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latent herpesvirus infection arms nk cells.natural killer (nk) cells were identified by their ability to kill target cells without previous sensitization. however, without an antecedent "arming" event, nk cells can recognize, but are not equipped to kill, target cells. how nk cells become armed in vivo in healthy hosts is unclear. because latent herpesviruses are highly prevalent and alter multiple aspects of host immunity, we hypothesized that latent herpesvirus infection would arm nk cells. here we show that nk cells from mice latently ...201020139098
three-dimensional visualization of gammaherpesvirus life cycle in host cells by electron tomography.gammaherpesviruses are etiologically associated with human tumors. a three-dimensional (3d) examination of their life cycle in the host is lacking, significantly limiting our understanding of the structural and molecular basis of virus-host interactions. here, we report the first 3d visualization of key stages of the murine gammaherpesvirus 68 life cycle in nih 3t3 cells, including viral attachment, entry, assembly, and egress, by dual-axis electron tomography. in particular, we revealed the tra ...201020152152
tumors induced by murine herpesvirus 60 or by cell line nb-78 derived from a tumor induced by murine herpesvirus 78 show presence of the inducing viruses.murine herpesviruses 60 and 78 (mhv-60, mhv-78), closely related to mouse herpesvirus strain 68 (mhv-68), are oncogenic lymphotropic gammaherpesviruses, which may serve as models for study of human oncogenic gammaherpesviruses such as epstein-barr virus (ebv) and kaposi's sarcoma-associated herpesvirus (kshv). in this work, we attempted to detect an analog of the mhv-68 orf73 gene in tumors induced in mice either directly by mhv-60 or indirectly by mhv-78 via inoculation of nb-78 cells derived f ...201020201615
murine gammaherpesvirus 68 lana is essential for virus reactivation from splenocytes but not long-term carriage of viral genome.orf73, which encodes the latency-associated nuclear antigen (lana), is a conserved gamma-2-herpesvirus gene. the murine gammaherpesvirus 68 (mhv68) lana (mlana) is critical for efficient virus replication and the establishment of latent infection following intranasal inoculation. to test whether the initial host immune response limits the capacity of mlana-null virus to traffic to and establish latency in the spleen, we infected type i interferon receptor knockout (ifn-alpha/betar(-/-)) mice via ...201020444892
use of a virus-encoded enzymatic marker reveals that a stable fraction of memory b cells expresses latency-associated nuclear antigen throughout chronic gammaherpesvirus infection.an integral feature of gammaherpesvirus infections is the ability to establish lifelong latency in b cells. during latency, the viral genome is maintained as an extrachomosomal episome, with stable maintenance in dividing cells mediated by the viral proteins epstein-barr nuclear antigen 1 (ebna-1) for epstein-barr virus and latency-associated nuclear antigen (lana) for kaposi's sarcoma-associated herpesvirus. it is believed that the expression of episome maintenance proteins is turned off in the ...201020484501
interleukin-27 expression following infection with the murine gammaherpesvirus 68.il-27 is a heterodimeric cytokine composed of p28 and epstein barr virus induced gene 3 (ebi3) protein subunits. in the present study, we questioned whether murine gammaherpesvirus 68 (hv-68) could induce expression of ebi3, p28, and il-27 in this mouse model of an ebv-like infection. cultured macrophages and dendritic cells exposed to hv-68 upregulated p28 mrna expression and increased secretion of the p28 and il-27 (p28+ebi3) proteins. b220(+) and cd11b(+) cells also upregulated p28 mrna expre ...201020493722
vaccination with murid herpesvirus-4 glycoprotein b reduces viral lytic replication but does not induce detectable virion neutralization.herpesviruses characteristically disseminate from immune hosts. therefore in the context of natural infection, antibody neutralizes them poorly. murid herpesvirus-4 (muhv-4) provides a tractable model with which to understand gammaherpesvirus neutralization. muhv-4 virions blocked for cell binding by immune sera remain infectious for igg-fc receptor(+) myeloid cells, so broadly neutralizing antibodies must target the virion fusion complex - glycoprotein b (gb) or gh/gl. while gb-specific neutral ...201020519454
cd4 t-cell help programs a change in cd8 t-cell function enabling effective long-term control of murine gammaherpesvirus 68: role of pd-1-pd-l1 interactions.we previously showed that agonistic antibodies to cd40 could substitute for cd4 t-cell help and prevent reactivation of murine gammaherpesvirus 68 (mhv-68) in the lungs of major histocompatibility complex (mhc) class ii(-/-) (cii(-/-)) mice, which are cd4 t cell deficient. although cd8 t cells were required for this effect, no change in their activity was detected in vitro. a key question was whether anti-cd40 treatment (or cd4 t-cell help) changed the function of cd8 t cells or another cell typ ...201020534854
the murine gammaherpesvirus-68 chemokine-binding protein m3 inhibits experimental autoimmune encephalomyelitis.chemokines are critical mediators of immune cell entry into the central nervous system (cns), as occurs in neuroinflammatory disease such as multiple sclerosis. chemokines are also implicated in the immune response to viral infections. many viruses encode proteins that mimic or block chemokine actions, in order to evade host immune responses. the murine gammaherpesvirus-68 encodes a chemokine-binding protein called m3, which has unique biochemical features that enable it to bind to and inhibit a ...201020537410
comparative study of murid gammaherpesvirus 4 infection in mice and in a natural host, bank voles.gammaherpesviruses are archetypal pathogenic persistent viruses. the known human gammaherpesviruses (epstein-barr virus and kaposi's sarcoma-associated herpesvirus) are host-specific and therefore lack a convenient in vivo infection model. this makes related animal gammaherpesviruses an important source of information. infection by murid herpesvirus 4 (muhv-4), a virus originally isolated from bank voles (myodes glareolus), was studied here. muhv-4 infection of inbred laboratory mouse strains (m ...201020538905
redefining the genetics of murine gammaherpesvirus 68 via transcriptome-based annotation.viral genetic studies typically focus on large open reading frames (orfs) identified during genome annotation (orf-based annotation). here we describe tools for examining viral gene expression nucleotide by nucleotide across the genome. using these tools on the 119,450 base pair (bp) genome of murine gammaherpesvirus 68 (gammahv68) allowed us to establish that gammahv68 rna expression was significantly more complex than predicted from orf-based annotation, including over 73,000 nucleotides of un ...201020542255
an in vitro system for studying murid herpesvirus-4 latency and reactivation.the narrow species tropisms of epstein-barr virus (ebv) and the kaposi's sarcoma -associated herpesvirus (kshv) have made murid herpesvirus-4 (muhv-4) an important tool for understanding how gammaherpesviruses colonize their hosts. however, while muhv-4 pathogenesis studies can assign a quantitative importance to individual genes, the complexity of in vivo infection can make the underlying mechanisms hard to discern. furthermore, the lack of good in vitro muhv-4 latency/reactivation systems with ...201020552028
