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pathogenesis of a model gammaherpesvirus in a natural host.murine gammaherpesvirus 68 (mhv-68) infection of laboratory mice (mus musculus) is an established model of gammaherpesvirus pathogenesis. the fact that m. musculus is not a host in the wild prompted us to reassess mhv-68 infection in wood mice (apodemus sylvaticus), a natural host. here, we report significant differences in mhv-68 infection in the two species: (i) following intranasal inoculation, mhv-68 replicated in the lungs of wood mice to levels approximately 3 log units lower than in balb/ ...201020130062
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
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
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
gammaherpesvirus-driven plasma cell differentiation regulates virus reactivation from latently infected b lymphocytes.gammaherpesviruses chronically infect their host and are tightly associated with the development of lymphoproliferative diseases and lymphomas, as well as several other types of cancer. mechanisms involved in maintaining chronic gammaherpesvirus infections are poorly understood and, in particular, little is known about the mechanisms involved in controlling gammaherpesvirus reactivation from latently infected b cells in vivo. recent evidence has linked plasma cell differentiation with reactivati ...200919956661
alternatively initiated gene 50/rta transcripts expressed during murine and human gammaherpesvirus reactivation from latency.in the process of characterizing the requirements for expression of the essential immediate-early transcriptional activator (rta) encoded by gene 50 of murine gammaherpesvirus 68 (mhv68), a recombinant virus was generated in which the known gene 50 promoter was deleted (g50pko). surprisingly, the g50pko mutant retained the ability to replicate in permissive murine fibroblasts, albeit with slower kinetics than wild-type mhv68. 5'-rapid amplification of cdna ends analyses of rna prepared from g50p ...200918971285
signaling through toll-like receptors induces murine gammaherpesvirus 68 reactivation in vivo.murine gammaherpesvirus 68 (mhv68) establishes a lifelong infection in mice and is used as a model pathogen to study the role of viral and host factors in chronic infection. the maintenance of chronic mhv68 infection, at least in some latency reservoirs, appears to be dependent on the capacity of the virus to reactivate from latency in vivo. however, the signals that lead to mhv68 reactivation in vivo are not well characterized. toll-like receptors (tlrs), by recognizing the specific patterns of ...200919019960
alcelaphine herpesvirus-1 open reading frame 57 encodes an immediate-early protein with regulatory function.alcelaphine herpesvirus-1 (alhv-1) is the causative agent of malignant catarrhal fever, a lymphoproliferative and degenerative disease of large ruminants and ungulate species. the alcelaphine herpesvirus-1 gene product encoded by open reading frame 57 (orf 57) is the positional homologue of the orf 57 of herpes virus saimiri (hvs), kaposi's sarcoma associated herpesvirus (kshv) and murine gammaherpesvirus 68 (mhv 68), the epstein-barr virus bmlf1 gene, the herpes simplex virus (hsv-1) icp 27 and ...200919031004
high-resolution functional profiling of a gammaherpesvirus rta locus in the context of the viral genome.gammaherpesviruses kaposi's sarcoma-associated herpesvirus and epstein-barr virus are associated with multiple human cancers. our goal was to develop a quantitative, high-throughput functional profiling system to identify viral cis-elements and protein subdomains critical for virus replication in the context of the herpesvirus genome. in gamma-2 herpesviruses, the transactivating factor rta is essential for initiation of lytic gene expression and viral reactivation. we used the rta locus as a mo ...200919073723
in vivo imaging of murid herpesvirus-4 infection.luciferase-based imaging allows a global view of microbial pathogenesis. we applied this technique to gammaherpesvirus infection by inserting a luciferase expression cassette into the genome of murine herpesvirus-4 (muhv-4). the recombinant virus strongly expressed luciferase in lytically infected cells without significant attenuation. we used it to compare different routes of virus inoculation. after intranasal infection of anaesthetized mice, luciferase was expressed in the nose and lungs for ...200919088269
orf30 and orf34 are essential for expression of late genes in murine gammaherpesvirus 68.a hallmark of productive infection by dna viruses is the coupling of viral late gene expression to genome replication. here we report the identification of open reading frame 30 (orf30) and orf34 as viral trans factors crucial for activating late gene transcription following viral dna replication during lytic infection of murine gammaherpesvirus 68 (mhv-68). the mutant virus lacking either orf30 or orf34 underwent normal dna replication but failed to express viral late gene transcripts, leading ...200919091863
