Publications

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a structural basis for brd2/4-mediated host chromatin interaction and oligomer assembly of kaposi sarcoma-associated herpesvirus and murine gammaherpesvirus lana proteins.kaposi sarcoma-associated herpesvirus (kshv) establishes a lifelong latent infection and causes several malignancies in humans. murine herpesvirus 68 (mhv-68) is a related γ2-herpesvirus frequently used as a model to study the biology of γ-herpesviruses in vivo. the kshv latency-associated nuclear antigen (klana) and the mhv68 mlana (orf73) protein are required for latent viral replication and persistence. latent episomal kshv genomes and klana form nuclear microdomains, termed 'lana speckles', ...201324146614
antiviral activity of angelicin against gammaherpesviruses.human gammaherpesviruses including epstein-barr virus (ebv) and kaposi's sarcoma-associated herpesvirus (kshv) are important pathogens as they persist in the host and cause various malignancies. however, few antiviral drugs are available to efficiently control gammaherpesvirus replication. here we identified the antiviral activity of angelicin against murine gammaherpesvirus 68 (mhv-68), genetically and biologically related to human gammaherpesviruses. angelicin, a furocoumarin naturally occurri ...201323892155
biological and pathogenetic characterization of different isolates of murine gammaherpesvirus 68 (mhv-68) in the context of study of human oncogenic gammaherpesviruses.study of murine gammaherpesvirus 68 (mhv-68), which was discovered in 1980 in slovakia, has led to many important findings regarding gammaherpesviral properties in general. nowadays, it is considered to be a universal model used for detailed studies to determine pathogenetic, immunological and molecular aspects of oncogenesis in analogy to epstein-barr virus (ebv) and kaposi΄s sarcoma-associated virus (kshv). the objective of this work is to characterize biological and pathogenetic properties of ...201323600868
illumination of murine gammaherpesvirus-68 cycle reveals a sexual transmission route from females to males in laboratory mice.transmission is a matter of life or death for pathogen lineages and can therefore be considered as the main motor of their evolution. gammaherpesviruses are archetypal pathogenic persistent viruses which have evolved to be transmitted in presence of specific immune response. identifying their mode of transmission and their mechanisms of immune evasion is therefore essential to develop prophylactic and therapeutic strategies against these infections. as the known human gammaherpesviruses, epstein ...201323593002
alpha beta-crystallin expression and presentation following infection with murine gammaherpesvirus 68.alpha beta-crystallin (cryab) is a small heat shock protein that can function as a molecular chaperone and has protective effects for cells undergoing a variety of stressors. surprisingly, cryab has been identified as one of the dominant autoantigens in multiple sclerosis. it has been suggested that autoimmune mediated destruction of this small heat shock protein may limit its protective effects, thereby exacerbating inflammation and cellular damage during multiple sclerosis. it is not altogethe ...201323586607
cd4 and cd8 t cells directly recognize murine gammaherpesvirus 68-immortalized cells and prevent tumor outgrowth.there has been extensive research regarding t cell recognition of epstein-barr virus-transformed cells; however, less is known regarding the recognition of b cells immortalized by gamma-2 herpesviruses. here we show that b cells immortalized by murine gammaherpesvirus 68 (mhv-68, γhv-68) can be controlled by either cd4 or cd8 t cells in vivo. we present evidence for the direct recognition of infected b cells by cd4 and cd8 t cells. these data will help in the development of immunotherapeutic app ...201323514885
an rs motif within the epstein-barr virus blrf2 tegument protein is phosphorylated by srpk2 and is important for viral replication.epstein-barr virus (ebv) is a gammaherpesvirus that causes infectious mononucleosis, b cell lymphomas, and nasopharyngeal carcinoma. many of the genes required for ebv virion morphogenesis are found in all herpesviruses, but some are specific to gammaherpesviruses. one of these gamma-specific genes, blrf2, encodes a tegument protein that has been shown to be essential for replication in other gammaherpesviruses. in this study, we identify blrf2 interacting proteins using binary and co-complex pr ...201323326445
modulation of b-cell tolerance by murine gammaherpesvirus 68 infection: requirement for orf73 viral gene expression and follicular helper t cells.viruses such as epstein-barr virus (ebv) have been linked to mechanisms that support autoantibody production in diseases such as systemic lupus erythematosus. however, the mechanisms by which viruses contribute to autoantibody production remain poorly defined. this stems in part, from the high level of seropositivity for ebv (> 95%) and the exquisite species specificity of ebv. in this study we overcame these problems by using murine gammaherpesvirus 68 (mhv68), a virus genetically and biologica ...201323311955
gammaherpesvirus latency induces antibody-associated thrombocytopenia in mice.human herpesviruses establish lifelong latency. viral recrudescence can lead to the development of cancers, immunoproliferative disorders, transplantation complications, and thrombocytopenia. although platelet-specific autoantibodies have been reported in patients infected with the epstein-barr virus (ebv), the mechanisms by which thrombocytopenia is induced remain unclear, as do the relative contributions of lytic viral replication and latent viral gene expression. the human gammaherpesviruses ...201323245703
stabilization of myc through heterotypic poly-ubiquitination by mlana is critical for γ-herpesvirus lymphoproliferation.host colonization by lymphotropic γ-herpesviruses depends critically on expansion of viral genomes in germinal center (gc) b-cells. myc is essential for the formation and maintenance of gcs. yet, the role of myc in the pathogenesis of γ-herpesviruses is still largely unknown. in this study, myc was shown to be essential for the lymphotropic γ-herpesvirus muhv-4 biology as infected cells exhibited increased expression of myc signature genes and the virus was unable to expand in myc defficient gc ...201323950719
activity and mechanism of action of hdvd, a novel pyrimidine nucleoside derivative with high levels of selectivity and potency against gammaherpesviruses.a novel nucleoside analogue, 1-[(2s,4s-2-(hydroxymethyl)-1,3-dioxolan-4-yl]5-vinylpyrimidine-2,4(1h,3h)-dione, or hdvd, was evaluated against a wide variety of herpesviruses and was found to be a highly selective inhibitor of replication of the gammaherpesviruses kaposi's sarcoma-associated herpesvirus (kshv) and epstein-barr virus (ebv). hdvd had also a pronounced inhibitory activity against murine herpesvirus 68 (mhv-68) and herpes simplex virus 1 (hsv-1). in contrast, replication of herpesvir ...201323345517
phosphoproteomic analyses reveal signaling pathways that facilitate lytic gammaherpesvirus replication.lytic gammaherpesvirus (ghv) replication facilitates the establishment of lifelong latent infection, which places the infected host at risk for numerous cancers. as obligate intracellular parasites, ghvs must control and usurp cellular signaling pathways in order to successfully replicate, disseminate to stable latency reservoirs in the host, and prevent immune-mediated clearance. to facilitate a systems-level understanding of phosphorylation-dependent signaling events directed by ghvs during ly ...201324068923