inhibition of nf-kappab signaling reduces virus load and gammaherpesvirus-induced pulmonary fibrosis.idiopathic pulmonary fibrosis (ipf) is a chronic progressive lung disorder of unknown etiology. several studies have demonstrated an association between pulmonary infection with a herpesvirus and ipf. based on those observations, we have developed a mouse model in which interferon (ifn)gammar(-/-) mice infected intranasally with murine gammaherpesvirus 68 (mhv68) develop lung fibrosis. we hypothesize that viral load was a critical factor for the development of fibrosis. because nuclear factor (n ...201020566741
vaccination against a hit-and-run viral cancer.cancers with viral aetiologies can potentially be prevented by antiviral vaccines. therefore, it is important to understand how viral infections and cancers might be linked. some cancers frequently carry gammaherpesvirus genomes. however, they generally express the same viral genes as non-transformed cells, and differ mainly in also carrying oncogenic host mutations. infection, therefore, seems to play a triggering or accessory role in disease. the hit-and-run hypothesis proposes that cumulative ...201020573854
dendritic cells loaded with tumor b cells elicit broad immunity against murine gammaherpesvirus 68 but fail to prevent long-term latency.it is still unknown whether a noninfectious gammaherpesvirus vaccine is able to prevent or reduce virus persistence. this led us to use dendritic cells loaded with tumor b cells as a vaccine approach for the murine gammaherpesvirus 68 (gammahv68) model of infection. dendritic cells loaded with uv-irradiated latently infected tumor b cells induce broad, strong, and long-lasting immunity against gammahv68. dendritic cell vaccination prevents the enlargement of lymph nodes and severely limits acute ...201020592077
identification of novel microrna-like molecules generated from herpesvirus and host trna transcripts.we applied deep sequencing technology to small rna fractions from cells lytically infected with murine gammaherpesvirus 68 (gammahv68) in order to define in detail small rnas generated from a cluster of trna-related polycistronic structures located at the left end of the viral genome. we detected 10 new candidate micrornas (mirnas), six of which were confirmed by northern blot analysis, leaving four as provisional. in addition, we determined that previously identified and annotated viral mirna m ...201020660200
identification and analysis of expression of novel micrornas of murine gammaherpesvirus 68.murine gammaherpesvirus 68 (mhv-68) is closely related to epstein-barr virus (ebv) and kaposi's sarcoma-associated herpesvirus (kshv) and provides a small-animal model with which to study the pathogenesis of gammaherpesvirus (gammahv) infections. to completely explore the potential of the mhv-68 system for the investigation of gammahv micrornas (mirnas), it would be desirable to know the number and expression patterns of all mirnas encoded by mhv-68. by deep sequencing of small rnas, we systemat ...201020668074
important role for the murid herpesvirus 4 ribonucleotide reductase large subunit in host colonization via the respiratory tract.viral enzymes that process small molecules provide potential chemotherapeutic targets. a key constraint-the replicative potential of spontaneous enzyme mutants-has been hard to define with human gammaherpesviruses because of their narrow species tropisms. here, we disrupted the murid herpesvirus 4 (muhv-4) orf61, which encodes its ribonucleotide reductase (rnr) large subunit. mutant viruses showed delayed in vitro lytic replication, failed to establish infection via the upper respiratory tract, ...201020668075
mononucleosis and antigen-driven t cell responses have different requirements for interleukin-2 signaling in murine gammaherpesvirus infection.interleukin-2 (il-2) has been implicated as being necessary for the optimal formation of primary cd8(+) t cell responses against various pathogens. here we have examined the role that il-2 signaling plays in several aspects of a cd8(+) t cell response against murine gammaherpesvirus 68 (mhv-68). exposure to mhv-68 causes a persistent infection, along with infectious mononucleosis, providing a model for studying these processes in mice. our study indicates that cd25 is necessary for optimal expan ...201020686022
inhibition of the phosphatidylinositol 3-kinase-akt pathway enhances gamma-2 herpesvirus lytic replication and facilitates reactivation from latency.cellular signalling pathways are critical in regulating the balance between latency and lytic replication of herpesviruses. here, we investigated the effect of the phosphatidylinositol 3-kinase (pi3k)-akt pathway on replication of two gamma-2 herpesviruses, murine gammaherpesvirus-68 (mhv-68) and human herpesvirus-8/kaposi's sarcoma-associated herpesvirus (hhv-8/kshv). we found that de novo infection of mhv-68 induced pi3k-dependent akt activation and the lytic replication of mhv-68 was enhanced ...201019864499
blimp-1-dependent plasma cell differentiation is required for efficient maintenance of murine gammaherpesvirus latency and antiviral antibody responses.recent evidence from the study of epstein-barr virus and kaposi's sarcoma-associated herpesvirus supports a model in which terminal differentiation of b cells to plasma cells leads to virus reactivation. here we address the role of blimp-1, the master transcriptional regulator of plasma cell differentiation, in murine gammaherpesvirus 68 (mhv68) latency and reactivation. blimp-1 expression in infected cells was dispensable for acute virus replication in the lung following intranasal inoculation ...201019889763
mhv68 complement regulatory protein facilitates mhv68 replication in primary macrophages in a complement independent manner.murine gammaherpesvirus-68 (mhv68) is genetically related to human epstein-barr virus and kaposi's sarcoma-associated herpesvirus and provides a tractable model to study gammaherpesvirus-host interactions in vivo and in vitro. the mhv68-encoded v-rca product inhibits murine complement activation and shares sequence homology with other virus and host regulators of complement activation. here we show that v-rca is required for efficient mhv68 replication in primary murine macrophages, but not in m ...201019910013
tpl2/ap-1 enhances murine gammaherpesvirus 68 lytic replication.how cellular factors regulate gammaherpesvirus lytic replication is not well understood. here, through functional screening of a cellular kinase expression library, we identified mitogen-activated protein kinase kinase kinase 8 (map3k8/tpl2) as a positive regulator of murine gammaherpesvirus 68 (mhv-68 or gammahv-68) lytic gene expression and replication. tpl2 enhances mhv-68 lytic replication by upregulating lytic gene expression and promoter activities of viral lytic genes, including rta and o ...201019939924
characterization of a novel wood mouse virus related to murid herpesvirus 4.two novel gammaherpesviruses were isolated, one from a field vole (microtus agrestis) and the other from wood mice (apodemus sylvaticus). the genome of the latter, designated wood mouse herpesvirus (wmhv), was completely sequenced. wmhv had the same genome structure and predicted gene content as murid herpesvirus 4 (muhv4; murine gammaherpesvirus 68). overall nucleotide sequence identity between wmhv and muhv4 was 85 % and most of the 10 kb region at the left end of the unique region was particu ...201019940063