selective uptake of small rna molecules in the virion of murine gammaherpesvirus 68.noncoding rnas are a feature of many herpesvirus genomes. they include micrornas, whose function is the subject of intense investigation, in addition to longer rna molecules such as the epstein-barr virus-encoded rnas and herpesvirus saimiri u rnas, which have been known for some time but whose function is still not well defined. murine gammaherpesvirus 68 (mhv-68) encodes eight viral trna-like molecules (vtrnas) of unknown function. investigating the kinetics of expression of the vtrnas, we obs ...200919109392
identification of the nuclear export and adjacent nuclear localization signals for orf45 of kaposi's sarcoma-associated herpesvirus.open reading frame 45 (orf45) of kaposi's sarcoma-associated herpesvirus 8 (kshv) is an immediate-early phosphorylated tegument protein and has been shown to play important roles at both early and late stages of viral infection. homologues of orf45 exist only in gammaherpesviruses, and their homology is limited. these homologues differ in their protein lengths and subcellular localizations. we and others have reported that kshv orf45 is localized predominantly in the cytoplasm, whereas its homol ...200919116250
murid herpesvirus-4 induces chronic inflammation of intrahepatic bile ducts in mice deficient in gamma-interferon signalling.aim: infection of gamma interferon receptor defective mice with murid herpesvirus-4 also known as murine gammaherpesvirus-68 results in multi-organ fibrosis. in this paper we characterise the pathological changes occurring in the liver in this model. methods: standard immunohistochemistry and in situ hybridisation techniques were used to identify the cellular changes and the presence of virus at different times post infection. results: in liver sections from infected gamma interferon receptor de ...200919208039
age-dependent pathogenesis of murine gammaherpesvirus 68 infection of the central nervous system.gammaherpesvirus infection of the central nervous system (cns) has been linked to various neurological diseases, including meningitis, encephalitis, and multiple sclerosis. however, little is known about the interactions between the virus and the cns in vitro or in vivo. murine gammaherpesvirus 68 (mhv-68 or (gamma)hv-68) is genetically related and biologically similar to human gammaherpesviruses, thereby providing a tractable animal model system in which to study both viral pathogenesis and rep ...200919214440
in vivo importance of heparan sulfate-binding glycoproteins for murid herpesvirus-4 infection.many herpesviruses bind to heparan sulfate (hs). murid herpesvirus-4 (muhv-4) does so via its envelope glycoproteins gp70 and gh/gl. muhv-4 gp150 further regulates an hs-independent interaction to make that hs-dependent too. cell binding by muhv-4 virions is consequently strongly hs-dependent. gp70 and gh/gl show some in vitro redundancy: an antibody-mediated blockade of hs binding by one is well tolerated, whereas a blockade of both severely impairs infection. in order to understand the importa ...200919218205
rta promoter demethylation and histone acetylation regulation of murine gammaherpesvirus 68 reactivation.gammaherpesviruses have a common biological characteristic, latency and lytic replication. the balance between these two phases in murine gammaherpesvirus 68 (mhv-68) is controlled by the replication and transcription activator (rta) gene. in this report, we investigated the effect of dna demethylation and histone acetylation on mhv-68 replication. we showed that distinctive methylation patterns were associated with mhv-68 at the rta promoter during latency or lytic replication. treatment of mhv ...200919234612
cd4 t cells mediate killing during persistent gammaherpesvirus 68 infection.cd4 t cells are critical for the control of gammaherpesvirus persistence, but their direct effector mechanisms of virus control in vivo are still poorly understood. in this study, we use murine gammaherpesvirus 68 (gammahv68) in in vitro and in vivo cytotoxicity assays to show cd4-dependent killing of gammahv68-loaded cells in mice persistently infected with gammahv68. our results underscore the cytotoxic capacity of cd4 t cells during gammahv68 persistence.200919244319
the interaction of the gammaherpesvirus 68 orf73 protein with cellular bet proteins affects the activation of cell cycle promoters.infection of mice with murine gammaherpesvirus 68 (mhv-68) provides a valuable animal model for gamma-2 herpesvirus (rhadinovirus) infection and pathogenesis. the mhv-68 orf73 protein has been shown to be required for the establishment of viral latency in vivo. this study describes a novel transcriptional activation function of the mhv-68 orf73 protein and identifies the cellular bromodomain containing bet proteins brd2/ring3, brd3/orfx, and brd4 as interaction partners for the mhv-68 orf73 prot ...200919244327