promyelocytic leukemia protein modulates establishment and maintenance of latent gammaherpesvirus infection in peritoneal cells.promyelocytic leukemia protein (pml) is an essential organizer of pml nuclear bodies (nbs), which carry out a variety of activities, including antiviral functions. herpesviruses from all subfamilies encode proteins that counteract pml nb-mediated antiviral defenses by multiple mechanisms. however, because of the species specificity of herpesviruses, only a limited number of in vivo studies have been undertaken to investigate the effect of pml or pml nbs on herpesvirus infection. to address this ...201323986598
glycoprotein b cleavage is important for murid herpesvirus 4 to infect myeloid cells.glycoprotein b (gb) is a conserved herpesvirus virion component implicated in membrane fusion. as with many-but not all-herpesviruses, the gb of murid herpesvirus 4 (muhv-4) is cleaved into disulfide-linked subunits, apparently by furin. preventing gb cleavage for some herpesviruses causes minor infection deficits in vitro, but what the cleavage contributes to host colonization has been unclear. to address this, we mutated the furin cleavage site (r-r-k-r) of the muhv-4 gb. abolishing gb cleavag ...201323903840
myxomavirus-derived serpin prolongs survival and reduces inflammation and hemorrhage in an unrelated lethal mouse viral infection.lethal viral infections produce widespread inflammation with vascular leak, clotting, and bleeding (disseminated intravascular coagulation [dic]), organ failure, and high mortality. serine proteases in clot-forming (thrombotic) and clot-dissolving (thrombolytic) cascades are activated by an inflammatory cytokine storm and also can induce systemic inflammation with loss of normal serine protease inhibitor (serpin) regulation. myxomavirus secretes a potent anti-inflammatory serpin, serp-1, that in ...201323774438
systemic and local infection routes govern different cellular dissemination pathways during gammaherpesvirus infection in vivo.human gammaherpesviruses cause morbidity and mortality associated with infection and transformation of lymphoid and endothelial cells. knowledge of cell types involved in virus dissemination from primary virus entry to virus latency is fundamental for the understanding of gammaherpesvirus pathogenesis. however, the inability to directly trace cell types with respect to virus dissemination pathways has prevented definitive conclusions regarding the relative contribution of individual cell types. ...201323408606
the absence of m1 leads to increased establishment of murine gammaherpesvirus 68 latency in igd-negative b cells.the secreted m1 protein of murine gammaherpesvirus 68 (mhv68) promotes effector vβ4(+) cd8(+) t cell expansion to impact virus control and immune-mediated pathologies in c57bl/6 mice, but not balb/c mice. we report a striking increase in the number of genome-positive, igd(-) b cells during chronic infection of both mouse strains. this suggests a novel role for m1 in influencing long-term maintenance in a major latency reservoir irrespective of the degree of vβ4(+) cd8(+) t cell expansion.201323302876
role of src homology domain binding in signaling complexes assembled by the murid γ-herpesvirus m2 protein.γ-herpesviruses express proteins that modulate b lymphocyte signaling to achieve persistent latent infections. one such protein is the m2 latency-associated protein encoded by the murid herpesvirus-4. m2 has two closely spaced tyrosine residues, tyr(120) and tyr(129), which are phosphorylated by src family tyrosine kinases. here we used mass spectrometry to identify the binding partners of tyrosine-phosphorylated m2. each m2 phosphomotif is shown to bind directly and selectively to sh2-containin ...201323258536
virtual screening of m3 protein antagonists for finding a model to study the gammaherpesvirus damaged immune system and chemokine related diseases.m3 protein is a chemokine decoy receptor involved in pathogenesis of persistent infection with gammaherpesvirus and complications related to the latency of this pathogen. we proposed that antagonists of the m3 would provide a unique opportunity for studying new therapeutic strategies in disordered immune system, immune-deficient states and role of chemokines in pathogenesis development.201324455481
murine gammaherpesvirus 68 encodes a second pml-modifying protein.the orf75c tegument protein of murine gammaherpesvirus 68 (mhv68) promotes the degradation of the antiviral promyelocytic leukemia (pml) protein. surprisingly, mhv68 expressing a degradation-deficient orf75c replicated in cell culture and in mice similar to the wild-type virus. however, in cells infected with this mutant virus, pml formed novel track-like structures that are induced by orf61, the viral ribonucleotide reductase large subunit. these findings may explain why orf75c mutant viruses u ...201424371073
rodent herpesvirus peru encodes a secreted chemokine decoy receptor.viruses have long been studied not only for their pathology and associated disease but also as model systems for understanding cellular and immunological processes. rodent herpesvirus peru (rhvp) is a recently characterized rhadinovirus related to murine gammaherpesvirus 68 (mhv68) and kaposi's sarcoma-associated herpesvirus (kshv) that establishes acute and latent infection in laboratory mice. rhvp encodes numerous unique proteins that we hypothesize might facilitate host immune evasion during ...201424173234
b cell response to herpesvirus infection of the olfactory neuroepithelium.viruses commonly infect the respiratory tract. analyses of host defense have focused on the lungs and the respiratory epithelium. spontaneously inhaled murid herpesvirus 4 (muhv-4) and herpes simplex virus 1 (hsv-1) instead infect the olfactory epithelium, where neuronal cilia are exposed to environmental antigens and provide a route across the epithelial mucus. we used muhv-4 to define how b cells respond to virus replication in this less well-characterized site. olfactory infection elicited ge ...201425253348
herpesvirus delivery to the murine respiratory tract.herpesvirus transmission is sporadic, and infection may be asymptomatic or present only with secondary lesions after dissemination. consequently host entry remains ill-understood. experimental infections can be informative, but depend on inoculations that are inherently artificial and so need validation. mice are a widely used experimental host. alert mice inhale readily small (5 μl) liquid volumes, and indian ink, luciferase or radiolabel delivered thus distributed to the nasopharynx and oropha ...201424928692
mouse cmv infection delays antibody class switch upon an unrelated virus challenge.poor immune protection upon vaccination is a critical determinant of immunosenescence. latent cytomegalovirus (cmv) infection has been associated with poor antibody responses to vaccination, but a causative role for cmv in the poor immune response requires experimental evidence and thus could not be confirmed in clinical studies. to test the hypothesis that latent cmv infection causes poor antibody responses, we infected young or adult mice with mouse cmv and challenged them with vesicular stoma ...201424462805
a gammaherpesvirus bcl-2 ortholog blocks b cell receptor-mediated apoptosis and promotes the survival of developing b cells in vivo.gammaherpesviruses such as epstein-barr virus (ebv) and kaposi's sarcoma-associated herpesvirus (kshv, hhv-8) establish lifelong latency in their hosts and are associated with the development of several types of malignancies, including a subset of b cell lymphomas. these viruses are thought to co-opt the process of b cell differentiation to latently infect a fraction of circulating memory b cells, resulting in the establishment of a stable latency setpoint. however, little is known about how thi ...201424516386
