to the cell cycle. for the first time we analyzed a rhadinovirus, the prototype herpesvirus saimiri (hvs), and compared it to the lymphocryptovirus epstein-barr virus (ebv). newly synthesized dna of latently infected b- or t-cells was first brdu-labeled; then we sorted the cells corresponding to cell cycle phases g(0/1), g(2/m), and s (4 fractions s(1)-s(4)) and performed anti-brdu chromatin immunoprecipita ...201020172574
comprehensive analysis of rhesus lymphocryptovirus microrna expression.rhesus lymphocryptovirus (rlcv) and epstein-barr virus (ebv) are closely related gammaherpesviruses that infect and cause disease in rhesus monkeys and humans, respectively. thus, rlcv is an important model system for ebv pathogenesis. both rlcv and ebv express micrornas (mirnas), several conserved in sequence and genomic location. we have applied deep sequencing technology to obtain an inventory of rlcv mirna expression in latently rlcv-infected monkey b cells. our data confirm the presence of ...201020219930
systemic spironucleosis in 2 immunodeficient rhesus macaques (macaca mulatta).spironucleus spp are parasites of fish and terrestrial vertebrates, including mice and turkeys, that rarely cause extraintestinal disease. two rhesus macaques (macaca mulatta) were experimentally inoculated with simian immunodeficiency virus mac251. both progressed to simian acquired immune deficiency syndrome within 1 year of inoculation and developed systemic protozoal infections in addition to common opportunistic infections, including rhesus cytomegalovirus, rhesus lymphocryptovirus, and rhe ...201020351359
reactivation of lymphocryptovirus (epstein-barr virus chimpanzee) and dominance in chimpanzees.nine male chimpanzees originally reared in solitary cages were set up to form a group. plasma viral load of the lymphocryptovirus (lcv) of chimpanzee [epstein-barr virus chimpanzee (ebvcmp)] was measured by real-time pcr. in the group formation (form) period, the first-ranking male showed an imminent increase in plasma ebvcmp load compared with 1 week before (pre-form) and 3 months after (post-form) group formation. other upper-ranking males such as the second-, third- and fourth-male also showe ...201020375224
cloning of the epstein-barr virus-related rhesus lymphocryptovirus as a bacterial artificial chromosome: a loss-of-function mutation of the rhbarf1 immune evasion gene.rhesus macaques are naturally infected with a gammaherpesvirus which is in the same lymphocryptovirus (lcv) genus as and closely related to epstein-barr virus (ebv). the rhesus macaque lcv (rhlcv) contains a repertoire of genes identical to that of ebv, and experimental rhlcv infection of naive rhesus macaques accurately models acute and persistent ebv infection of humans. we cloned the lcl8664 rhlcv strain as a bacterial artificial chromosome to create recombinant rhlcv for investigation in thi ...201021084476
mapping regions of epstein-barr virus (ebv) glycoprotein b (gb) important for fusion function with gh/gl.glycoproteins gb and gh/gl are required for entry of epstein-barr virus (ebv) into cells, but the role of each glycoprotein and how they function together to mediate fusion is unclear. analysis of the functional homology of gb from the closely related primate gammaherpesvirus, rhesus lymphocryptovirus (rh-lcv), showed that ebv gb could not complement rh gb due to a species-specific dependence between gb and gl. to map domains of gb required for this interaction, we constructed a panel of ebv/rh ...201121376360
gammaherpesviruses of new world primatesnumerous gamma-herpesviruses, a large subfamily of the herpes group, have limited pathogenic potential upon primary infection of their natural host. they are most relevant however as tumor viruses of the hematopoietic system and form an important chapter of viral oncology. the prototype of the genus lymphocryptovirus (γ1-herpesvirus), epstein-barr virus (ebv), was the first clearly identified human herpesvirus. ebv causes lymphomas of b-cell origin and other lymphoproliferati ...200721348092
gammaherpesviruses entry and early events during infectionthe two human gammaherpesviruses, epstein–barr virus (ebv), a gamma 1 lymphocryptovirus and kaposi’s sarcoma associated virus (kshv), a gamma 2 rhadinovirus, have many features in common. they share an architecture that is typical of all members of the herpesvirus family, they share an ability to establish latency in lymphocytes, and they are both initiators or potentiators of human tumors. for the virologist some of the challenges they present are the same, in particular ...200721348095
partial molecular characterisation of new world non-human primate lymphocryptoviruses.the description of numerous viruses belonging to the lymphocryptovirus genus from different old and new world non-human primate species during the past 10 years has led to developing and supporting co-speciational evolution hypotheses for these viruses and their hosts. among the different primate species tested, only a few were from the new world. this study attempted to achieve a better understanding of the evolutionary processes within the platyrrhini branch. molecular screening of 253 blood d ...201121827873
Antibodies to lytic infection proteins in lymphocryptovirus-infected rhesus macaques: a model for humoral immune responses to epstein-barr virus infection.Humoral immune responses to rhesus lymphocryptovirus (rhLCV) lytic infection proteins were evaluated in the rhesus macaque animal model for Epstein-Barr virus (EBV) infection. We found a hierarchy of humoral responses to 14 rhLCV lytic infection proteins in naturally infected rhesus macaques, with (i) widespread and robust responses to four glycoproteins expressed as late proteins, (ii) frequent but less robust responses to a subset of early proteins, and (iii) low-level responses to immediate-e ...201121734064
Soluble rhesus lymphocryptovirus gp350 protects against infection and reduces viral loads in animals that become infected with virus after challenge.Epstein-Barr virus (EBV) is a human lymphocryptovirus that is associated with several malignancies. Elevated EBV DNA in the blood is observed in transplant recipients prior to, and at the time of post-transplant lymphoproliferative disease; thus, a vaccine that either prevents EBV infection or lowers the viral load might reduce certain EBV malignancies. Two major approaches have been suggested for an EBV vaccine- immunization with either EBV glycoprotein 350 (gp350) or EBV latency proteins (e.g. ...201122028652
Establishing the Carcinogenic Risk of Immunomodulatory Drugs.The first effective immunosuppressive drug (ISD) was azathioprine, approved in 1968. Early experience with this drug suggested that patients might have an excess risk of tumors including lymphoma and skin tumors. Comparison among various registries has shown that the cumulative risk of tumors increases over time. The risk is additionally increased by the more intense immunosuppressive regimens needed for lung or heart-lung transplants. The link between immunosuppression and tumorigenesis was fur ...201122105649
Persistent infection drives the development of CD8+ T cells specific for late lytic infection antigens in lymphocryptovirus-infected macaques and Epstein-Barr virus-infected humans.We examined the CD8(+) T cell repertoire against lytic infection antigens in rhesus macaques persistently infected with the Epstein-Barr virus (EBV)-related lymphocryptovirus (rhLCV). CD8(+) T cells specific for late (L) antigens were detected at rates comparable to those for early antigens and were associated with increasing duration of infection. L antigen-specific CD8(+) T cells were also readily detected in adult, EBV-positive humans. Thus, viral major histocompatibility complex class I (MHC ...201121917961
summary of roundtable discussion meeting: non-human primates to assess risk for ebv-related lymphomas in humans.epstein-barr virus (ebv)-associated lymphomas are a known risk for immunosuppressed individuals. non-clinical methods to determine the potential of new immunomodulatory compounds to produce ebv-associated lymphomas (hazard identification) have not been developed. since lymphocryptovirus (lcv) in non-human primates (nhp) has similar characteristics to ebv in humans, a roundtable meeting was held in october 2010 to explore how the potential for ebv-related lymphomas in humans can be assessed by us ...201122136193
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