mature and functional viral mirnas transcribed from novel rna polymerase iii promoters.murid herpesvirus 4 (muhv-4) micrornas were previously cloned from latently infected tumor cells and predicted to be processed from a series of rna polymerase iii primary transcripts. we detected maturely processed muhv-4 mirnas within total rna from lytically infected cells in vitro and infected tissues ex vivo, using a highly sensitive reverse ligation meditated rt-pcr strategy. we determined that the muhv-4 micrornas are biologically active during infection by a luciferase reporter system. we ...201019948768
prospects of a novel vaccination strategy for human gamma-herpesviruses.due to the oncogenic potential associated with persistent infection of human gamma-herpesviruses, including epstein-barr virus (ebv or hhv-4) and kaposi's sarcoma-associated herpesvirus (kshv or hhv-8), vaccine development has focused on subunit vaccines. however, the results using an animal model of mouse infection with a related rodent virus, murine gamma-herpesvirus 68 (mhv-68, γhv-68, or muhv-4), have shown that the only effective vaccination strategy is based on live attenuated viruses, inc ...201020717741
histone deacetylases and the nuclear receptor corepressor regulate lytic-latent switch gene 50 in murine gammaherpesvirus 68-infected macrophages.gammaherpesviruses are important oncogenic pathogens that transit between lytic and latent life cycles. silencing the lytic gene expression program enables the establishment of latency and a lifelong chronic infection of the host. in murine gammaherpesvirus 68 (mhv68, γhv68), essential lytic switch gene 50 controls the interchange between lytic and latent gene expression programs. however, negative regulators of gene 50 expression remain largely undefined. we report that the mhv68 lytic cycle is ...201020719946
immature and transitional b cells are latency reservoirs for a gammaherpesvirus.gammaherpesviruses, including kaposi's sarcoma-associated herpesvirus (kshv; also known as human herpesvirus 8 [hhv-8]), epstein-barr virus (ebv), and murine gammaherpesvirus 68 (mhv68; also known as gammaherpesvirus 68 [γhv68] or murine herpesvirus 4 [muhv-4]), establish lifelong latency in the resting memory b cell compartment. however, little is known about how this reservoir of infected mature b cells is maintained for the life of the host. in the context of a normal immune system, the matur ...201020926565
involvement of tlr2 in recognition of acute gammaherpesvirus-68 infection.toll-like receptors (tlrs) play a crucial role in the activation of innate immunity in response to many viruses. we previously reported the implication of tlr2 in the recognition of epstein-barr virus (ebv) by human monocytes. because murine gammaherpesvirus-68 (mhv-68) is a useful model to study human gammaherpesvirus pathogenesis in vivo, we evaluated the importance of mouse tlr2 in the recognition of mhv-68.201021060793
the bovine herpesvirus 4 bo10 gene encodes a nonessential viral envelope protein that regulates viral tropism through both positive and negative effects.all gammaherpesviruses encode a glycoprotein positionally homologous to the epstein-barr virus gp350 and the kaposi's sarcoma-associated herpesvirus (kshv) k8.1. in this study, we characterized the positional homologous glycoprotein of bovine herpesvirus 4 (bohv-4), encoded by the bo10 gene. we identified a 180-kda gene product, gp180, that was incorporated into the virion envelope. a bo10 deletion virus was viable but showed a growth deficit associated with reduced binding to epithelial cells. ...201021068242
altered host response to murine gammaherpesvirus 68 infection in mice lacking the tachykinin 1 gene and the receptor for substance p.the tachykinins are implicated in neurogenic inflammation and the neuropeptide substance p in particular has been shown to be a proinflammatory mediator. a role for the tachykinins in host response to viral infection has been previously demonstrated using either tac1- or nk1 receptor-deficient transgenic mice. however, due to redundancy in the peptide-receptor complexes we wished determine whether a deficiency in tac1 and nk1(r) in combination exhibited an enhanced phenotype. tac1 and nk1(r)-def ...201021106239
in vivo activation of toll-like receptor-9 induces an age-dependent abortive lytic cycle reactivation of murine gammaherpesvirus-68.infection of mice with murine gammaherpesvirus-68 (γhv-68) serves as a model to understand the pathogenesis of persistent viral infections, including the potential for co-infections to modulate viral latency. we have previously found that infection of neonates (8-day-old mice) with γhv-68 resulted in a high level of persistence of the virus in the lungs as well as the spleen, in contrast to infection of adult mice, for which long-term latency was only readily detected in the spleen. in this stud ...201021142440
construction and characterization of an infectious murine gammaherpesivrus-68 bacterial artificial chromosome.here we describe the cloning of a sequenced wums isolate of murine gammaherpesvirus-68 (mhv-68, γhv-68, also known as muhv-4) as a bacterial artificial chromosome (bac). we engineered the insertion of the bac sequence flanked by loxp sites into the left end of the viral genome before the m1 open reading frame. the infectious viruses were reconstituted following transfection of the mhv-68 bac dna into cells. the mhv-68 bac-derived virus replicated indistinguishably from the wild-type virus in cul ...201021197474
identification and sequencing of a novel rodent gammaherpesvirus that establishes acute and latent infection in laboratory mice.gammaherpesviruses encode numerous immunomodulatory molecules that contribute to their ability to evade the host immune response and establish persistent, lifelong infections. as the human gammaherpesviruses are strictly species specific, small animal models of gammaherpesvirus infection, such as murine gammaherpesvirus 68 (γhv68) infection, are important for studying the roles of gammaherpesvirus immune evasion genes in in vivo infection and pathogenesis. we report here the genome sequence and ...201121209105
pathogenesis and host control of gammaherpesviruses: lessons from the mouse.gammaherpesviruses are lymphotropic viruses that are associated with the development of lymphoproliferative diseases, lymphomas, as well as other nonlymphoid cancers. most known gammaherpesviruses establish latency in b lymphocytes. research on epstein-barr virus (ebv) and murine gammaherpesvirus 68 (mhv68/γhv68/mhv4) has revealed a complex relationship between virus latency and the stage of b cell differentiation. available data support a model in which gammaherpesvirus infection drives b cell ...201121219186
3,4-methylenedioxymethamphetamine (mdma) alters acute gammaherpesvirus burden and limits interleukin 27 responses in a mouse model of viral infection.to test whether 3,4-methylenedioxymethamphetamine (mdma, "ecstasy") abuse might increase the susceptibility, or alter the immune response, to murine gammaherpesvirus 68 (hv-68) and/or bacterial lipopolysaccharide.201121269783
sleep and fatigue in mice infected with murine gammaherpesvirus 68.fatigue, a common symptom of many acute and chronic medical conditions, reduces both quality of life and workplace productivity and can be disabling. however, the pathophysiologic mechanisms that underlie fatigue can be difficult to study in human populations due to the patient heterogeneity, the variety of underlying causes and potential triggering events, and an inability to collect samples that may be essential to elucidation of mechanisms (e.g., brain). although the etiology of chronic fatig ...201121272632