type i interferon signaling enhances cd8+ t cell effector function and differentiation during murine gammaherpesvirus 68 infection.cd8(+) t cell responses are critical to the control of replication and reactivation associated with gammaherpesvirus infection. type i interferons (ifns) have been shown to have direct and indirect roles in supporting cd8(+) t cell development and function during viral infection; however, the role of type i interferons during latent viral infection has not been examined. mice deficient in type i ifn signaling (ifnar1(-/-) mice) have high levels of reactivation during infection with murine gammah ...201425253356
gammaherpesvirus latency differentially impacts the generation of primary versus secondary memory cd8+ t cells during subsequent infection.unlike laboratory animals, humans are infected with multiple pathogens, including the highly prevalent herpesviruses. the purpose of these studies was to determine the effect of gammaherpesvirus latency on t cell number and differentiation during subsequent heterologous viral infections. mice were first infected with murine gammaherpesvirus 68 (mhv68), a model of epstein-barr virus (ebv) infection, and then after latency was established, they were challenged with the armstrong strain of lymphocy ...201425142586
maturation and vesicle-mediated egress of primate gammaherpesvirus rhesus monkey rhadinovirus require inner tegument protein orf52.the tegument layer of herpesviruses comprises a collection of proteins that is unique to each viral species. in rhesus monkey rhadinovirus (rrv), a close relative of the human oncogenic pathogen kaposi's sarcoma-associated herpesvirus, orf52 is a highly abundant tegument protein tightly associated with the capsid. we now report that orf52 knockdown during rrv infection of rhesus fibroblasts led to a greater than 300-fold reduction in the viral titer by 48 h but had little effect on the number of ...201424899183
a tissue culture model of murine gammaherpesvirus replication reveals roles for the viral cyclin in both virus replication and egress from infected cells.passage through the eukaryotic cell cycle is regulated by the activity of cyclins and their cyclin-dependent kinase partners. rhadinoviruses, such as kaposi's sarcoma-associated herpesvirus (kshv) and murine gammaherpesvirus 68 (mhv68), encode a viral homologue of mammalian d-type cyclins. in mhv68, the interaction of the viral cyclin with its cdk partners is important for acute replication in the lungs following low dose inoculation. attempts to further study this requirement in vitro have been ...201424695529
murine gammaherpesvirus 68 reactivation from b cells requires irf4 but not xbp-1.gammaherpesviruses display tropism for b cells and, like all known herpesviruses, exhibit distinct lytic and latent life cycles. one well-established observation among members of the gammaherpesvirus family is the link between viral reactivation from latently infected b cells and plasma cell differentiation. importantly, a number of studies have identified a potential role for a creb/atf family member, x-box binding protein 1 (xbp-1), in trans-activating the immediate early bzlf-1 or brlf1/gene ...201425078688
virus-encoded micrornas facilitate gammaherpesvirus latency and pathogenesis in vivo.gammaherpesviruses, including epstein-barr virus (ebv), kaposi sarcoma-associated herpesvirus (kshv, or hhv-8), and murine gammaherpesvirus 68 (mhv68, γhv68, or muhv-4), are b cell-tropic pathogens that each encode at least 12 micrornas (mirnas). it is predicted that these regulatory rnas facilitate infection by suppressing host target genes involved in a wide range of key cellular pathways. however, the precise contribution that gammaherpesvirus mirnas make to viral life cycle and pathogenesis ...201424865551
expansion of murine gammaherpesvirus latently infected b cells requires t follicular help.x linked lymphoproliferative disease (xlp) is an inherited immunodeficiency resulting from mutations in the gene encoding the slam associated protein (sap). one of the defining characteristics of xlp is extreme susceptibility to infection with epstein-barr virus (ebv), a gammaherpesvirus belonging to the genus lymphocryptovirus, often resulting in fatal infectious mononucleosis (fim). however, infection of sap deficient mice with the related murine gammaherpesvirus 68 (mhv68), a gammaherpesvirus ...201424789087
a shutoff and exonuclease mutant of murine gammaherpesvirus-68 yields infectious virus and causes rna loss in type i interferon receptor knockout cells.significant loss of rna followed by severely reduced cellular protein pool, a phenomenon termed host shutoff, is associated with a number of lytic virus infections and is a critical player in viral pathogenesis. until recently, viral dna exonucleases were associated only with processing of viral genomic dna and its encapsidation. however, recent observations have identified host shutoff and exonuclease function for the highly conserved viral exonucleases in γ-herpesviruses, which include kaposi' ...201424552788
is murine gammaherpesvirus-68 (mhv-68) a suitable immunotoxicological model for examining immunomodulatory drug-associated viral recrudescence?immunosuppressive agents are used for treatment of a variety of autoimmune diseases including rheumatoid arthritis (ra), systemic lupus erythematosis (sle), and psoriasis, as well as for prevention of tissue rejection after organ transplantation. recrudescence of herpesvirus infections, and increased risk of carcinogenesis from herpesvirus-associated tumors are related with immunosuppressive therapy in humans. post-transplant lymphoproliferative disorder (ptld), a condition characterized by deve ...201424512328
baff receptor deficiency limits gammaherpesvirus infection.lymphocyte colonization by gammaherpesviruses (γhvs) is an important target for cancer prevention. however, how it works is not clear. epstein-barr virus drives autonomous b cell proliferation in vitro but in vivo may more subtly exploit the proliferative pathways provided by lymphoid germinal centers (gcs). murid herpesvirus 4 (muhv-4), which realistically infects inbred mice, provides a useful tool with which to understand further how a γhv colonizes b cells in vivo. not all γhvs necessarily b ...201424501409
murine gammaherpesvirus-68 orf38 encodes a tegument protein and is packaged into virions during secondary envelopment.tegument is the unique structure of a herpesvirion which occupies the space between nucleocapsid and envelope. accumulating data have indicated that interactions among tegument proteins play a key role in virion morphogenesis. morphogenesis of gammaherpesviruses including kaposi's sarcoma-associated herpesvirus (kshv) and epstein-barr virus (ebv) is poorly understood due to the lack of efficient de novo lytic replication in cell culture. murine gammaherpesvirus-68 (mhv-68) is genetically related ...201424474202
unconventional sequence requirement for viral late gene core promoters of murine gammaherpesvirus 68.infection with the human gammaherpesviruses, epstein-barr virus (ebv) and kaposi's sarcoma-associated herpesvirus (kshv), is associated with several cancers. during lytic replication of herpesviruses, viral genes are expressed in an ordered cascade. however, the mechanism by which late gene expression is regulated has not been well characterized in gammaherpesviruses. in this study, we have investigated the cis element that mediates late gene expression during de novo lytic infection with murine ...201424403583