glycoprotein l sets the neutralization profile of murid herpesvirus 4.antibodies readily neutralize acute, epidemic viruses, but are less effective against more indolent pathogens such as herpesviruses. murid herpesvirus 4 (muhv-4) provides an accessible model for tracking the fate of antibody-exposed gammaherpesvirus virions. glycoprotein l (gl) plays a central role in muhv-4 entry: it allows gh to bind heparan sulfate and regulates fusion-associated conformation changes in gh and gb. however, gl is non-essential: heparan sulfate binding can also occur via gp70, ...200919264603
murid herpesvirus-4 lacking thymidine kinase reveals route-dependent requirements for host colonization.gammaherpesviruses infect at least 90 % of the world's population. infection control is difficult, in part because some fundamental features of host colonization remain unknown, for example whether normal latency establishment requires viral lytic functions. since human gammaherpesviruses have narrow species tropisms, answering such questions requires animal models. murid herpesvirus-4 (muhv-4) provides one of the most tractable. muhv-4 genomes delivered to the lung or peritoneum persist without ...200919264614
nf-kappab p50 plays distinct roles in the establishment and control of murine gammaherpesvirus 68 latency.nf-kappab signaling is critical to the survival and transformation of cells infected by the human gammaherpesviruses epstein-barr virus and kaposi's sarcoma-associated herpesvirus. here we have examined how elimination of the nf-kappab transcription factor p50 from mice affects the life cycle of murine gammaherpesvirus 68 (mhv68). notably, mice lacking p50 in every cell type were unable to establish a sufficiently robust immune response to control mhv68 infection, leading to high levels of laten ...200919264770
identification and functional characterization of the left origin of lytic replication of murine gammaherpesvirus 68.murine gammaherpesvirus 68 (mhv-68) replicates robustly in cell culture, providing a model for studying viral genome replication during de novo infection of tumor-associated herpesviruses. we have previously identified a 1.25-kb origin of lytic replication (orilyt) for mhv-68. to further investigate the molecular mechanism of viral genome replication, we first fine-mapped essential cis-elements from this orilyt fragment using a transposon-mediated high-density mutagenesis method. the result prov ...200919285330
termination of nf-kappab activity through a gammaherpesvirus protein that assembles an ec5s ubiquitin-ligase.host colonisation by lymphotropic gammaherpesviruses depends critically on the expansion of viral genomes in germinal centre (gc) b cells. yet, host and virus molecular mechanisms involved in driving such proliferation remain largely unknown. here, we show that the orf73 protein encoded by the murid herpesvirus-4 (muhv-4) inhibits host nuclear factor-kappa b (nf-kappab) transcriptional activity through poly-ubiquitination and subsequent proteasomal-dependent nuclear degradation of the nf-kappab ...200919322197
identification of infected b-cell populations by using a recombinant murine gammaherpesvirus 68 expressing a fluorescent protein.infection of inbred mice with murine gammaherpesvirus 68 (mhv68) has proven to be a powerful tool to study gammaherpesvirus pathogenesis. however, one of the limitations of this system has been the inability to directly detect infected cells harvested from infected animals. to address this issue, we generated a transgenic virus that expresses the enhanced yellow fluorescent protein (yfp), driven by the human cytomegalovirus immediate-early promoter and enhancer, from a neutral locus within the v ...200919386718
the chemokine-binding protein m3 as a tool to understand the chemokine network in vivo.murine herpesvirus 68 (mhv-68) codes for a secreted chemokine-binding protein, termed m3, which interacts with a broad range of chemokines with very high affinity, inhibiting chemokine function both in vitro and in vivo. here we describe the transgenic methodology used to study the role of m3 as an immune modulator in vivo.200919446726
the m10 locus of murine gammaherpesvirus 68 contributes to both the lytic and the latent phases of infection.murine gammaherpesvirus 68 (mhv-68) is closely related to epstein-barr virus and kaposi's sarcoma-associated herpesvirus (kshv) and provides a small-animal model to study the pathogenesis of gammaherpesvirus (gammahv) infections. according to the colinear organization of the gammahv genomes, the m10 locus is situated at a position equivalent to the k12 locus of kshv, which codes for proteins of the kaposin family. the m10 locus of mhv-68 has been predicted to code for three overlapping open read ...200919493995
the conserved ul24 family of human alpha, beta and gamma herpesviruses induces cell cycle arrest and inactivation of the cyclinb/cdc2 complex.the conserved murine gammaherpesvirus 68 orf20 has recently been demonstrated to induce g2 cell cycle arrest followed by apoptosis in human and mouse cells. here, we demonstrate that its homologues ul24 in hsv-1, orf20 in kshv and ul76 in hcmv are also inducers of cell cycle arrest followed by apoptosis in both human and mouse cells. the mechanism of action is similar to that reported for mhv-68 orf20, inactivating the mitotic complex cyclinb/cdc2.200919526192