vertical transmission of murine gammaherpesvirus 68 in mice.the mouse infected with murine gammaherpesvirus 68 (mhv-68) is accepted animal model for investigation of pathogenesis, oncogenesis, immunology and molecular biology of gammaherpesviruses in their natural host. however, little is known about the host range, epidemiology and pathogenesis of this natural pathogen of free-living murid rodents. therefore we addressed the question of transplacental transmission of mhv-68 from pregnant balb/c mice chronically infected with the virus to their fetuses a ...201121434705
reconstitution of interactions of murine gammaherpesvirus 68 m11 with bcl-2 family proteins in yeast.one of the mechanisms of defense against viral infection is induction of apoptosis in infected cells. to escape this line of protection, genomes of many viruses encode for proteins that inhibit apoptosis. murid herpesvirus 4 gene m11 encodes for homologue of cellular bcl-2 proteins that inhibits apoptosis and autophagy in infected cell. to study a role of m11 in regulation of apoptosis we have established a yeast model system in which the action of m11 together with proapoptotic proteins bax, ba ...201121439939
chemokine binding protein m3 of murine gammaherpesvirus 68 modulates the host response to infection in a natural host.murine ?-herpesvirus 68 (mhv-68) infection of mus musculus-derived strains of mice is an attractive model of ?-herpesvirus infection. surprisingly, however, ablation of expression of mhv-68 m3, a secreted protein with broad chemokine-binding properties in vitro, has no discernable effect during experimental infection via the respiratory tract. here we demonstrate that m3 indeed contributes significantly to mhv-68 infection, but only in the context of a natural host, the wood mouse (apodemus sylv ...201121445235
in vivo function of the murid herpesvirus-4 ribonucleotide reductase small subunit.the difficulty of eliminating herpesvirus carriage makes host entry a key target for infection control. however, its viral requirements are poorly defined. murid herpesvirus-4 (muhv-4) can potentially provide insights into gammaherpesvirus host entry. upper respiratory tract infection requires the muhv-4 thymidine kinase (tk) and ribonucleotide reductase large subunit (rnr-l), suggesting a need for increased nucleotide production. however, both tk and rnr-l are likely to be multifunctional. we t ...201121471322
mhv-68 producing mifnα1 is severely attenuated in vivo and effectively protects mice against challenge with wt mhv-68.human gammaherpesviruses such as epstein-barr virus (ebv) cause lifelong infections and associated diseases, by virtue of their ability to establish latent infection. many studies performed in the past years in murine herpesvirus 68 (mhv-68) model of infection suggested that the limited immunity generated against isolated viral components by subunit vaccines cannot counteract the multiple immune evasion strategies operated by gammaherpesviruses. indeed, a significant inhibition of long-term late ...201121481326
the human cytomegalovirus gene products essential for late viral gene expression assemble into pre- replication complexes before viral dna replication.the regulation of human cytomegalovirus (hcmv) late gene expression by viral proteins is poorly understood and these viral proteins could be a target for novel antivirals. hcmv open reading frames (orfs) ul79, 87, and 95 have homology with late gene transcription factors of murine gammaherpesvirus 68 orfs 18, 24, and 34, respectively. to determine whether these hcmv proteins are also essential for late gene transcription of a betaherpesvirus, we mutated hcmv orfs ul79, 87, or 95. cells were infe ...201121507978
deep sequencing reveals direct targets of gammaherpesvirus-induced mrna decay and suggests that multiple mechanisms govern cellular transcript escape.one characteristic of lytic infection with gammaherpesviruses, including kaposi's sarcoma-associated herpesvirus (kshv), epstein-barr virus (ebv) and murine herpesvirus 68 (mhv68), is the dramatic suppression of cellular gene expression in a process known as host shutoff. the alkaline exonuclease proteins (kshv sox, mhv-68 musox and ebv bglf5) have been shown to induce shutoff by destabilizing cellular mrnas. here we extend previous analyses of cellular mrna abundance during lytic infection to c ...201121573023
a mechanistic basis for potent, gb-directed gammaherpesvirus neutralization.glycoprotein b is a conserved, essential component of gammaherpes virions and so potentially vulnerable to neutralization. however, few good gb-specific neutralizing antibodies have been identified. here we show that murid herpesvirus-4 is strongly neutralized by monoclonal antibodies that recognize an epitope close to one of the gb fusion loops. antibody binding did not stop gb interacting with its cellular ligands or initiating its fusion-associated conformation change, but did stop gb resolvi ...201121593277
suppression of tlr9 immunostimulatory motifs in the genome of a gammaherpesvirus.multiple receptors within the innate immune system have evolved to recognize nucleic acids as signatures of viral infection. it is believed that this specificity is essential for viral detection, as viruses often lack other invariant features that can serve as suitable targets for innate receptors. one such innate receptor, tlr9, has been implicated in the detection of many dsdna viruses. in this study, we investigate the detection of murine gammaherpesvirus 68 (mhv68) by tlr9. we find that the ...201121666062
global mrna degradation during lytic gammaherpesvirus infection contributes to establishment of viral latency.during a lytic gammaherpesvirus infection, host gene expression is severely restricted by the global degradation and altered 3' end processing of mrna. this host shutoff phenotype is orchestrated by the viral sox protein, yet its functional significance to the viral lifecycle has not been elucidated, in part due to the multifunctional nature of sox. using an unbiased mutagenesis screen of the murine gammaherpesvirus 68 (mhv68) sox homolog, we isolated a single amino acid point mutant that is sel ...201121811408
tlr9-induced interferon beta is associated with protection from gammaherpesvirus-induced exacerbation of lung fibrosis.abstract: background: we have demonstrated previously that murine gammaherpesvirus 68 (gamma-hv68) infection exacerbates established pulmonary fibrosis. because tlr9 may be important in controlling the immune response to gamma-hv68 infection, we examined how tlr9 signaling effects exacerbation of fibrosis in response to viral infection using models of bleomycin- and fluorescein isothiocyanate-induced pulmonary fibrosis in wild-type (balb/c) and tlr9-/- mice. results: we demonstrate that in the a ...201121810214
neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions.previously, we reported that murine ?herpesvirus-68 (m1-mhv-68) induces pulmonary artery (pa) neointimal lesions in s100a4-overexpressing, but not in wild-type (c57), mice. lesions were associated with heightened lung elastase activity and pa elastin degradation. we now investigate a direct relationship between elastase and pa neointimal lesions, the nature and source of the enzyme, and its presence in clinical disease. we found an association exists between the percentage of pas with neointimal ...201121763677
