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disruption of lana in rhesus rhadinovirus generates a highly lytic recombinant virus.rhesus monkey rhadinovirus (rrv) is a gammaherpesvirus that is closely related to human kaposi's sarcoma-associated herpesvirus (kshv/hhv-8). rrv is the closest relative to kshv that has a fully sequenced genome and serves as an in vitro and an in vivo model system for kshv. the latency-associated nuclear antigen (lana) protein of both kshv and rrv plays key roles in the establishment and maintenance of these herpesviruses. we have constructed a rrv recombinant virus (rrvdeltalana/gfp) in which ...200919587030
cloning and analysis of micrornas encoded by the primate gamma-herpesvirus rhesus monkey rhadinovirus.several pathogenic human herpesviruses have recently been shown to express virally encoded micrornas in infected cells. although the function of these micrornas is largely unknown, they are hypothesized to play a role in mediating viral replication by downregulating cellular mrnas encoding antiviral factors. here, we report the cloning and analysis of micrornas encoded by rhesus monkey rhadinovirus (rrv), an animal virus model for the pathogenic human gamma-herpesvirus kaposi's sarcoma-associate ...200717451774
rhesus monkey rhadinovirus: a model for the study of kshv.rhesus monkey rhadinovirus (rrv) is one of the closest phylogenetic relatives to the human pathogen kaposi sarcoma-associated herpesvirus (kshv)-a gamma-2 herpesvirus and the etiologic agent of three malignancies associated with immunosuppression. in contrast to kshv, rrv displays robust lytic-phase growth in culture, replicating to high titer, and therefore holds promise as an effective model for studying primate gammaherpesvirus lytic gene transcription as well as virion structure, assembly, a ...200717089793
whole-genome transcription profiling of rhesus monkey rhadinovirus.rhesus monkey rhadinovirus (rrv) and kaposi's sarcoma-associated herpesvirus (kshv; also called human herpesvirus 8) belong to the gamma-2 grouping of herpesviruses. rrv and kshv share a high degree of sequence similarity, and their genomes are organized in a similar fashion. rrv serves as an excellent animal model system to study the gamma herpesvirus life cycle both in vitro and in vivo. we have developed a high-sensitivity, high-throughput, high-specificity real-time quantitative reverse tran ...200515956606
comparison of the rta/orf50 transactivator proteins of gamma-2-herpesviruses.the viral immediate-early transactivator rta/orf50 is necessary and sufficient to initiate kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (kshv/hhv-8) reactivation from latently infected cells. since rta/orf50 is conserved among all known gamma-2-herpesviruses, we investigated whether the murine gamma-68-herpesvirus (mhv-68) and rhesus monkey rhadinovirus (rrv) homologs can functionally substitute for kshv rta/orf50. (i) our comparison of 12 kshv promoters showed that most responded ...200415113928
de novo infection with rhesus monkey rhadinovirus leads to the accumulation of multiple intranuclear capsid species during lytic replication but favors the release of genome-containing virions.rhesus monkey rhadinovirus (rrv) is one of the closest phylogenetic relatives to the human pathogen kaposi's sarcoma-associated herpesvirus (kshv), yet it has the distinct experimental advantage of entering efficiently into lytic replication and growing to high titers in culture. rrv therefore holds promise as a potentially attractive model with which to study gammaherpesvirus structure and assembly. we have isolated rrv capsids, determined their molecular composition, and identified the genes e ...200314645602
three-dimensional structures of the a, b, and c capsids of rhesus monkey rhadinovirus: insights into gammaherpesvirus capsid assembly, maturation, and dna packaging.rhesus monkey rhadinovirus (rrv) exhibits high levels of sequence homology to human gammaherpesviruses, such as kaposi's sarcoma-associated herpesvirus, and grows to high titers in cell cultures, making it a good model system for studying gammaherpesvirus capsid structure and assembly. we have purified rrv a, b, and c capsids, thus for the first time allowing direct structure comparisons by electron cryomicroscopy and three-dimensional reconstruction. the results show that the shells of these ca ...200314645575
rhesus monkey rhadinovirus (rrv): construction of a rrv-gfp recombinant virus and development of assays to assess viral replication.rhesus monkey rhadinovirus (rrv) is a gamma-2-herpesvirus that is closely related to kaposi's sarcoma-associated herpesvirus (kshv/hhv-8). lack of an efficient culture system to grow high titers of virus, and the lack of an in vivo animal model system, has hampered the study of kshv replication and pathogenesis. rrv is capable of replicating to high titers on fibroblasts, thus facilitating the construction of recombinant rhadinoviruses. in addition, the ability to experimentally infect naïve rhe ...200312890626