murine gammaherpesvirus 68 infection of ifngamma unresponsive mice: a small animal model for gammaherpesvirus-associated b-cell lymphoproliferative disease.gammaherpesviruses are tightly controlled by the host immune response, with gammaherpesvirus-associated malignancies prevalent in immune-suppressed individuals. previously, infection of ifngamma-unresponsive mice with gammaherpesvirus 68 (gammahv68) showed that ifngamma controlled chronic infection, limiting chronic diseases including arteritis and pulmonary fibrosis. here, we show that gammahv68-infected ifngamma receptor-deficient (ifngammar(-/-)) mice uniformly develop angiocentric inflammato ...200919531651
infection with murine gammaherpesvirus 68 exacerbates inflammatory bowel disease in il-10-deficient mice.we questioned whether infection with murine gammaherpesvirus 68 (hv-68) might exacerbate inflammatory bowel disease using mice deficient in il-10 (il-10-/-) as a model of developing colitis.200919544045
host shutoff is a conserved phenotype of gammaherpesvirus infection and is orchestrated exclusively from the cytoplasm.lytic infection with the two human gammaherpesviruses, kaposi's sarcoma-associated herpesvirus (kshv) and epstein-barr virus (ebv), leads to significant depletion of the cellular transcriptome. this host shutoff phenotype is driven by the conserved herpesviral alkaline exonuclease, termed sox in kshv and bglf5 in ebv, which in gammaherpesviruses has evolved the genetically separable ability to target cellular mrna. we now show that host shutoff is also a prominent consequence of murine gammaherp ...200919587049
immune control of mammalian gamma-herpesviruses: lessons from murid herpesvirus-4.many acute viral infections can be controlled by vaccination; however, vaccinating against persistent infections remains problematic. herpesviruses are a classic example. here, we discuss their immune control, particularly that of gamma-herpesviruses, relating the animal model provided by murid herpesvirus-4 (muhv-4) to human infections. the following points emerge: (i) cd8(+) t-cell evasion by herpesviruses confers a prominent role in host defence on cd4(+) t cells. cd4(+) t cells inhibit muhv- ...200919605591
perturbation of lytic and latent gammaherpesvirus infection in the absence of the inhibitory receptor ceacam1.control of gammaherpesvirus infections requires a complex, well orchestrated immune response regulated by positive and negative co-signaling molecules. while the impact of co-stimulatory molecules has been addressed in various studies, the role of co-inhibitory receptors has not been tested. the itim-bearing ceacam1 is an inhibitory receptor expressed by a variety of immune cells, including b, t and nk cells. using ceacam1(-/-) mice, we analyzed the in vivo function of ceacam1 during acute and l ...200919621080
antibody limits in vivo murid herpesvirus-4 replication by igg fc receptor-dependent functions.antibody is an important antiviral defence. however, it is considered to do little against human gamma-herpesviruses, which establish predominantly latent infections regulated by t cells. one limitation on analysing these infections has been that latency is already well-established at clinical presentation; early infection may still be accessible to antibody. here, using murid herpesvirus-4 (muhv-4), we tested the impact of adoptively transferred antibody on early gamma-herpesvirus infection. im ...200919625459
a novel cre recombinase imaging system for tracking lymphotropic virus infection in vivo.detection, isolation, and identification of individual virus infected cells during long term infection are critical to advance our understanding of mechanisms of pathogenesis for latent/persistent viruses. however, current approaches to study these viruses in vivo have been hampered by low sensitivity and effects of cell-type on expression of viral encoded reporter genes. we have designed a novel cre recombinase (cre)-based murine system to overcome these problems, and thereby enable tracking an ...200919652715
open reading frame 33 of a gammaherpesvirus encodes a tegument protein essential for virion morphogenesis and egress.tegument is a unique structure of herpesvirus, which surrounds the capsid and interacts with the envelope. morphogenesis of gammaherpesvirus is poorly understood due to lack of efficient lytic replication for epstein-barr virus and kaposi's sarcoma-associated herpesvirus/human herpesvirus 8, which are etiologically associated with several types of human malignancies. murine gammaherpesvirus 68 (mhv-68) is genetically related to the human gammaherpesviruses and presents an excellent model for stu ...200919656880