ccaat/enhancer binding proteins play a role in orilyt-dependent genome replication during mhv-68 de novo infection.murine gammaherpesvirus 68 (mhv-68), a member of the gammaherpesvirus family, replicates robustly in permissive cell lines and is able to infect laboratory mice. mhv-68 has emerged as a model for studying the basic aspects of viral replication and host-virus interactions of its human counterparts. herpesvirus genome replication is mediated through a cis-element in the viral genome called the origin of lytic replication (orilyt). a family of transcription factors, ccaat/enhancer binding proteins ...201121748596
strain-dependent requirement for ifn-+¦ for respiratory control and immunotherapy in murine gammaherpesvirus infection.abstract interferon-+¦ (ifn-+¦) and perforin (pfp) are important effector mechanisms used by cd8 t cells to clear virus-infected cells. in this study, we used ifn-+¦/pfp double knockout mice to address if these two effector molecules play redundant roles in the control of acute infection with murine gammaherpesvirus-68 (mhv-68) in balb/c mice. perforin knockout (ko) mice and wild-type mice cleared infectious virus from the lungs, even following high-dose infection. however, the ifn-+¦ ko and ifn ...201121830899
a role for dna-dependent activator of interferon regulatory factor in the recognition of herpes simplex virus type 1 by glial cells.abstract:201121838860
molecular detection of murine herpesvirus 68 in ticks feeding on free-living reptiles.the mhv-68 (designed as murid herpesvirus 4 (muhv 4) strain 68) isolated from two rodents, myodes glareolus and apodemus flavicollis, is considered as a natural pathogen of free-living murid rodents. recently, the detection of mhv antibodies in the blood of animals living in the same biotope as mhv-infected mice has suggested that ticks may have a role in the transmission of this pathogen. ixodes ricinus is one the most abundant tick species in europe known to transmit multiple pathogens causing ...201121732020
murid herpesvirus-4 exploits dendritic cells to infect b cells.dendritic cells (dcs) play a central role in initiating immune responses. some persistent viruses infect dcs and can disrupt their functions in vitro. however, these viruses remain strongly immunogenic in vivo. thus what role dc infection plays in the pathogenesis of persistent infections is unclear. here we show that a persistent, b cell-tropic gamma-herpesvirus, murid herpesvirus-4 (muhv-4), infects dcs early after host entry, before it establishes a substantial infection of b cells. dc-specif ...201122102809
Dynamic association of gammaherpesvirus DNA with core histone during de novo lytic infection of primary cells.Association of herpesvirus DNA with histones has important implications for lytic and latent infections; thus herpesviruses arbitrate interactions with histones to productively infect host cells. While regulation of alpha and betaherpesvirus chromatin during lytic infection has been actively investigated, very little is known about interaction of gammaherpesvirus DNA with histones upon de novo lytic infection. Murine gammaherpesvirus-68 (MHV68) is a rodent pathogen that offers a tractable system ...201122018782
Persistent infection of a gammaherpesvirus in the central nervous system.Human gammaherpesvirus infections of the central nervous system (CNS) have been linked to various neurological diseases. Murine gammaherpesvirus 68 (MHV-68), genetically related and biologically similar to human gammaherpesviruses, infects the CNS in laboratory mice. However, viral persistency of MHV-68 has not been studied following CNS infection. In this study, we undertook the noninvasive bioluminescence imaging of a recombinant MHV-68 expressing the firefly luciferase (M3FL) to monitor virus ...201122169075
distinct domains in orf52 tegument protein mediate essential functions in murine gammaherpesvirus 68 virion tegumentation and secondary envelopment.epstein-barr virus and kaposi's sarcoma-associated herpesvirus are etiologically associated with several types of human malignancies. however, as these two human gammaherpesviruses do not replicate efficiently in cultured cells, the morphogenesis of gammaherpesvirus virions is poorly understood. murine gammaherpesvirus 68 (mhv-68) provides a tractable model to define common, conserved features of gammaherpesvirus biology. orf52 of mhv-68 is conserved among gammaherpesviruses. we have previously ...201122090138
a gammaherpesvirus cooperates with interferon-alpha/beta-induced irf2 to halt viral replication, control reactivation, and minimize host lethality.the gammaherpesviruses, including epstein-barr virus (ebv) and kaposi's sarcoma-associated herpesvirus (kshv), establish latency in memory b lymphocytes and promote lymphoproliferative disease in immunocompromised individuals. the precise immune mechanisms that prevent gammaherpesvirus reactivation and tumorigenesis are poorly defined. murine gammaherpesvirus 68 (mhv68) is closely related to ebv and kshv, and type i (alpha/beta) interferons (ifnαβ) regulate mhv68 reactivation from both b cells a ...201122114555
partial genome sequence of murine gammaherpesvirus 72 and its analysis.murine gammaherpesvirus 68 (mhv-68)-infected mouse is a well known model for studies of epstein-barr virus (ebv)-related lymphoproliferative diseases (lpd). murine gammaherpesvirus 72 (mhv-72) has been considered a close relative of mhv-68 but its replication in murine mammary gland cells and kinetics of infection of mice were found to be different. pathological studies of a long-term-infection of mice revealed a similar or higher malignancy development rate in mhv-72-infected mice as compared w ...201122149497
de novo infection of b cells during murine gammaherpesvirus 68 latency.the mechanisms by which gammaherpesviruses maintain latency are unclear. here we used a murine gammaherpesvirus model to show that previously uninfected b cells in immunocompetent mice can acquire virus during latency. in vivo depletion of t cells allowed viral reactivation, as measured by increased viral loads, but not enhanced transfer of virus to new cells. in the absence of both immune t cells and antibody following the transfer of latently infected cells into naïve animals, there was robust ...201121849446
virally-induced upregulation of heparan sulfate on b cells via the action of type i ifn.cell surface heparan sulfate (hs) is an important coreceptor for many cytokines, chemokines, and growth factors. in this study, we report that splenic murine b cells express very little hs and that upon infection with either gammaherpesvirus (murine gammaherpesvirus 68) or betaherpesvirus (murine cytomegalovirus), hs is rapidly upregulated at the surface of b cells. hs upregulation was not observed in mice deficient for the type i ifn (ifn-i) receptor. additionally, treatment of wild-type mice w ...201122048770
murine γ-herpesvirus 68 evades host cytokine production via rta-induced rela degradation.cytokines play crucial roles in curtailing the propagation and spread of pathogens within the host. as obligate pathogens, γ-herpesviruses have evolved a plethora of mechanisms to evade host immune responses. we have previously shown that murine γ-herpesvirus 68 (γhv68) induces the degradation of rela, an essential subunit of the transcriptionally active nfκb dimer, to evade cytokine production. here, we report that the immediately early gene product of γhv68, replication transactivator (rta), f ...201122130545