kinetics of expression of rhesus monkey rhadinovirus (rrv) and identification and characterization of a polycistronic transcript encoding the rrv orf50/rta, rrv r8, and r8.1 genes.rhesus monkey rhadinovirus (rrv) is a close relative of kaposi's sarcoma-associated herpesvirus (kshv; human herpesvirus 8). rrv serves as an in vitro and an in vivo model for kshv, and the mapping of its transcription program during lytic replication is significant since it represents de novo infection in the absence of stimulation with phorbol esters. further, the rrv lytic system facilitates the making of recombinant viruses, and hence transcription profiling of the wild-type virus is importa ...200212208960
identification of the bzip and rta homologues in the genome of rhesus monkey rhadinovirus.rhesus monkey rhadinovirus (rrv) is a gamma2-herpesvirus identified from the peripheral blood mononuclear cells of rhesus macaques (macaca mulatta). serologic studies suggested that the infections of rrv are prevalent among rhesus monkeys. rrv can be efficiently propagated and grows to a high titer in cultured rhesus monkey fibroblasts, thus providing a valuable model to study the rhadinovirus replication. by comparative genomic studies, here we describe the identification of two potential trans ...200212127781
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
t-cell lymphoproliferative disorder in an aged rhesus macaque.a cd8+ t-cell leukemia was diagnosed in an aged female rhesus macaque. although leukemia and lymphoma in nonhuman primates are commonly associated with simian t-lymphotropic virus, gibbon ape leukemia virus, oncogenic herpesviruses, and types c, d, and e retroviruses, this monkey was not infected with any of these viruses. however, the monkey did have antibodies against herpesvirus saimiri. this likely represents cross-reactivity of the herpesvirus saimiri assay with rhesus monkey rhadinovirus ( ...200010935045
the primary sequence of rhesus monkey rhadinovirus isolate 26-95: sequence similarities to kaposi's sarcoma-associated herpesvirus and rhesus monkey rhadinovirus isolate 17577.the primary sequence of the long unique region l-dna (l for low gc) of rhesus monkey rhadinovirus (rrv) isolate 26-95 was determined. the l-dna consists of 130,733 bp that contain 84 open reading frames (orfs). the overall organization of the rrv26-95 genome was found to be very similar to that of human kaposi sarcoma-associated herpesvirus (kshv). blast search analysis revealed that in almost all cases rrv26-95 coding sequences have a greater degree of similarity to corresponding kshv sequences ...200010708456
primate herpesviral oncogenes.gammaherpesviruses are the most rapidly growing members of the herpesviridae family. gamma herpesviruses share similarity in their genome organizations and in early and late lytic genes that are required for viral replication. a distinct characteristic of gamma herpesviruses is their ability to establish latent infection in lymphoid cells, and some of these viruses are closely associated with abnormal proliferation and cancer in primates. the first open reading frame of the primate gamma herpesv ...199910515596
use of a recombinant gamma-2 herpesvirus vaccine vector against dengue virus in rhesus monkeys.research on vaccine approaches that can provide long-term protection against dengue virus infection is needed. here we describe the construction, immunogenicity, and preliminary information on the protective capacity of recombinant, replication-competent rhesus monkey rhadinovirus (rrv), a persisting herpesvirus. one rrv construct expressed nonstructural protein 5 (ns5), while a second recombinant expressed a soluble variant of the e protein (e85) of dengue virus 2 (denv2). four rhesus macaques ...201728592531
a herpesvirus of rhesus monkeys related to the human kaposi's sarcoma-associated herpesvirus.a herpesvirus that is related to but distinct from the kaposi's sarcoma-associated herpesvirus (kshv, or human herpesvirus 8) was isolated from rhesus monkeys. the sequence of 10.6 kbp from virion dna revealed the presence of an interleukin-6 homolog similar to what is present in kshv and a closer relatedness of the dna polymerase and glycoprotein b reading frames to those of kshv than to those of any other herpesvirus. this rhesus monkey herpesvirus replicated lytically and to high titers in cu ...19979371642