a gammaherpesvirus ubiquitin-specific protease is involved in the establishment of murine gammaherpesvirus 68 infection.murine gammaherpesvirus 68 (mhv-68) contains a ubiquitin (ub)-specific cysteine protease (usp) domain embedded within the large tegument protein orf64, as do all other herpesviruses. the biological role of this protease is still unclear, but for the alphaherpesvirus marek's disease virus, its usp is involved in t-cell lymphoma formation. we here study the role of the mhv-68 usp, encoded by orf64. by constructing a mutant virus with a single cysteine-to-alanine replacement in the active site of o ...200919706716
murine gammaherpesvirus 68 infection of gamma interferon-deficient mice on a balb/c background results in acute lethal pneumonia that is dependent on specific viral genes.gamma interferon (ifn-gamma) is critical for the control of chronic infection with murine gammaherpesvirus 68 (gammahv68). current data indicate that ifn-gamma has a lesser role in the control of acute replication of gammahv68. here, we show that ifn-gamma-deficient mice on the balb/c genetic background poorly control acute viral replication and succumb to early death by acute pneumonia. notably, this acute, lethal pneumonia was dependent not only on the viral dose, but also on specific viral ge ...200919710134
mucosal immunization with recombinant adenoviral vectors expressing murine gammaherpesvirus-68 genes m2 and m3 can reduce latent viral load.gammaherpesviruses establish life-long latent infections in their hosts. if the host becomes immunosuppressed, these viruses may reactivate and cause severe disease, and even in immunocompetent individuals the gammaherpesviruses are presumed to have an oncogenic potential. murine gammaherpesvirus-68 (mhv-68) is a member of the gammaherpesvirinae subfamily and represents a useful murine model for this category of infections, in which new vaccination strategies may initially be evaluated. two atte ...200919748577
murine gammaherpesvirus 68 genes both induce and suppress lymphoproliferative disease.gammaherpesvirus infection is associated with an increased incidence of lymphoproliferative disease in immunocompromised hosts. murine gammaherpesvirus 68 (gammahv68) infection of balb beta(2)-microglobulin-deficient (balb beta(2)m(-/-)) mice provides an animal model for analysis of the mechanisms responsible for the induction of a lymphoproliferative disease, atypical lymphoid hyperplasia (alh), that is pathologically similar to posttransplant lymphoproliferative disease associated with epstein ...200817977975
differential regulation of the cyclin-dependent kinase inhibitors p21(cip1) and p27(kip1) by phosphorylation directed by the cyclin encoded by murine herpesvirus 68.members of the gamma2-herpesvirus family encode cyclin-like proteins that have the ability to deregulate mammalian cell cycle control. here we report the key features of the viral cyclin encoded by murine herpesvirus 68, m cyclin. m cyclin preferentially associated with and activated cdk2; the m cyclin/cdk2 holoenzyme displayed a strong reliance on phosphorylation of the cdk t loop for activity. cdk2 associated with m cyclin exhibited substantial resistance to the cdk inhibitor proteins p21(cip) ...200817997402
islet expression of m3 uncovers a key role for chemokines in the development and recruitment of diabetogenic cells in nod mice.type 1 diabetes is an autoimmune disease characterized by a local inflammatory reaction in and around islets followed by selective destruction of insulin-secreting beta-cells. we tested the hypothesis that chemokines affect different mechanisms responsible for the development of diabetes in nod mice.200818003753
detection and analysis of horizontal gene transfer in herpesvirus.horizontal gene transfers, where a significant proportion of the coding dna is contributed by external sources, might give rise to extremely dynamic genomes, which brings impact on the ecological and pathogenic characters of the recipient organisms. therefore it is important to computationally discriminate between horizontal transferred genes and normal genes. in this paper, we introduce a novel method for identifying horizontal transferred genes. this method, which relies on a gene's nucleotide ...200817905462
protective vaccination with hepatitis c virus ns3 but not core antigen in a novel mouse challenge model.efficient vaccines against hepatitis c virus (hcv) infection are urgently needed. vaccine development has been hampered by the lack of suitable small animal models to reliably test the protective capacity of immmunization.200818076128
a repetitive region of gammaherpesvirus genomic dna is a ligand for induction of type i interferon.innate immune responses against viral infection, especially the induction of type i interferon, are critical for limiting the replication of the virus. although it has been shown that dna can induce type i interferon, to date no natural dna ligand of a virus that induces type i interferon has been described. here we screened the genome of murine gammaherpesvirus 68 with mutations at various genomic locations to map the region of dna that induces type i interferon. a repetitive region termed the ...200818077715