murine gammaherpesvirus m2 protein induction of irf4 via the nfat pathway leads to il-10 expression in b cells.reactivation of the gammaherpesviruses epstein-barr virus (ebv), kaposi's sarcoma-associated herpesvirus (kshv) and murine gammaherpesvirus 68 (mhv68) from latently infected b cells has been linked to plasma cell differentiation. we have previously shown that the mhv68 m2 protein is important for virus reactivation from b cells and, when expressed alone in primary murine b cells, can drive b cell differentiation towards a pre-plasma cell phenotype. in addition, expression of m2 in primary murine ...201424391506
pervasive transcription of a herpesvirus genome generates functionally important rnas.pervasive transcription is observed in a wide range of organisms, including humans, mice, and viruses, but the functional significance of the resulting transcripts remains uncertain. current genetic approaches are often limited by their emphasis on protein-coding open reading frames (orfs). we previously identified extensive pervasive transcription from the murine gammaherpesvirus 68 (mhv68) genome outside known orfs and antisense to known genes (termed expressed genomic regions [egrs]). similar ...201424618256
establishment of murine gammaherpesvirus latency in b cells is not a stochastic event.murid γ-herpesvirus-4 (muhv-4) promotes polyclonal b cell activation and establishes latency in memory b cells via unclear mechanisms. we aimed at exploring whether b cell receptor specificity plays a role in b cell susceptibility to viral latency and how this is related to b cell activation. we first observed that muhv-4-specific b cells represent a minority of the latent population, and to better understand the influence of the virus on non-muhv-4 specific b cells we used the swhel mouse model ...201425079788
to the editor: murine gammaherpesvirus 68 (mhv-68) escapes from nk-cell-mediated immune surveillance by a ceacam1-mediated immune evasion mechanism. 201424976512
defining immune engagement thresholds for in vivo control of virus-driven lymphoproliferation.persistent infections are subject to constant surveillance by cd8+ cytotoxic t cells (ctl). their control should therefore depend on mhc class i-restricted epitope presentation. many epitopes are described for γ-herpesviruses and form a basis for prospective immunotherapies and vaccines. however the quantitative requirements of in vivo immune control for epitope presentation and recognition remain poorly defined. we used murid herpesvirus-4 (muhv-4) to determine for a latently expressed viral ep ...201424967892
activation of nf-κb via endosomal toll-like receptor 7 (tlr7) or tlr9 suppresses murine herpesvirus 68 reactivation.in order to understand and possibly treat b-cell malignancies associated with latent gammaherpesvirus infection, it is vital to understand the factors that control the balance between the two transcriptional states of gammaherpesviruses: latency and lytic replication. we used murine gammaherpesvirus 68 (mhv 68) as a model system to investigate how engagement of endosomal toll-like receptors (tlrs) impacts reactivation from latency in vitro and establishment of latent infection in vivo. we found ...201424942583
the gammaherpesviruses kaposi's sarcoma-associated herpesvirus and murine gammaherpesvirus 68 modulate the toll-like receptor-induced proinflammatory cytokine response.the human pathogen kaposi's sarcoma-associated herpesvirus (kshv), the etiological agent of kaposi's sarcoma, primary effusion lymphoma, and multicentric castleman's disease, establishes lifelong latency upon infection. murine gammaherpesvirus 68 (mhv68) is a well-established model for kshv. toll-like receptors (tlrs) play a crucial role for the innate immune response to pathogens. although kshv and mhv68 are detected by tlrs, studies suggest they modulate tlr4 and tlr9 signaling, respectively. ...201424899179
promotion of a subdominant cd8 t cell response during murine gammaherpesvirus 68 infection in the absence of cd4 t cell help.cd8 and cd4 t cells are each critically important for immune control of murine gammaherpesvirus 68 (γhv68) infection. in immunocompetent mice, acute γhv68 infection results in lifelong latency, but in the absence of cd4 t cell help, mice succumb to viral recrudescence and disease. however, the requirements for cd4 t cell help in the generation and maintenance of antiviral cd8 t cell responses are incompletely understood, and it is unclear whether there are epitope-specific differences in the req ...201424789784
a conserved rna polymerase iii promoter required for gammaherpesvirus tmer transcription and microrna processing.canonical rna polymerase iii (pol iii) type 2 promoters contain a single a and b box and are well documented for their role in trna and sine transcription in eukaryotic cells. the genome of murid herpesvirus 4 (muhv-4) contains eight polycistronic trna-microrna encoded rna (tmer) genes that are transcribed from a rna pol iii type 2-like promoter containing triplicated a box elements. here, we demonstrate that the triplicated a box sequences are required in their entirety to produce functional mu ...201424747015
host restriction of murine gammaherpesvirus 68 replication by human apobec3 cytidine deaminases but not murine apobec3.humans encode seven apobec3 (a3a-a3h) cytidine deaminase proteins that differ in their expression profiles, preferred nucleotide recognition sequence and capacity for restriction of rna and dna viruses. we identified apobec3 hotspots in numerous herpesvirus genomes. to determine the impact of host apobec3 on herpesvirus biology in vivo, we examined whether murine apobec3 (ma3) restricts murine gammaherpesvirus 68 (mhv68). viral replication was impaired by several human apobec3 proteins, but not ...201424725948
a murid gamma-herpesviruses exploits normal splenic immune communication routes for systemic spread.gamma-herpesviruses (γhvs) are widespread oncogenic pathogens that chronically infect circulating lymphocytes. how they subvert the immune check-point function of the spleen to promote persistent infection is not clear. we show that murid herpesvirus-4 (muhv-4) enters the spleen by infecting marginal zone (mz) macrophages, which provided a conduit to mz b cells. relocation of mz b cells to the white pulp allowed virus transfer to follicular dendritic cells. from here the virus reached germinal c ...201424721574
murine gammaherpesvirus 68 encoding open reading frame 11 targets tank binding kinase 1 to negatively regulate the host type i interferon response.upon viral infection, type i interferons, such as alpha and beta interferon (ifn-α and ifn-β, respectively), are rapidly induced and activate multiple antiviral genes, thereby serving as the first line of host defense. many dna and rna viruses counteract the host interferon system by modulating the production of ifns. in this study, we report that murine gammaherpesvirus 68 (mhv-68), a double-stranded dna virus, encodes open reading frame 11 (orf11), a novel immune modulator, to block ifn-β prod ...201424696485
ifnγ and perforin cooperate to control infection and prevent fatal pathology during persistent gammaherpesvirus infection in mice.infection with murine gammaherpesvirus 68 has become an accepted model for studying the virus/host interactions with regard to gammaherpesvirus infections. previous studies using gene-deficient mice have revealed that neither ifnγ nor perforin is essential in controlling the outcome of infection or the virus load during chronic infection in c57bl/6 mice. however, pronounced multiorgan fibrosis and splenic atrophy are observed in mice lacking ifnγ or the ifnγ receptor. to study the interplay betw ...201424684620