characterization of cytoplasmic motifs important in rhesus rhadinovirus gb processing and trafficking.rhesus monkey rhadinovirus (rrv) is highly related to kaposi's sarcoma-associated herpesvirus (kshv), a human gamma-herpesvirus etiologically-linked with several cancers. glycoprotein b (gb) homologues are encoded by all herpesviruses and play a role in virus attachment, entry, and in egress. we have found that rrv gb, like kshv gb, is cleaved at a consensus furin cleavage site and is modified by both n-linked and o-linked glycosylation. mutagenesis of three tyrosine- based trafficking motifs, a ...201020060555
identification and functional characterization of a spliced rhesus rhadinovirus gene with homology to the k15 gene of kaposi's sarcoma-associated herpesvirus.rhesus monkey rhadinovirus (rrv) is a gamma-2 herpesvirus related to the human kaposi's sarcoma-associated herpesvirus (kshv or human herpesvirus 8). this study identified an alternatively spliced gene at the right side of the rrv genome (strain 17577) between open reading frame 75 and the terminal repeat region. of its eight exons, the first seven encoded up to 12 transmembrane domains, whilst the eighth exon encoded a predicted c-terminal cytoplasmic domain. structurally and positionally, this ...200919264656
extreme dependence of gh and gl expression on orf57 and association with highly unusual codon usage in rhesus monkey rhadinovirus.standard vectors for high-level expression elicited undetectable levels of the gh and gl glycoproteins of rhesus monkey rhadinovirus (rrv) following transient-transfection assays under a variety of conditions. these same vectors and conditions yielded high levels of rrv gb expression. unlike other genes of rrv, both the gh and gl genes were noted to have a highly aberrant, suboptimal codon usage. high levels of rrv gh and gl expression were achieved by two alternative means: codon optimization o ...200818480451
glycoprotein gene sequence variation in rhesus monkey rhadinovirus.gene sequences for seven glycoproteins from 20 independent isolates of rhesus monkey rhadinovirus (rrv) and of the corresponding seven glycoprotein genes from nine strains of the kaposi's sarcoma-associated herpesvirus (kshv) were obtained and analyzed. phylogenetic analysis revealed two discrete groupings of rrv gh sequences, two discrete groupings of rrv gl sequences and two discrete groupings of rrv gb sequences. we called these phylogenetic groupings gh(a), gh(b), gl(a), gl(b), gb(a) and gb( ...201020172576
infection and persistence of rhesus monkey rhadinovirus in immortalized b-cell lines.similar to its close relative human herpesvirus 8, rhesus monkey rhadinovirus (rrv) persists predominantly in b cells of its natural host. rhesus monkey b-cell lines immortalized by the epstein-barr-related virus from rhesus monkeys (rhebv) were used as targets for infection by rrv. these cultured b cells were susceptible to infection by rrv and continued to produce low titers of rrv for months of continuous culture. infection by rrv did not detectably alter the growth rates of these b-cell line ...200616537632
mass spectrometric analyses of purified rhesus monkey rhadinovirus reveal 33 virion-associated proteins.the repertoire of proteins that comprise intact gammaherpesviruses, including the human pathogen kaposi's sarcoma-associated herpesvirus (kshv), is likely to have critical functions not only in viral structure and assembly but also in the early stages of infection and evasion of the host's rapidly deployed antiviral defenses. to develop a better understanding of these proteins, we analyzed the composition of rhesus monkey rhadinovirus (rrv), a close phylogenetic relative of kshv. unlike kshv, rr ...200616415032
a genetic system for rhesus monkey rhadinovirus: use of recombinant virus to quantitate antibody-mediated neutralization.rhesus monkey rhadinovirus (rrv), a simian gamma-2 herpesvirus closely related to the kaposi sarcoma-associated herpesvirus, replicates lytically in cultured rhesus monkey fibroblasts and establishes persistence in b cells. overlapping cosmid clones were generated that encompass the entire 130-kilobase-pair genome of rrv strain 26-95, including the terminal repeat regions required for its replication. cloned rrv that was produced by cotransfection of overlapping cosmids spanning the entire rrv26 ...200616415030
functional divergence of kaposi's sarcoma-associated herpesvirus and related gamma-2 herpesvirus thymidine kinases: novel cytoplasmic phosphoproteins that alter cellular morphology and disrupt adhesion.the nucleoside kinase encoded by kaposi's sarcoma-associated herpesvirus (kshv) is a relatively inefficient enzyme with substrate specificity for thymidine alone, unlike alphaherpesvirus thymidine kinases (tks). similar to all gammaherpesvirus tks, kshv tk is composed of two distinct domains, a conserved c-terminal kinase and a novel and uncharacterized n terminus. ectopic expression of kshv tk in adherent cells induced striking morphological changes and anchorage independence although cells sur ...200516282465