specific mutation of a γ-herpesvirus-expressed antigen in response to cd8 t cell selection in vivo.herpesviruses are thought to be highly genetically stable and their use as vaccine vectors has been proposed. however, studies of the human γ-herpesvirus, epstein-barr virus, have found viral isolates containing mutations in hla class i-restricted epitopes. using murine γ-herpesvirus 68 expressing ovalbumin (ova), we examined the stability of a γ-herpesvirus antigenic locus under strong cd8 t cell selection in vivo. ova-specific cd8 t cells selected viral isolates containing mutations in the ova ...201122171269
bovine herpesvirus 4 glycoprotein l is non-essential for infectivity but triggers virion endocytosis during entry.the core entry machinery of mammalian herpesviruses comprises glycoproteins b, h and l (gb, gh and gl). gh and gl form a heterodimer with a central role in viral membrane fusion. when archetypal alpha- or beta-herpesviruses lack gl, gh misfolds and progeny virions are non-infectious. however, the gl of the rhadinovirus murid herpesvirus 4 (muhv-4) is non-essential for infection. in order to define more generally what role gl plays in rhadinovirus infections, we disrupted its coding sequence in b ...201122205754
Replication and transcription activator (RTA) of murine gammaherpesvirus 68 binds to an RTA-responsive element and activates the expression of ORF18.The replication and transcription activator (RTA), mainly encoded by open reading frame 50, is an immediate-early gene product that is conserved among all characterized gammaherpesviruses. Previous studies have demonstrated that RTA proteins of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) can activate the promoter of many viral early lytic genes through direct or indirect mechanisms. Murine gammaherpesvirus 68 (MHV-68) is genetically related to KSHV and EBV, and th ...201121849436
murine gamma-herpesvirus immortalization of fetal liver-derived b cells requires both the viral cyclin d homolog and latency-associated nuclear antigen.human gammaherpesviruses are associated with the development of lymphoproliferative diseases and b cell lymphomas, particularly in immunosuppressed hosts. understanding the molecular mechanisms by which human gammaherpesviruses cause disease is hampered by the lack of convenient small animal models to study them. however, infection of laboratory strains of mice with the rodent virus murine gammaherpesvirus 68 (mhv68) has been useful in gaining insights into how gammaherpesviruses contribute to t ...201121931547
placental viral infection sensitizes to endotoxin-induced pre-term labor: a double hit hypothesis.among pregnant women, acquired viral infections with a concurrent bacterial infection is a detrimental factor associated to poor prognosis. we evaluate the effect of a viral infection that does not lead to pre-term labor on the response to low doses of lipopolysaccharide (lps). our objectives were (i) to characterize the effect of a viral infection concurrent with exposure to microbial products on pregnancy outcome and (ii) to characterize the placental and fetal immune responses to the viral se ...201120712808
herpesvirus saimiri antagonizes nuclear domain 10-instituted intrinsic immunity via an orf3-mediated selective degradation of cellular protein sp100.in recent studies, the nuclear domain 10 (nd10) components pml, sp100, human daxx (hdaxx), and atrx were identified to be cellular restriction factors that are able to inhibit the replication of several herpesviruses. the antiviral function of nd10, however, is antagonized by viral effector proteins by a variety of strategies, including degradation of pml or relocalization of nd10 proteins. in this study, we analyzed the interplay between infection with herpesvirus saimiri (hvs), the prototypic ...201222278248
unbiased mutagenesis of mhv68 lana reveals a dna-binding domain required for lana function in vitro and in vivo.the latency-associated nuclear antigen (lana), encoded by orf73, is a conserved gene among the γ2-herpesviruses (rhadinoviruses). the kaposi's sarcoma-associated herpesvirus (kshv) lana is consistently expressed in kshv-associated malignancies. in the case of the rodent γ2-herpesvirus, murine gammaherpesvirus 68 (mhv68), the lana homolog (mlana) is required for efficient virus replication, reactivation from latency and immortalization of murine fetal liver-derived b cells. to gain insights into ...201222969427
vaccine prospect of kaposi sarcoma-associated herpesvirus.infection of kaposi sarcoma-associated herpesvirus (kshv) or human herpesvirus-8 (hhv-8) is estimated to account for 34,000 new cancer cases globally. unlike other herpesviruses, kshv is not ubiquitous but is highly prevalent in some areas, such as sub-saharan africa where kaposi sarcoma is the leading cancer among adults. while latent infection of kshv plays a major and direct role in tumorigenesis, viral lytic replication also makes significant contributions to this process. efforts to develop ...201222795202
a heparan-dependent herpesvirus targets the olfactory neuroepithelium for host entry.herpesviruses are ubiquitous pathogens that cause much disease. the difficulty of clearing their established infections makes host entry an important target for control. however, while herpesviruses have been studied extensively in vitro, how they cross differentiated mucus-covered epithelia in vivo is unclear. to establish general principles we tracked host entry by murid herpesvirus-4 (muhv-4), a lymphotropic rhadinovirus related to the kaposi's sarcoma-associated herpesvirus. spontaneously ac ...201223133384
noncanonical micrornas and endogenous sirnas in lytic infection of murine gammaherpesvirus.microrna (mirna) and endogenous small interfering rna (endo-sirna) are two essential classes of small noncoding rnas (sncrnas) in eukaryotes. the class of mirna is diverse and there exist noncanonical mirnas that bypass the canonical mirna biogenesis pathway. in order to identify noncanonical mirnas and endo-sirnas responding to virus infection and study their potential function, we sequenced small-rna species from cells lytically infected with murine gammaherpesvirus 68 (mhv68). in addition to ...201223110115
partial genome analysis of murine gammaherpesvirus 4556.murine gammaherpesvirus 68 (mhv-68) -infected mouse is an animal model of gammaherpesvirus infection in man and domestic animals. murine gammaherpesvirus 4556 (mhv-4556), isolated from apodemus flavicollis ticks has been considered a close relative of mhv-68 but different in some features of infection in vitro and in vivo. previous comparison of mhv-4556 with mhv-68 has revealed their diversity in immune evasion protein mk3. in this study, hindiii and ecori restriction profiles of the mhv-4556 g ...201223043597
myeloid infection links epithelial and b cell tropisms of murid herpesvirus-4.gamma-herpesviruses persist in lymphocytes and cause disease by driving their proliferation. lymphocyte infection is therefore a key pathogenetic event. murid herpesvirus-4 (muhv-4) is a rhadinovirus that like the related kaposi's sarcoma-associated herpesvirus persists in b cells in vivo yet infects them poorly in vitro. here we used muhv-4 to understand how virion tropism sets the path to lymphocyte colonization. virions that were highly infectious in vivo showed a severe post-binding block to ...201223028329
amplification of jnk signaling is necessary to complete the murine gammaherpesvirus 68 lytic replication cycle.several studies have previously defined host-derived signaling events capable of driving lytic gammaherpesvirus replication or enhancing immediate-early viral gene expression. yet signaling pathways that regulate later stages of the productive gammaherpesvirus replication cycle are still poorly defined. in this study, we utilized a mass spectrometric approach to identify c-jun as an abundant cellular phosphoprotein present in late stages of lytic murine gammaherpesvirus 68 (mhv68) infection. kin ...201223015701