unique structures in a tumor herpesvirus revealed by cryo-electron tomography and microscopy.gammaherpesviruses, including the human pathogens epstein-barr virus and kaposi's sarcoma-associated herpesvirus, are causative agents of lymphomas and other malignancies. the structural characterization of these viruses has been limited due to difficulties in obtaining adequate amount of virion particles. here we report the first three-dimensional structural characterization of a whole gammaherpesvirus virion by an emerging integrated approach of cryo-electron tomography combined with single-pa ...200818096403
tlr9 contributes to antiviral immunity during gammaherpesvirus infection.the human gammaherpesviruses kaposi's sarcoma-associated herpesvirus and ebv cause important infections. as pathogenetic studies of the human infections are restricted, murine gammaherpesvirus 68 serves as a model to study gammaherpesvirus pathogenesis. tlrs are a conserved family of receptors detecting microbial molecular patterns. among the tlrs, tlr9 recognizes unmethylated cpg dna motifs present in bacterial and viral dna. the aim of this study was to assess the role of tlr9 in gammaherpesvi ...200818097045
control of memory cd8+ t cell differentiation by cd80/cd86-cd28 costimulation and restoration by il-2 during the recall response.memory cd8+ t cell responses have been considered to be independent of cd80/cd86-cd28 costimulation. however, recall responses are often severely blunted in cd28-/- mice. whether this impairment represents a requirement for cd28 costimulation for proper memory cd8+ t cell development or a requirement during the recall response is unknown. furthermore, how cd28 costimulation affects the phenotype and function of memory cd8+ t cells has not been characterized in detail. in this study, we investiga ...200818178855
selection of mutant cho clones resistant to murine gammaherpesvirus 68 infection.murine gammaherpesvirus 68 (mhv68) is used as a model to study gammaherpesvirus pathogenesis both in tissue culture systems and in vivo. we used a gene-trapping approach to get insight into cellular factors involved in mhv68 infection. by generating a library of gene-trapped cho cells, we were able to isolate several clones that exhibited various degrees of resistance to mhv68-induced cytopathic effect. clones that showed the highest degree of resistance were affected at the early stage of the v ...200818191980
up-regulation of murid herpesvirus 4 orf50 by hypoxia: possible implication for virus reactivation from latency.murid herpesvirus 4 (muhv-4) is a member of the gammaherpesvirus subfamily capable to establish a long-lasting latency and induce occasional malignancies. because muhv-4 is associated with cancer in a subset of virus-infected mice and because tumor development is often linked with hypoxia, we studied the influence of hypoxia on the biology of this virus. using immunofluorescence and facs analysis we detected increased proportion of muhv-4 positive cells in the latently infected nb-78 cell line e ...200818221814
systematic mutagenesis of the murine gammaherpesvirus 68 m2 protein identifies domains important for chronic infection.murine gammaherpesvirus 68 (mhv68) infection of inbred mice represents a genetically tractable small-animal model for assessing the requirements for the establishment of latency, as well as reactivation from latency, within the lymphoid compartment. by day 16 postinfection, mhv68 latency in the spleen is found in b cells, dendritic cells, and macrophages. however, as with epstein-barr virus, by 3 months postinfection mhv68 latency is predominantly found in isotype-switched memory b cells. the mh ...200818234799
role for myd88 signaling in murine gammaherpesvirus 68 latency.toll-like receptors (tlrs) are known predominantly for their role in activating the innate immune response. recently, tlr signaling via myd88 has been reported to play an important function in development of a b-cell response. since b cells are a major latency reservoir for murine gammaherpesvirus 68 (mhv68), we investigated the role of tlr signaling in the establishment and maintenance of mhv68 latency in vivo. mice deficient in myd88 (myd88(-/-)) or tlr3 (tlr3(-/-)) were infected with mhv68. a ...200818256152
ecstasy (3,4-methylenedioxymethamphetamine) limits murine gammaherpesvirus-68 induced monokine expression.while ecstasy (3,4-methylenedioxymethamphetamine, mdma) has been shown to modulate immune responses, no studies have addressed drug-induced alterations to viral infection. in this study, bone marrow-derived macrophages were exposed to mdma, then infected with murine gammaherpesvirus-68, and the expression of monokines assessed. mdma-induced reductions in virus-stimulated monokine mrna expression were observed in a dose-dependent manner. in particular, il-6 mrna expression and secretion was signi ...200818280699