vaccine protection against simian immunodeficiency virus in monkeys using recombinant gamma-2 herpesvirus.recombinant strains of replication-competent rhesus monkey rhadinovirus (rrv) were constructed in which strong promoter/enhancer elements were used to drive expression of simian immunodeficiency virus (siv) env or gag or a rev-tat-nef fusion protein. cultured rhesus monkey fibroblasts infected with each recombinant strain were shown to express the expected protein. three rrv-negative and two rrv-positive rhesus monkeys were inoculated intravenously with a mixture of these three recombinant rrvs. ...201121900170
the latency-associated nuclear antigen of rhesus monkey rhadinovirus inhibits viral replication through repression of orf50/rta transcriptional activation.rhesus monkey rhadinovirus (rrv) is a gamma-2-herpesvirus that is closely related to kaposi's sarcoma-associated herpesvirus/human herpesvirus-8. we have previously reported that the transcript for rrv latency-associated nuclear antigen (r-lana) is expressed during lytic replication in rhesus fibroblasts. in this article, we report the development of a latent culture system for rrv and show that mrna specific for r-lana is expressed during latency as well. we have characterized the r-lana protei ...200515709032
viral flice inhibitory protein of rhesus monkey rhadinovirus inhibits apoptosis by enhancing autophagosome formation.rhesus monkey rhadinovirus (rrv) is a gamma-2 herpesvirus closely related to human herpesvirus 8 (hhv8). rrv encodes viral flice inhibitory protein (vflip), which has death effector domains. little is known about rrv vflip. this study intended to examine its function in apoptosis. here we found that rrv vflip inhibits apoptosis induced by tumor necrosis factor-α (tnf-α) and cycloheximide. in hela cells with vflip expression, the cleavage of poly [adp-ribose] polymerase 1 (parp-1) and activities ...201222745754
viral fgarat homolog orf75 of rhesus monkey rhadinovirus effects proteasomal degradation of the nd10 components sp100 and pml.nuclear domain 10 (nd10) components restrict herpesviral infection, and herpesviruses antagonize this restriction by a variety of strategies, including degradation or relocalization of nd10 proteins. the rhesus monkey rhadinovirus (rrv) shares many key biological features with the closely related kaposi's sarcoma-associated herpesvirus (kshv; human herpesvirus 8) and readily infects cells of both human and rhesus monkey origin. we used the clustered regularly interspaced short palindromic repeat ...201627356898
maturation and vesicle-mediated egress of primate gammaherpesvirus rhesus monkey rhadinovirus require inner tegument protein orf52.the tegument layer of herpesviruses comprises a collection of proteins that is unique to each viral species. in rhesus monkey rhadinovirus (rrv), a close relative of the human oncogenic pathogen kaposi's sarcoma-associated herpesvirus, orf52 is a highly abundant tegument protein tightly associated with the capsid. we now report that orf52 knockdown during rrv infection of rhesus fibroblasts led to a greater than 300-fold reduction in the viral titer by 48 h but had little effect on the number of ...201424899183
distinct roles for extracellular signal-regulated kinase 1 (erk1) and erk2 in the structure and production of a primate gammaherpesvirus.during their progression from intranuclear capsids to mature trilaminar virions, herpesviruses incorporate an extensive array of viral as well as a smaller subset of cellular proteins. our laboratory previously reported that rhesus monkey rhadinovirus (rrv), a close homolog of the human pathogen kaposi's sarcoma-associated herpesvirus (kshv), is comprised of at least 33 different virally encoded proteins. in the current study, we found that rrv infection activated the extracellular signal-regula ...201222740395
importance of codon usage for the temporal regulation of viral gene expression.the glycoproteins of herpesviruses and of hiv/siv are made late in the replication cycle and are derived from transcripts that use an unusual codon usage that is quite different from that of the host cell. here we show that the actions of natural transinducers from these two different families of persistent viruses (rev of siv and orf57 of the rhesus monkey rhadinovirus) are dependent on the nature of the skewed codon usage. in fact, the transinducibility of expression of these glycoproteins by ...201526504241