characterization of omental immune aggregates during establishment of a latent gammaherpesvirus infection.herpesviruses are characterized by their ability to establish lifelong latent infection. the gammaherpesvirus subfamily is distinguished by lymphotropism, establishing and maintaining latent infection predominantly in b lymphocytes. consequently, gammaherpesvirus pathogenesis is closely linked to normal b cell physiology. murine gammaherpesvirus 68 (mhv68) pathogenesis in laboratory mice has been extensively studied as a model system to gain insights into the nature of gammaherpesvirus infection ...201222952645
an expanded myeloid derived suppressor cell population does not play a role in gammaherpesvirus-exacerbated breast cancer metastases.mice latently infected with murine gammaherpesvirus 68 (hv-68) and transplanted with 4 t1 breast cancer cells developed exacerbated metastatic lesions when compared to controls. the mechanisms responsible for this viral-exacerbated disease were not clear. the ability of hv-68 infection to induce s100a8 and s100a9 production and to expand a population of cd11b+gr-1+ cells suggested that increased numbers, or activity, of viral-expanded myeloid derived suppressor cells (mdscs) might contribute to ...201222946998
activation of the unfolded protein response by 2-deoxy-d-glucose inhibits kaposi's sarcoma-associated herpesvirus replication and gene expression.lytic replication of the kaposi's sarcoma-associated herpesvirus (kshv) is essential for the maintenance of both the infected state and characteristic angiogenic phenotype of kaposi's sarcoma and thus represents a desirable therapeutic target. during the peak of herpesvirus lytic replication, viral glycoproteins are mass produced in the endoplasmic reticulum (er). normally, this leads to er stress which, through an unfolded protein response (upr), triggers phosphorylation of the α subunit of euk ...201222926574
murine gammaherpesvirus 68 lana acts on terminal repeat dna to mediate episome persistence.murine gammaherpesvirus 68 (mhv68) orf73 (mlana) has sequence homology to kaposi's sarcoma-associated herpesvirus (kshv) latency-associated nuclear antigen (lana). lana acts on the kshv terminal repeat (tr) elements to mediate kshv episome maintenance. disruption of mlana expression severely reduces the ability of mhv68 to establish latent infection in mice, consistent with the possibility that mlana mediates episome persistence. here we assess the roles of mlana and mhv68 tr (mtr) elements in e ...201222915819
epidemiology and fitness effects of wood mouse herpesvirus in a natural host population.rodent gammaherpesviruses have become important models for understanding human herpesvirus diseases. in particular, interactions between murid herpesvirus 4 and mus musculus (a non-natural host species) have been extensively studied under controlled laboratory conditions. however, several fundamental aspects of murine gammaherpesvirus biology are not well understood, including how these viruses are transmitted from host to host, and their impacts on host fitness under natural conditions. here, w ...201222915692
experimental infection of laboratory-bred bank voles (myodes glareolus) with murid herpesvirus 4.muhv-4 is a natural pathogen of rodents of the genus apodemus (e.g., wood mice, yellow-necked mice) and myodes glareolus (bank voles). we report experimental muhv-4 infection of bank voles in comparison with infection of a. sylvaticus (wood mice) and balb/c mice. like in wood mice, the level of productive replication in the lungs of bank voles was significantly lower than in balb/c mice. in contrast to other hosts, however, the level of latent infection in the lung and spleen of bank voles was e ...201222782137
ctcf and sp1 interact with the murine gammaherpesvirus 68 internal repeat elements.herpesviruses maintain a dynamic balance between latency and productive infection. this is a complex process regulated by viral and cellular factors. we have developed a murine gammaherpesvirus 68 (mhv-68) model system in which to study mechanisms underlying balance between latency and lytic infection. we have generated an epithelial cell line that carries mhv-68 in a tightly latent form by using a bacterial artificial chromosome clone of the virus genome with a mutation in the mhv-68 major lyti ...201222706977
murine gammaherpesvirus 68 glycoprotein 150 does not contribute to latency amplification in vivo.murine gammaherpesvirus 68 (mhv-68) is used as a model to study the function of gammaherpesvirus glycoproteins. gp150 of mhv-68, encoded by open reading frame m7, is a positional homolog of gp350/220 of ebv and of gp35/37 of kshv. since it had been proposed that gp350/220 of ebv might be a suitable vaccine antigen to protect from ebv-associated diseases, gp150 has been applied as a model vaccine in the mhv-68 system. when analyzing the function of gp150, previous studies yielded conflicting resu ...201222681851
exacerbated metastatic disease in a mouse mammary tumor model following latent gammaherpesvirus infection. 201222642913
murine gammaherpesvirus-68 expands, but does not activate, cd11b+ gr-1+ splenocytes in vivo.murine gammaherpesvirus 68 (hv-68) is an efficient pathogen, capable of infecting and establishing lifelong latency in rodents. while many studies have demonstrated the ability of this viral infection to modulate immune responses, a unifying mechanism for hv-68-induced subversion of a protective host response remains elusive. we questioned whether infection with hv-68 could expand a population of myeloid derived suppressor cells (mdsc) as one mechanism for altering protective immunity.201222507226
murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity.gammaherpesvirus infections, such as those caused by ebv, have been suggested to promote the development of autoimmunity. to test this idea, we infected healthy wt and lupus-prone b6.sle123 mice with an ebv-related and rodent-specific gammaherpesvirus, γhv68. although acute γhv68 infection increased autoantibody levels for 4 to 6 wk, latent infection inhibited these responses for 1 y. the inhibition of autoantibody expression was only observed in b6.sle123 females and not in males, which already ...201222474381
tracking murine gammaherpesvirus 68 infection of germinal center b cells in vivo.infection of mice with murine gammaherpesvirus 68 (mhv68) provides a tractable small animal model to study various aspects of persistent gammaherpesvirus infection. we have previously utilized a transgenic mhv68 that expresses enhanced yellow fluorescent protein (eyfp) to identify infected cells. while this recombinant mhv68 has been useful for identifying infected cell populations by flow cytometry, it has been suboptimal for identification of infected cells in tissue sections due to the high s ...201222427999
virion endocytosis is a major target for murid herpesvirus-4 neutralization.herpesviruses consistently transmit from immunocompetent carriers, implying that their neutralization is hard to achieve. murid herpesvirus-4 (muhv-4) exploits host igg fc receptors to bypass blocks to cell binding, and ph-dependent protein conformation changes to unveil its fusion machinery only after endocytosis. nevertheless, neutralization remains possible by targeting the virion glycoprotein h (gh)-gl heterodimer, and the neutralizing antibody responses of muhv-4 carriers are improved by bo ...201222377583