enhanced response of t cells from murine gammaherpesvirus 68-infected mice lacking the suppressor of t cell receptor signaling molecules sts-1 and sts-2.the human gammaherpesviruses establish life-long infections that are associated with the development of lymphomas and neoplasms, especially in immunocompromised individuals. t cells play a crucial role in the control of gammaherpesvirus infection through multiple functions, including the direct killing of infected cells, production of cytokines such as interferon-γ (ifn-γ), and costimulation of b cells. impaired t cell function in mice infected with murine gammaherpesvirus 68 (mhv68) leads to in ...201424587276
identification of alternative transcripts encoding the essential murine gammaherpesvirus lytic transactivator rta.the essential immediate early transcriptional activator rta, encoded by gene 50, is conserved among all characterized gammaherpesviruses. analyses of a recombinant murine gammaherpesvirus 68 (mhv68) lacking both of the known gene 50 promoters (g50dblko) revealed that this mutant retained the ability to replicate in the simian kidney epithelial cell line vero but not in permissive murine fibroblasts following low-multiplicity infection. however, g50dblko replication in permissive fibroblasts was ...201424574412
prevention of tumor formation by latent gammaherpesvirus infection.recent reports suggested that chronic herpesvirus infection, as a constituent of the so-called virome, may not only exert harmful effects but may also be beneficial to the host, for example mediating increased resistance to secondary infections or to tumors. to further challenge this concept, specifically regarding increased resistance to tumors, we infected chimeric hla-dr4-h2-e (dr4) mice, a mouse strain which spontaneously develops hematological tumors, with the rodent herpesvirus murine gamm ...201526714031
murine gammaherpesvirus 68 lana and sox homologs counteract atm-driven p53 activity during lytic viral replication.tumor suppressor p53 is activated in response to numerous cellular stresses, including viral infection. however, whether murine gammaherpesvirus 68 (mhv68) provokes p53 during the lytic replication cycle has not been extensively evaluated. here, we demonstrate that mhv68 lytic infection induces p53 phosphorylation and stabilization in a manner that is dependent on the dna damage response (ddr) kinase ataxia telangiectasia mutated (atm). the induction of p53 during mhv68 infection occurred in mul ...201526676792
deletion of murid herpesvirus 4 orf63 affects the trafficking of incoming capsids toward the nucleus.gammaherpesviruses are important human and animal pathogens. despite the fact that they display the classical architecture of herpesviruses, the function of most of their structural proteins is still poorly defined. this is especially true for tegument proteins. interestingly, a potential role in immune evasion has recently been proposed for the tegument protein encoded by kaposi's sarcoma-associated herpesvirus open reading frame 63 (orf63). to gain insight about the roles of orf63 in the life ...201526676769
cells transformed by murine herpesvirus 68 (mhv-68) release compounds with transforming and transformed phenotype suppressing activity resembling growth factors.in this study, we investigated the medium of three cell lines transformed with murine herpesvirus 68 (mhv-68) in vitro and in vivo, 68/hdf, 68/nih3t3, and s11e, for the presence of compounds resembling growth factors of some herpesviruses which have displayed transforming and transformed phenotype suppressing activity in normal and tumor cells. when any of spent medium was added to cell culture we observed the onset of transformed phenotype in baby hamster kidney cells (bhk-21) cells and transfo ...201526666191
epigenetic modification of rta (orf50) promoter is not responsible for distinct reactivation patterns of murine gammaherpesviruses.gammaherpesviruses-encoded replication and transcription activator (rta) (orf50) plays an essential role in the initiation of viral lytic gene expression and reactivation from latency. the rta expression is influenced by many viral and cellular factors, including epigenetic modifications, mainly dna methylation and histone modifications. murine gammaherpesvirus 68 (mhv-68), belonging to the species murid herpesvirus (muhv-4), is widely used as a model to study human gammaherpesvirus infections i ...201526666189
infection-induced retrotransposon-derived noncoding rnas enhance herpesviral gene expression via the nf-κb pathway.short interspersed nuclear elements (sines) are highly abundant, rna polymerase iii-transcribed noncoding retrotransposons that are silenced in somatic cells but activated during certain stresses including viral infection. how these induced sine rnas impact the host-pathogen interaction is unknown. here we reveal that during murine gammaherpesvirus 68 (mhv68) infection, rapidly induced sine rnas activate the antiviral nf-κb signaling pathway through both mitochondrial antiviral-signaling protein ...201526584434
murid gammaherpesvirus latency-associated protein m2 promotes the formation of conjugates between transformed b lymphoma cells and t helper cells.establishment of persistent infection in memory b cells by murid herpesvirus-4 (muhv-4) depends on the proliferation of latently infected germinal center b cells, for which t cell help is essential. whether the virus is capable of modulating b-t helper cell interaction for its own benefit is still unknown. here, we investigate if the muhv-4 latency associated m2 protein, which assembles multiprotein complexes with b cell signaling proteins, plays a role. we observed that m2 led to the upregulati ...201526544979
downregulation of poly(adp-ribose) polymerase 1 by a viral processivity factor facilitates lytic replication of gammaherpesvirus.in kaposi's sarcoma-associated herpesvirus (kshv), poly(adp-ribose) polymerase 1 (parp-1) acts as an inhibitor of lytic replication. here, we demonstrate that kshv downregulated parp-1 upon reactivation. the viral processivity factor of kshv (pf-8) interacted with parp-1 and was sufficient to degrade parp-1 in a proteasome-dependent manner; this effect was conserved in murine gammaherpesvirus 68. pf-8 knockdown in kshv-infected cells resulted in reduced lytic replication upon reactivation with i ...201526157130
copper(ii) complexes with new fluoroquinolones: synthesis, structure, spectroscopic and theoretical study, dna damage, cytotoxicity and antiviral activity.copper(ii) complexes with fluoroquinolones in the presence of the nitrogen donor heterocyclic ligands 1,10-phenanthroline have been considered in detail. the phenanthroline moiety was introduced into the ligand environment with the aim to determine whether the nuclease activity is feasible. all suitable x-ray structures of the complexes under study reveal a distorted square pyramidal coordination geometry for cu(ii) atom. the conformational and spectroscopic (ft-ir and uv-visible) behavior has b ...201526116423
b-cell-independent lymphoid tissue infection by a b-cell-tropic rhadinovirus.lymphocytes provide gammaherpesviruses with a self-renewing substrate for persistent infection and with transport to mucosal sites for host exit. their role in the initial colonization of new hosts is less clear. murid herpesvirus 4 (muhv-4), an experimentally accessible, b-cell-tropic rhadinovirus (gamma-2 herpesvirus), persistently infects both immunocompetent and b-cell-deficient mice. a lack of b-cells did not compromise muhv-4 entry into lymphoid tissue, which involved myeloid cell infectio ...201525986632