the gammaherpesvirus m2 protein manipulates the fyn/vav pathway through a multidocking mechanism of assembly.to establish latent infections in b-cells, gammaherpesviruses express proteins in the infected b-cells of the host that spuriously activate signalling pathways located downstream of the b-cell receptor. one such protein is m2, a murine gammaherpesvirus 68-encoded molecule that activates the vav1/rac1 pathway via the formation of trimolecular complexes with scr family members. previous reports have shown that the formation of this heteromolecular complex involves interactions between a proline ri ...200818301737
the murid herpesvirus-4 gh/gl binds to glycosaminoglycans.the first contact a virus makes with cells is an important determinant of its tropism. murid herpesvirus-4 (muhv-4) is highly dependent on glycosaminoglycans (gags) for cell binding. its first contact is therefore likely to involve a gag-binding virion glycoprotein. we have previously identified two such proteins, gp70 and gp150. gp70 binds strongly to gags. however, deleting it makes little difference to muhv-4 cell binding or gag-dependence. deleting gp150, by contrast, frees muhv-4 from gag d ...200818301747
induction of tachykinin production in airway epithelia in response to viral infection.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 lung challenge has been previously demonstrated but has been focused predominantly on the release of the tachykinins from nerves innervating the lung. we have previously demonstrated the most dramatic phenotype described for the substance p encoding gene preprotachykinin-a (ppt-a) to date in contro ...200818320026
a gammaherpesvirus-secreted activator of vbeta4+ cd8+ t cells regulates chronic infection and immunopathology.little is known about herpesvirus modulation of t cell activation in latently infected individuals or the implications of such for chronic immune disorders. murine gammaherpesvirus 68 (mhv68) elicits persistent activation of cd8(+) t cells bearing a vbeta4(+) t cell receptor (tcr) by a completely unknown mechanism. we show that a novel mhv68 protein encoded by the m1 gene is responsible for vbeta4(+) cd8(+) t cell stimulation in a manner reminiscent of a viral superantigen. during infection, m1 ...200818332178
the mhv68 m2 protein drives il-10 dependent b cell proliferation and differentiation.murine gammaherpesvirus 68 (mhv68) establishes long-term latency in memory b cells similar to the human gammaherpesvirus epstein barr virus (ebv). ebv encodes an interleukin-10 (il-10) homolog and modulates cellular il-10 expression; however, the role of il-10 in the establishment and/or maintenance of chronic ebv infection remains unclear. notably, mhv68 does not encode an il-10 homolog, but virus infection has been shown to result in elevated serum il-10 levels in wild-type mice, and il-10 def ...200818389062
infection of neonates with murine gammaherpesvirus 68 results in enhanced viral persistence in lungs and absence of infectious mononucleosis syndrome.we used the murine gammaherpesvirus 68 (gammahv-68), which serves as a model for human gammaherpesvirus infection, to determine whether age at infection altered the pattern of gammaherpesvirus pathogenesis. we infected mice intranasally at 8 days old (pups) and 6 weeks old (adults) to investigate differences in gammahv-68 pathogenesis. there was no difference between adults or pups in acute infection in the lungs at 6 days post-infection (p.i.). however, mice infected as pups exhibited a more di ...200818420788
murine gammaherpesvirus-induced fibrosis is associated with the development of alternatively activated macrophages.murine gammaherpesvirus 68 (mhv-68) is a natural pathogen of rodents closely related to the human gammaherpesviruses kaposi's sarcoma-associated herpesvirus and ebv. following intranasal infection, the virus replicates in the lung epithelium prior to establishing latent infection in lymphoid tissue. infection of mice deficient in ifn-gammar signaling (ifn-gammar-/-) results in a multiple organ fibrosis, in which the spleen is severely affected. we show here that by day 12 postinfection, prior to ...200818436582
an essential role for the proximal but not the distal cytoplasmic tail of glycoprotein m in murid herpesvirus 4 infection.murid herpesvirus-4 (muhv-4) provides a tractable model with which to define common, conserved features of gamma-herpesvirus biology. the multi-membrane spanning glycoprotein m (gm) is one of only 4 glycoproteins that are essential for muhv-4 lytic replication. gm binds to gn and is thought to function mainly secondary envelopment and virion egress, for which several predicted trafficking motifs in its c-terminal cytoplasmic tail could be important. we tested the contribution of the gm cytoplasm ...200818461133
glycoprotein b switches conformation during murid herpesvirus 4 entry.herpesviruses are ancient pathogens that infect all vertebrates. the most conserved component of their entry machinery is glycoprotein b (gb), yet how gb functions is unclear. a striking feature of the murid herpesvirus 4 (muhv-4) gb is its resistance to neutralization. here, we show by direct visualization of infected cells that the muhv-4 gb changes its conformation between extracellular virions and those in late endosomes, where capsids are released. specifically, epitopes on its n-terminal c ...200818474550