progressive accumulation of activated erk2 within highly stable orf45-containing nuclear complexes promotes lytic gammaherpesvirus infection.de novo infection with the gammaherpesvirus rhesus monkey rhadinovirus (rrv), a close homolog of the human oncogenic pathogen, kaposi's sarcoma-associated herpesvirus (kshv), led to persistent activation of the mek/erk pathway and increasing nuclear accumulation of perk2 complexed with the rrv protein, orf45 (r45) and cellular rsk. we have previously shown that both lytic gene expression and virion production are dependent on the activation of erk [1]. using confocal microscopy, sequential pull- ...201424722398
activation of lymphocyte signaling by the r1 protein of rhesus monkey rhadinovirus.rhesus monkey rhadinovirus (rrv) is a gamma-2 herpesvirus that exhibits a considerable degree of similarity to the human kaposi's sarcoma-associated herpesvirus (kshv). the r1 protein of rrv is distantly related to the k1 protein of kshv, and r1, like k1, can contribute to cell growth transformation. in this study we analyzed the ability of the cytoplasmic tail of r1 to function as a signal transducer. the cytoplasmic domain of the r1 protein contains several tyrosine residues whose phosphorylat ...200010684288
identification of the r1 oncogene and its protein product from the rhadinovirus of rhesus monkeys.rhesus monkey rhadinovirus (rrv) is a gamma-2 herpesvirus that is most closely related to the human kaposi's sarcoma-associated herpesvirus (kshv). we have identified a distinct open reading frame at the left end of rrv and designated it r1. the position of the r1 gene is equivalent to that of the saimiri transforming protein (stp) of herpesvirus saimiri (hvs) and of k1 of kshv, other members of the gamma-2 or rhadinovirus subgroup of herpesviruses. the r1 sequence revealed an open reading frame ...199910233975
identification of a thymidylate synthase gene within the genome of chilo iridescent virus.the thymidylate synthase (ts, ec 2.1.1.45) is essential for the de novo synthesis of dtmp in pro- and eucaryotic organisms. consequently it plays a major role in the replication of the dna genome of a cell or a dna virus. the gene encoding the ts of chilo iridescent virus (civ) was identified by nucleotide sequence analysis of the viral genome and was mapped within the ecori civ dna fragments g and r. computer assisted analysis of the dna nucleotide sequence between the genome coordinates 0.482 ...19989926400
rhesus monkey rhadinovirus orf57 induces gh and gl glycoprotein expression through the post-transcriptional accumulation of target mrnas.open reading frame 57 (orf57) of gamma-2 herpesviruses is a key regulator of viral gene expression. it has been variously reported to enhance expression of viral genes by transcriptional, post-transcriptional, or translational activation mechanisms. previously we have shown that expression of gh and gl of rhesus monkey rhadinovirus, a close relative of the human kaposi's sarcoma-associated herpesvirus (kshv), could be dramatically rescued by codon optimization as well as by orf57 co-expression. ...201121613403
rhesus monkey rhadinovirus uses eph family receptors for entry into b cells and endothelial cells but not fibroblasts.cellular ephrin receptor tyrosine kinases (ephrin receptors, ephs) were found to interact efficiently with the gh/gl glycoprotein complex of the rhesus monkey rhadinovirus (rrv). since epha2 was recently identified as a receptor for the kaposi's sarcoma-associated herpesvirus (kshv) (hahn et al., nature medicine 2012), we analyzed rrv and kshv in parallel with respect to eph-binding and eph-dependent entry. ten of the 14 eph proteins, including both a- and b-type, interacted with rrv gh/gl. two ...201323696734
use of a gamma-2 herpesvirus as a vector to deliver antibodies to rhesus monkeys.the gamma-2 herpesvirus of rhesus monkeys, rhesus monkey rhadinovirus (rrv), persists principally in b cells of its host. we constructed recombinant strains of rrv expressing the rhesus monkey-derived anti-siv monoclonal antibodies 4l6 and 5l7 and compared the rrv-mediated in vivo delivery of these antibodies in rhesus monkeys with previous studies that utilized intramuscular delivery with an adeno-associated virus (aav) vector. recombinant rrv-4l6 and rrv-5l7 were both shown to stably produce t ...201728660888
a conserved leucine zipper motif in gammaherpesvirus orf52 is critical for distinct microtubule rearrangements.productive viral infection often depends on the manipulation of the cytoskeleton. herpesviruses, including rhesus monkey rhadinovirus (rrv) and its close homolog, the oncogenic human gammaherpesvirus kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (kshv/hhv8), exploit microtubule (mt)-based retrograde transport to deliver their genomes to the nucleus. subsequently, during the lytic phase of the life cycle, the maturing viral particles undergo orchestrated translocation to specialized ...201728615210
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