detection of murine herpesvirus 68 (mhv-68) in dermacentor reticulatus ticks.murid herpesvirus 4 (muhv 4) strain 68 (mhv-68) is a natural pathogen of murid rodents, which serves as hosts to dermacentor reticulatus ticks. these ticks are known to transmit multiple pathogens, which can cause diseases in humans and animals. recently, the detection of mhv-68 antibodies in the blood of animals living in the same biotope as virus-infected mice has suggested the role of ticks in pathogen circulation in nature. herein, to identify mhv-68 in d. reticulatus ticks, dna samples from ...201525947097
interleukin 21 signaling in b cells is required for efficient establishment of murine gammaherpesvirus latency.the human gammaherpesviruses take advantage of normal b cell differentiation pathways to establish life-long infection in memory b cells. murine gammaherpesvirus 68 (mhv68) infection of laboratory strains of mice also leads to life-long infection in memory b cells. to gain access to the memory b cell population, mhv68 infected b cells pass through the germinal center reaction during the onset of latency and require signals from t follicular helper (tfh) cells for proliferation. interleukin 21 (i ...201525875847
murine gammaherpesvirus 68 pathogenesis is independent of caspase-1 and caspase-11 in mice and impairs interleukin-1β production upon extrinsic stimulation in culture.gammaherpesviruses establish lifelong infections that are associated with the development of cancer. these viruses subvert many aspects of the innate and adaptive immune response of the host. the inflammasome, a macromolecular protein complex that controls inflammatory responses to intracellular danger signals generated by pathogens, is both activated and subverted during human gammaherpesvirus infection in culture. the impact of the inflammasome response on gammaherpesvirus replication and late ...201525855746
rhadinovirus host entry by co-operative infection.rhadinoviruses establish chronic infections of clinical and economic importance. several show respiratory transmission and cause lung pathologies. we used murid herpesvirus-4 (muhv-4) to understand how rhadinovirus lung infection might work. a primary epithelial or b cell infection often is assumed. muhv-4 targeted instead alveolar macrophages, and their depletion reduced markedly host entry. while host entry was efficient, alveolar macrophages lacked heparan - an important rhadinovirus binding ...201525790477
possible role of different animal species in maintenance and spread of murine gammaherpesvirus 68 in the nature.murine gammaherpesvirus 68 (mhv-68), isolated from a bank vole (clethrionomys glareolus) in slovakia in 1976 is a natural pathogen of wild murid rodents. this review is focused to biological properties of this pathogen, the mode of its maintenance in murid rodents as reservoir animals, mechanisms of its spread to other animals in the same biotope as well as to livestock and household animals. potential role of ticks as vectors and the possibility of infection of humans with this virus are consid ...201525790046
murine gammaherpesvirus 68 orf48 is an rta-responsive gene product and functions in both viral lytic replication and latency during in vivo infection.replication and transcription activator (rta) of gammaherpesvirus is an immediate early gene product and regulates the expression of many downstream viral lytic genes. orf48 is also conserved among gammaherpesviruses; however, its expression regulation and function remained largely unknown. in this study, we characterized the transcription unit of orf48 from murine gammaherpesvirus 68 (mhv-68) and analyzed its transcriptional regulation. we showed that rta activates the orf48 promoter via an rta ...201525762743
murine gammaherpesvirus (mhv-68) transforms cultured cells in vitro.human dermal fibroblasts and mouse nih/3t3 cells acquired the transformed phenotype ('criss-cross' pattern of growth) after infection with ultraviolet-irradiated murine gammaherpesvirus (muhv-4 strain 68; mhv-68). these cells with changed phenotype could be serially cultured for 5-6 passages (35-40 days), and then they entered into crisis and most of them died. in a small number of cultures, however, foci of newly transformed cells appeared from which two stable cell lines were derived. after 6- ...201525677084
evasion of innate cytosolic dna sensing by a gammaherpesvirus facilitates establishment of latent infection.herpesviruses are dna viruses harboring the capacity to establish lifelong latent-recurrent infections. there is limited knowledge about viruses targeting the innate dna-sensing pathway, as well as how the innate system impacts on the latent reservoir of herpesvirus infections. in this article, we report that murine gammaherpesvirus 68 (mhv68), in contrast to α- and β-herpesviruses, induces very limited innate immune responses through dna-stimulated pathways, which correspondingly played only a ...201525595793
mesenchymal stem cells detect and defend against gammaherpesvirus infection via the cgas-sting pathway.mesenchymal stem cells (mscs) are widely used in clinical settings to treat tissue injuries and autoimmune disorders due to their multipotentiality and immunomodulation. long-term observations reveal several complications after mscs infusion, especially herpesviral infection. however, the mechanism of host defense against herpesviruses in mscs remains largely unknown. here we showed that murine gammaherpesvirus-68 (mhv-68), which is genetically and biologically related to human gammaherpesviruse ...201525592282
absence of the uracil dna glycosylase of murine gammaherpesvirus 68 impairs replication and delays the establishment of latency in vivo.uracil dna glycosylases (ung) are highly conserved proteins that preserve dna fidelity by catalyzing the removal of mutagenic uracils. all herpesviruses encode a viral ung (vung), and yet the role of the vung in a pathogenic course of gammaherpesvirus infection is not known. first, we demonstrated that the vung of murine gammaherpesvirus 68 (mhv68) retains the enzymatic function of host ung in an in vitro class switch recombination assay. next, we generated a recombinant mhv68 with a stop codon ...201525589640
murine gammaherpesvirus 68 orf35 is required for efficient lytic replication and latency.murine gammaherpesvirus (mhv) 68, a natural pathogen of field mice, is related to human gammaherpesviruses, epstein–barr virus (ebv; human herpesvirus 4) and kaposi’s sarcoma-associated herpesvirus (kshv; human herpesvirus 8). the orf35 of mhv-68 and its homologues of ebv and kshv are located in the gene cluster composed of orf34–orf38 in which each gene overlaps with adjacent genes. although mhv-68 orf35 was reported to be an essential gene, its function during infection is presently unknown. i ...201526459827
host entry by gamma-herpesviruses--lessons from animal viruses?the oncogenicity of gamma-herpesviruses (γhvs) motivates efforts to control them and their persistence makes early events key targets for intervention. human γhvs are often assumed to enter naive hosts orally and infect b cells directly. however, neither assumption is supported by direct evidence, and vaccination with the epstein-barr virus (ebv) gp350, to block virion binding to b cells, failed to reduce infection rates. thus, there is a need to re-evaluate assumptions about γhv host entry. giv ...201526246389
gammaherpesvirus co-infection with malaria suppresses anti-parasitic humoral immunity.immunity to non-cerebral severe malaria is estimated to occur within 1-2 infections in areas of endemic transmission for plasmodium falciparum. yet, nearly 20% of infected children die annually as a result of severe malaria. multiple risk factors are postulated to exacerbate malarial disease, one being co-infections with other pathogens. children living in sub-saharan africa are seropositive for epstein barr virus (ebv) by the age of 6 months. this timing overlaps with the waning of protective m ...201525996913