viral cyclins mediate separate phases of infection by integrating functions of distinct mammalian cyclins.gammaherpesvirus cyclins have expanded biochemical features relative to mammalian cyclins, and promote infection and pathogenesis including acute lung infection, viral persistence, and reactivation from latency. to define the essential features of the viral cyclin, we generated a panel of knock-in viruses expressing various viral or mammalian cyclins from the murine gammaherpesvirus 68 cyclin locus. viral cyclins of both gammaherpesvirus 68 and kaposi's sarcoma-associated herpesvirus supported a ...201222319441
tiled microarray identification of novel viral transcript structures and distinct transcriptional profiles during two modes of productive murine gammaherpesvirus 68 infection.we applied a custom tiled microarray to examine murine gammaherpesvirus 68 (mhv68) polyadenylated transcript expression in a time course of de novo infection of fibroblast cells and following phorbol ester-mediated reactivation from a latently infected b cell line. during de novo infection, all open reading frames (orfs) were transcribed and clustered into four major temporal groups that were overlapping yet distinct from clusters based on the phorbol ester-stimulated b cell reactivation time co ...201222318145
herpesvirus glycoproteins undergo multiple antigenic changes before membrane fusion.herpesvirus entry is a complicated process involving multiple virion glycoproteins and culminating in membrane fusion. glycoprotein conformation changes are likely to play key roles. studies of recombinant glycoproteins have revealed some structural features of the virion fusion machinery. however, how the virion glycoproteins change during infection remains unclear. here using conformation-specific monoclonal antibodies we show in situ that each component of the murid herpesvirus-4 (muhv-4) ent ...201222253913
role of endoplasmic reticulum stress in age-related susceptibility to lung fibrosis.the incidence of idiopathic pulmonary fibrosis (ipf) increases with age. the mechanisms that underlie the age-dependent risk for ipf are unknown. based on studies that suggest an association of ipf and γherpesvirus infection, we infected young (2-3 mo) and old (≥18 mo) c57bl/6 mice with the murine γherpesvirus 68. acute murine γherpesvirus 68 infection in aging mice resulted in severe pneumonitis and fibrosis compared with young animals. progressive clinical deterioration and lung fibrosis in th ...201222227563
the virion-associated open reading frame 49 of murine gammaherpesvirus 68 promotes viral replication both in vitro and in vivo as a derepressor of rta.replication and transcription activator (rta), an immediate-early gene, is a key molecular switch to evoke lytic replication of gammaherpesviruses. open reading frame 49 (orf49) is conserved among gammaherpesviruses and shown to cooperate with rta in regulating virus lytic replication. here we show a molecular mechanism and in vivo functions of murine gammaherpesvirus 68 (mhv-68 or γhv-68) orf49. mhv-68 orf49 was transcribed and translated as a late gene. the orf49 protein was associated with a ...201222090108
open reading frame 23 of murine gammaherpesvirus 68 is nonessential for in vitro and in vivo infection.although open reading frame (orf) 23 is conserved among gammaherpesviruses, its role during infection is not known. here, we studied the expression of orf23 of murine gammaherpesvirus 68 (mhv-68) and its role during infection. orf23 mrna was detected in infected cells as a late transcript. the orf23 protein product could be expressed and detected as an n-terminally flag-tagged protein by western blot and indirect immunofluorescence. to investigate the role of orf23 in the infection cycle of a ga ...201222258865
zap inhibits murine gammaherpesvirus 68 orf64 expression and is antagonized by rta.zinc finger antiviral protein (zap) is an interferon-inducible host antiviral factor that specifically inhibits the replication of certain viruses, including hiv-1 and ebola virus. zap functions as a dimer formed through intermolecular interactions of its n-terminal tails. zap binds directly to specific viral mrnas and inhibits their expression by repressing translation and/or promoting degradation of the target mrna. zap is not a universal antiviral factor, since some viruses grow normally in z ...201223255809
zinc finger antiviral protein inhibits murine gammaherpesvirus 68 m2 expression and regulates viral latency in cultured cells.zinc finger antiviral protein (zap) is a host factor that specifically inhibits the replication of certain viruses by binding to specific viral mrnas and repressing mrna expression. here we report that zap inhibits expression of murine gammaherpesvirus 68 (mhv-68) m2, which plays important roles in establishment and maintenance of viral latency. downregulation of endogenous zap in cells harboring latent mhv-68 promoted lytic replication of the virus. these results suggest that zap inhibits m2 ex ...201222951821
mhv68 latency modulates the host immune response to influenza a virus.murine gammaherpesvirus 68 (mhv68) is a natural rodent pathogen that has been used as a model to study the pathogenesis of human gammaherpesviruses. like other herpesviruses, mhv68 causes acute infection and establishes life-long latency in the host. recently, it has been shown that mice latently infected with mhv68 have resistance to unrelated pathogens in secondary infection models. we therefore hypothesized that latent mhv68 infection could modulate the host response to influenza a virus. to ...201323807051
murine gammaherpesvirus 68 orf75c contains ubiquitin e3 ligase activity and requires pml sumoylation but not other known cellular pml regulators, ck2 and e6ap, to mediate pml degradation.all gammaherpsviruses encode at least one gene related to the cellular formylglycinamide ribonucleotide amidotransferase (fgarat) enzyme but their biological roles are relatively unknown. the murine gammaherpesvirus 68 (mhv68) vfgarat, orf75c, mediates a proteasome-dependent degradation of the antiviral promyelocytic leukemia (pml) protein by an unknown mechanism, which is addressed in this study. we found that orf75c interacts weakly with pml and sumo-modified forms of pml are important for its ...201323541081
proteomic characterization of murid herpesvirus 4 extracellular virions.gammaherpesvirinae, such as the human epstein-barr virus (ebv) and the kaposi's sarcoma associated herpesvirus (kshv) are highly prevalent pathogens that have been associated with several neoplastic diseases. as ebv and kshv are host-range specific and replicate poorly in vitro, animal counterparts such as murid herpesvirus-4 (muhv-4) have been widely used as models. in this study, we used muhv-4 in order to improve the knowledge about proteins that compose gammaherpesviruses virions. to this en ...201324386290
crystal structure of the gamma-2 herpesvirus lana dna binding domain identifies charged surface residues which impact viral latency.latency-associated nuclear antigen (lana) mediates γ2-herpesvirus genome persistence and regulates transcription. we describe the crystal structure of the murine gammaherpesvirus-68 lana c-terminal domain at 2.2 å resolution. the structure reveals an alpha-beta fold that assembles as a dimer, reminiscent of epstein-barr virus ebna1. a predicted dna binding surface is present and opposite this interface is a positive electrostatic patch. targeted dna recognition substitutions eliminated dna bindi ...201324146618
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