identification of closely spaced but distinct transcription initiation sites for the murine gammaherpesvirus 68 latency-associated m2 gene.murine gammaherpesvirus 68 (mhv68) infection of mice provides a tractable small-animal system for assessing viral requirements for establishment of and reactivation from latency. the m2 gene product has no homology to any known proteins but has been shown to play a role in both the establishment of mhv68 latency and reactivation from latency. furthermore, we have recently shown that m2 expression in primary murine b cells leads to enhanced proliferation, survival, and differentiation toward a pr ...200818480430
establishment of b-cell lines latently infected with reactivation-competent murine gammaherpesvirus 68 provides evidence for viral alteration of a dna damage-signaling cascade.gammaherpesvirus 68 (gammahv68, or mhv68) is a naturally occurring rodent pathogen that replicates to high titer in cell culture and is amenable to in vivo experimental evaluation of viral and host determinants of gammaherpesvirus disease. however, the inability of mhv68 to transform primary murine b cells in culture, the absence of a robust cell culture latency system, and the paucity of mhv68-positive tumor cell lines have limited an understanding of the molecular mechanisms by which mhv68 mod ...200818495760
murine gammaherpesvirus 68 open reading frame 75c tegument protein induces the degradation of pml and is essential for production of infectious virus.promyelocytic leukemia nuclear body (pml nb) proteins mediate an intrinsic cellular host defense response against virus infections. herpesviruses express proteins that modulate pml or pml-associated proteins by a variety of strategies, including degradation of pml or relocalization of pml nb proteins. the consequences of pml-herpesvirus interactions during infection in vivo have yet to be investigated in detail, largely because of the species-specific tropism of many human herpesviruses. murine ...200818508901
rvsv(m delta 51)-m3 is an effective and safe oncolytic virus for cancer therapy.oncolytic vesicular stomatitis virus (vsv) is being developed as a novel therapeutic agent for cancer treatment, although it is toxic in animals when administered systemically at high doses. its safety can be substantively improved by an m delta 51 deletion in the viral genome, and yet vsv(m delta 51) induces a much greater, robust cellular inflammatory response in the host than wild-type vsv, which severely attenuates its oncolytic potency. we have reported that the oncolytic potency of wild-ty ...200818533893
a replication-defective gammaherpesvirus efficiently establishes long-term latency in macrophages but not in b cells in vivo.murine gammaherpesvirus 68 (gammahv68 or mhv68) is genetically related to the human gammaherpesviruses epstein-barr virus (ebv) and kaposi's sarcoma-associated herpesvirus (kshv), providing a useful system for in vivo studies of the virus-host relationship. to begin to address fundamental questions about the mechanisms of the establishment of gammaherpesvirus latency, we previously generated a replication-defective gammahv68 lacking the expression of the single-stranded dna binding protein encod ...200818562537
chemokine-binding activities of m3 protein encoded by murine gammaherpesvirus 72.murine gammaherpesvirus 68 (mhv-68) contains gene-encoding m3 protein expressed during the acute and persistent phase of infection. this protein features a chemokine-binding activities (parry et al., 2000; van berkel et al., 2000). in this study, we demonstrated that the murine gammaherpesvirus 72 (mhv-72) also contained m3 gene with the codon-changing mutation at the position 920 nt converting amino acid (aa) 307 asp (gac) to gly (ggc). the mutation in the m3 protein was localized near chemokin ...200818564895
multiple functions for orf75c in murid herpesvirus-4 infection.all gamma-herpesviruses encode at least one homolog of the cellular enzyme formyl-glycineamide-phosphoribosyl-amidotransferase. murid herpesvirus-4 (muhv-4) encodes 3 (orfs 75a, 75b and 75c), suggesting that at least some copies have acquired new functions. here we show that the corresponding proteins are all present in virions and localize to infected cell nuclei. despite these common features, orfs 75a and 75b did not substitute functionally for a lack of orf75c, as orf75c virus knockouts were ...200818648660
the murid herpesvirus-4 gl regulates an entry-associated conformation change in gh.the glycoprotein h (gh)/gl heterodimer is crucial for herpesvirus membrane fusion. yet how it functions is not well understood. the murid herpesvirus-4 gh, like that of other herpesviruses, adopts its normal virion conformation by associating with gl. however, gh switched back to a gl-independent conformation after virion endocytosis. this switch coincided with a conformation switch in gb and with capsid release. virions lacking gl constitutively expressed the down-stream form of gh, prematurely ...200818665235
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