roles of epstein-barr virus bglf3.5 gene and two upstream open reading frames in lytic viral replication in hek293 cells.the epstein-barr virus (ebv) predominantly establishes a latent infection in b lymphocytes, but a small percentage of infected cells switch from the latent state to the lytic cycle, leading to potent viral dna replication and progeny viruses production. we here focused on a lytic gene bglf3.5, and first established bglf3.5 mutants by marker cassette insertion. unexpectedly, this insertion mutant failed to produce bglf4 protein and thus progeny production was severely inhibited. then we carefully ...201525965794
gammaherpesvirus tegument protein orf33 is associated with intranuclear capsids at an early stage of the tegumentation process.herpesvirus nascent capsids, after assembly in the nucleus, must acquire a variety of tegument proteins during maturation. however, little is known about the identity of the tegument proteins that are associated with capsids in the nucleus or the molecular mechanisms involved in the nuclear egress of capsids into the cytoplasm, especially for the two human gammaherpesviruses epstein-barr virus (ebv) and kaposi's sarcoma-associated herpesvirus (kshv), due to a lack of efficient lytic replication ...201525717105
murine gammaherpesvirus-68 (mhv-68) is not horizontally transmitted amongst laboratory mice by cage contact.murine gammaherpesvirus-68 (mhv-68), a natural pathogen of mice, is being evaluated as a model of epstein barr virus (ebv) infection for use in investigation of the effects of immunomodulatory therapy on herpesvirus pathogenesis in humans. immunosuppressive agents are used for treatment of a variety of autoimmune diseases as well as for prevention of tissue rejection after organ transplantation and can result in recrudescence of latent herpesvirus infections. prior to examination of mhv-68 as a ...201525412621
identification of viral and host proteins that interact with murine gammaherpesvirus 68 latency-associated nuclear antigen during lytic replication: a role for hsc70 in viral replication.latency-associated nuclear antigen (lana) is a conserved, multifunctional protein encoded by members of the rhadinovirus subfamily of gammaherpesviruses, including kaposi sarcoma-associated herpesvirus (kshv) and murine gammaherpesvirus 68 (mhv68). we previously demonstrated that mhv68 lana (mlana) is required for efficient lytic replication. however, mechanisms by which mlana facilitates viral replication, including interactions with cellular and viral proteins, are not known. thus, we performe ...201526581985
subcapsular sinus macrophages limit acute gammaherpesvirus dissemination.lymphocyte proliferation, mobility and longevity make them prime targets for virus infection. myeloid cells that process and present environmental antigens to lymphocytes are consequently an important line of defence. subcapsular sinus macrophages (ssms) filter the afferent lymph and communicate with b-cells. how they interact with b-cell-tropic viruses is unknown. we analysed their encounter with murid herpesvirus-4 (muhv-4), an experimentally accessible gammaherpesvirus related to kaposi's sar ...201525872742
immune protection against virus challenge in aging mice is not affected by latent herpesviral infections.latent herpesvirus infections alter immune homeostasis. to understand if this results in aging-related loss of immune protection against emerging infections, we challenged old mice carrying latent mouse cytomegalovirus (cmv), herpes simplex virus 1 (hsv-1), and/or murine gammaherpesvirus 68 (mhv-68) with influenza virus, west nile virus (wnv), or vesicular stomatitis virus (vsv). we observed no increase in mortality or weight loss compared to results seen with herpesvirus-negative counterparts a ...201526339051
the interferon-inducible mouse apolipoprotein l9 and prohibitins cooperate to restrict theiler's virus replication.apolipoprotein l9b (apol9b) is an interferon-stimulated gene (isg) that has antiviral activity and is weakly expressed in primary mouse neurons as compared to other cell types. here, we show that both apol9 isoforms (apol9b and apol9a) inhibit replication of theiler's murine encephalomyelitis virus (tmev) but not replication of vesicular stomatitis virus (vsv), murid herpesvirus-4 (muhv-4), or infection by a lentiviral vector. apol9 genes are strongly expressed in mouse liver and, to a lesser ex ...201526196674
soluble m3 proteins of murine gammaherpesviruses 68 and 72 expressed in escherichia coli: analysis of chemokine-binding properties.m3 protein of murine gammaherpesvirus 68 (mhv-68) was identified as a viral chemokine-binding protein 3 (vckbp-3) capable to bind a broad spectrum of chemokines and their receptors. during both acute and latent infection mhv-68 m3 protein provides a selective advantage for the virus by inhibiting the antiviral and inflammatory response. a unique mutation asp307gly was identified in the m3 protein of murine gammaherpesvirus 72 (mhv-72), localized near chemokine-binding domain. study on chemokine- ...201526666184
the role of latently infected b cells in cns autoimmunity.the onset of multiple sclerosis (ms) is caused by both genetic and environmental factors. among the environmental factors, it is believed that previous infection with epstein-barr virus (ebv) may contribute in the development of ms. ebv has been associated with other autoimmune diseases, such as systemic lupus erythematous, and cancers like burkitt's lymphoma. ebv establishes a life-long latency in b cells with occasional reactivation of the virus throughout the individual's life. the role playe ...201526579121
alveolar macrophages are a prominent but nonessential target for murine cytomegalovirus infecting the lungs.cytomegaloviruses (cmvs) infect the lungs and cause pathological damage there in immunocompromised hosts. how lung infection starts is unknown. inhaled murine cmv (mcmv) directly infected alveolar macrophages (ams) and type 2 alveolar epithelial cells (aec2s) but not type 1 alveolar epithelial cells (aec1s). in contrast, herpes simplex virus 1 infected aec1s and murid herpesvirus 4 (muhv-4) infected aec1s via ams. mcmv-infected ams prominently expressed viral reporter genes from a human cmv ie1 ...201526719275
murine cytomegalovirus exploits olfaction to enter new hosts.viruses transmit via the environmental and social interactions of their hosts. herpesviruses have colonized mammals since their earliest origins, suggesting that they exploit ancient, common pathways. cytomegaloviruses (cmvs) are assumed to enter new hosts orally, but no site has been identified. we show by live imaging that murine cmv (mcmv) infects nasally rather than orally, both after experimental virus uptake and during natural transmission. replication-deficient virions revealed the primar ...201627118588
interplay of murine gammaherpesvirus 68 with nf-kappab signaling of the host.herpesviruses establish a chronic infection in the host characterized by intervals of lytic replication, quiescent latency, and reactivation from latency. murine gammaherpesvirus 68 (mhv68) naturally infects small rodents and has genetic and biologic parallels with the human gammaherpesviruses (ghvs), kaposi's sarcoma-associated herpesvirus and epstein-barr virus. the murine gammaherpesvirus model pathogen system provides a platform to apply cutting-edge approaches to dissect the interplay of ga ...201627582728
the small noncoding rnas (sncrnas) of murine gammaherpesvirus 68 (mhv-68) are involved in regulating the latent-to-lytic switch in vivo.the human gammaherpesviruses epstein-barr virus (ebv) and kaposi's sarcoma-associated herpesvirus (kshv), which are associated with a variety of diseases including tumors, produce various small noncoding rnas (sncrnas) such as micrornas (mirnas). like all herpesviruses, they show two stages in their life cycle: lytic replication and latency. during latency, hardly any viral proteins are expressed to avoid recognition by the immune system. thus, sncrnas might be exploited since they are less like ...201627561205
ablation of stat3 in the b cell compartment restricts gammaherpesvirus latency in vivo.a challenging property of gammaherpesviruses is their ability to establish lifelong persistence. the establishment of latency in b cells is thought to involve active virus engagement of host signaling pathways. pathogenic effects of these viruses during latency or following reactivation can be devastating to the host. many cancers, including those associated with members of the gammaherpesvirus family, kaposi's sarcoma-associated herpesvirus and epstein-barr virus, express elevated levels of act ...201627486189
latency-associated nuclear antigen e3 ubiquitin ligase activity impacts gammaherpesvirus-driven germinal center b cell proliferation.viruses have evolved mechanisms to hijack components of cellular e3 ubiquitin ligases, thus modulating the ubiquitination pathway. however, the biological relevance of such mechanisms for viral pathogenesis in vivo remains largely unknown. here, we utilized murid herpesvirus 4 (muhv-4) infection of mice as a model system to address the role of muhv-4 latency-associated nuclear antigen (mlana) e3 ligase activity in gammaherpesvirus latent infection. we show that specific mutations in the mlana so ...201627307564
a gammaherpesvirus noncoding rna is essential for hematogenous dissemination and establishment of peripheral latency.recent intense investigations have uncovered important functions for a diverse array of novel noncoding rna (ncrna) species, including micrornas (mirnas) and long noncoding rnas. not surprisingly, viruses from multiple families have evolved to encode their own regulatory rnas; however, the specific in vivo functions of these ncrnas are largely unknown. the human gammaherpesviruses epstein-barr virus (ebv) and kaposi's sarcoma-associated herpesvirus (kshv) are highly ubiquitous pathogens that are ...201627110595
in vivo examination of mouse apobec3- and human apobec3a- and apobec3g-mediated restriction of parvovirus and herpesvirus infection in mouse models.apobec3 knockout and human apobec3a and -3g transgenic mice were tested for their ability to be infected by the herpesviruses herpes simplex virus 1 and murine herpesvirus 68 and the parvovirus minute virus of mice (mvm). knockout, apobec3a and apobec3g transgenic, and wild-type mice were equally infected by the herpesviruses, while apobec3a but not mouse apobec3 conferred resistance to mvm. no viruses showed evidence of cytidine deamination by mouse or human apobec3s. these data suggest that in ...201627356895
type i interferons direct gammaherpesvirus host colonization.gamma-herpesviruses colonise lymphocytes. murid herpesvirus-4 (muhv-4) infects b cells via epithelial to myeloid to lymphoid transfer. this indirect route entails exposure to host defences, and type i interferons (ifn-i) limit infection while viral evasion promotes it. to understand how ifn-i and its evasion both control infection outcomes, we used mx1-cre mice to tag floxed viral genomes in ifn-i responding cells. epithelial-derived muhv-4 showed low ifn-i exposure, and neither disrupting viral ...201627223694
enzymatically enhanced collisions on ultramicroelectrodes for specific and rapid detection of individual viruses.we report the specific collision of a single murine cytomegalovirus (mcmv) on a platinum ultramicroelectrode (ume, radius of 1 μm). antibody directed against the viral surface protein glycoprotein b functionalized with glucose oxidase (gox) allowed for specific detection of the virus in solution and a biological sample (urine). the oxidation of ferrocene methanol to ferrocenium methanol was carried out at the electrode surface, and the ferrocenium methanol acted as the cosubstrate to gox to cata ...201627217569
transforming activity of murine herpesvirus 68 putative growth factor is related to the ability to change cytoskeletal structure.murine herpesvirus 68 (mhv-68) can transform cells in vitro and in vivo. we investigated putative murine herpesvirus growth factors (mhgfs) obtained by the separation of cell-free media from mhv-68-transformed cells on an fplc sephadex g15 column. the transforming activity of the mhgfa fraction was related to depolymerization of actin, disruption of the microtubule network, and punctate-reticular changes of the golgi. the mhgfw fraction had only repressing activity on the transformed phenotype. ...201628052265
type i interferons and nk cells restrict gammaherpesvirus lymph node infection.gammaherpesviruses establish persistent, systemic infections and cause cancers. murid herpesvirus 4 (muhv-4) provides a unique window into the early events of host colonization. it spreads via lymph nodes. while dendritic cells (dc) pass muhv-4 to lymph node b cells, subcapsular sinus macrophages (ssm), which capture virions from the afferent lymph, restrict its spread. understanding how this restriction works offers potential clues to a more comprehensive defense. type i interferon (ifn-i) bloc ...201627466430
tegument protein orf45 plays an essential role in virion morphogenesis of murine gammaherpesvirus 68.tegument proteins play critical roles in herpesvirus morphogenesis. orf45 is a conserved tegument protein of gammaherpesviruses; however, its role in virion morphogenesis is largely unknown. in this work, we determined the ultrastructural localization of murine gammaherpesvirus 68 (mhv-68) orf45 and found that this protein was incorporated into virions around the site of host-derived vesicles. notably, the absence of orf45 inhibited nucleocapsid egress and blocked cytoplasmic virion maturation, ...201627226376
multiple lytic origins of replication are required for optimal gammaherpesvirus fitness in vitro and in vivo.an unresolved question in herpesvirus biology is why some herpesviruses contain more than one lytic origin of replication (orilyt). using murine gammaherpesvirus 68 (mhv-68) as model virus containing two orilyts, we demonstrate that loss of either of the two orilyts was well tolerated in some situations but not in others both in vitro and in vivo. this was related to the cell type, the organ or the route of inoculation. depending on the cell type, different cellular proteins, for example hexim1 ...201627007137
sequence variability among murine herpesvirus isolates shows possible effect of long-term in vitro passaging on their genome.no abstract keywords: murine herpesvirus 68; virus isolates; sequence analysis; restriction fragment length polymorphism.201626982476
molecular detection of murine gammaherpesvirus 68 (mhv-68) in haemaphysalis concinna ticks collected in slovakia.murine gammaherpesvirus 68 (mhv-68) is a natural pathogen of murid rodents, which serve as hosts to haemaphysalis concinna ticks. the occurrence of mhv-68 was investigated in a total of 47 h. concinna adult ticks collected on the vegetation in gabčíkovo, situated in south-western slovakia (47º54´0´´n, 17º35´0´´e), from may 2013 to may 2014. dna from ticks was purified and screened by nested pcr targeting orf50 of mhv-68 and the copy number of virus genome in ticks was determined by a real-time p ...201727928925
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