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autophagy genes enhance murine gammaherpesvirus 68 reactivation from latency by preventing virus-induced systemic inflammation.host genes that regulate systemic inflammation upon chronic viral infection are incompletely understood. murine gammaherpesvirus 68 (mhv68) infection is characterized by latency in macrophages, and reactivation is inhibited by interferon-γ (ifn-γ). using a lysozyme-m-cre (lysmcre) expression system, we show that deletion of autophagy-related (atg) genes fip200, beclin 1, atg14, atg16l1, atg7, atg3, and atg5, in the myeloid compartment, inhibited mhv68 reactivation in macrophages. atg5 deficiency ...026764599
cloning and molecular characterization of the murine herpesvirus 68 genome.murine herpesvirus 68 (mhv-68) is a naturally occurring herpesvirus of small free-living rodents. in order to facilitate the molecular characterization of the virus genome, a library of cloned restriction fragments has been produced and restriction enzyme cleavage maps deduced for the enzymes bamhi, ecori and hindiii. the mhv-68 genome comprises a region of unique dna of approximately 118 kbp which is flanked by variable numbers of a 1.23 kb repeat unit. the organization of the mhv-68 genome is, ...19902351958
murine herpesvirus 68 is genetically related to the gammaherpesviruses epstein-barr virus and herpesvirus saimiri.short nucleotide sequence analysis of seven restriction fragments of murine herpesvirus 68 (mhv-68) dna has been undertaken and used to determine the overall genome organization and relatedness of this virus to other well characterized representatives of the alpha-, beta- and gammaherpesvirus subgroups. nine genes have been identified which encode amino acid sequences with greater similarity to proteins of the gammaherpesvirus epstein-barr virus (ebv) than to the homologous products of the alpha ...19902161903
murine gammaherpesvirus 68 establishes a latent infection in mouse b lymphocytes in vivo.murine gammaherpesvirus 68 (mhv-68) is able to persist in spleen cells of infected mice. to determine the cell type harbouring persistent virus, spleen cells from infected animals were separated into immunoglobulin (ig)-positive (b cell-enriched), ig-negative (t cell-enriched) and plastic-adherent (macrophage-enriched) fractions. these cells were co-cultivated with permissive bhk-21 cells in an infectious centre assay. the consistent recovery and enrichment of infectious centres in the ig-positi ...19921469366
virological and pathological features of mice infected with murine gamma-herpesvirus 68.the primary infection of balb/c mice with murine herpesvirus 68 (mhv-68) was investigated. when the virus was introduced intranasally, the lung was the main tissue infected, the virus being associated with alveolar epithelium and mononuclear cells. a productive infection lasted for 10 days, after which viral dna could be detected by in situ hybridization up to 30 days after infection. at that time lymphoproliferative accumulations were also observed in the lung, with formation of germinal centre ...19921328491
pathogenesis of murine gammaherpesvirus infection in mice deficient in cd4 and cd8 t cells.murine gammaherpesvirus is a natural pathogen of wild mice. the virus infects alveolar cells and spleen cells during the primary infection and establishes a latent/persistent infection in b lymphocytes. little is known about the immunological response to gammaherpesviruses during a primary infection. to address this issue, we investigated the pathogenesis of murine herpesvirus 68 (mhv-68) infection in mice deficient in cd4 or cd8 t-cell populations. infection of the lung and spleen were greatly ...19938394447
interactions of murine gammaherpesvirus 68 with b and t cell lines.murine gammaherpesvirus is a natural pathogen of wild rodents. we have established that in vivo the virus persists in b lymphocytes in a latent form and therefore has similar biological properties to epstein-barr virus and related gamma-i-herpesviruses. in this report we have established a persistent infection in mouse myeloma (b) cells (nso cell line), but not in mouse thymoma (t) cells (bw 5147 cell line). the virus persists indefinitely in myeloma cells, without any apparent cytopathic effect ...19938460488
characterization of murine gammaherpesvirus 68 glycoprotein b (gb) homolog: similarity to epstein-barr virus gb (gp110).murine gammaherpesvirus 68 (mhv-68) is a natural pathogen of murid rodents and displays similar pathobiological characteristics to those of the human gammaherpesvirus epstein-barr virus (ebv). however, in contrast to ebv, mhv-68 will replicate in epithelial cells in vitro. it has therefore been proposed that mhv-68 may be of use as a model for the study of gammaherpesviruses, ebv in particular, both in vitro and in vivo. the ebv homolog of herpes simplex virus glycoprotein b (gb), termed gp110, ...19948083987
interactions of the murine gammaherpesvirus with the immune system.our understanding of the host response to gammaherpesviruses comes largely from studies on epstein-barr virus. a recent addition to this family is murine herpesvirus-68 which, like epstein-barr virus, establishes a latent infection in b lymphocytes and is associated with lymphoproliferative disease. this virus provides a unique opportunity to explore the relationship between gammaherpesviruses and the immune system.19947946042
lymphoproliferative disease in mice infected with murine gammaherpesvirus 68.murine gammaherpesvirus is a natural pathogen of wild rodents. in the laboratory it establishes an infection of epithelial cells and persists in b lymphocytes in a latent form. inbred mice chronically infected with the virus develop a lymphoproliferative disease (lpd) similar to that seen in patients infected with epstein-barr virus. the frequency of lpd over a period of 3 years was 9% of all infected animals, with 50% of these displaying high grade lymphomas. the incidence of lpd was greatly in ...19947943173
murine gammaherpesvirus-68 encodes homologues of thymidine kinase and glycoprotein h: sequence, expression, and characterization of pyrimidine kinase activity.we have sequenced a 4.5-kb fragment of dna spanning the junction of the bamhi d and e fragments of murine gammaherpesvirus-68 (mhv-68). this sequence was found to code for two major open reading frames (orfs) of 1934 and 2192 bp which showed significant homology to the thymidine kinase (tk) and glycoprotein h (gh) sequences of other gammaherpesviruses. upstream from the tk gene another orf was found which showed amino acid sequence homology to the hsv1 ul24 gene. analysis of the 1934-bp orf reve ...19968638414
progressive loss of cd8+ t cell-mediated control of a gamma-herpesvirus in the absence of cd4+ t cells.a unique experimental model has been developed for dissecting the integrity of cd8+ t cell-mediated immunity to a persistent gammaherpesvirus under conditions of cd4+ t cell deficiency. respiratory challenge of major histocompatibility complex class ii -/- and +/+ c57bl/6j mice with the murine gammaherpesvirus 68 (mhv-68) leads to productive infection of both lung and adrenal epithelial cells. virus titers peak within 5-10 d, and are no longer detected after day 15. persistent, latent infection ...19969064346
absence of splenic latency in murine gammaherpesvirus 68-infected b cell-deficient mice.murine gammaherpesvirus 68 (mhv-68) is a natural pathogen of mice which causes an acute lung infection and establishes a latent infection in b lymphocytes. in this paper we describe the infection in transgenic b cell-deficient (mumt) mice, to determine whether a latent infection can be established in a mouse lacking circulating b lymphocytes. little difference was observed in the acute lung infection, although there was a slight delay in virus clearance in the mumt mice. this indicates that anti ...19968922476
mature b cells are required for acute splenic infection, but not for establishment of latency, by murine gammaherpesvirus 68.murine gammaherpesvirus 68 (gamma hv-68; also referred to as mhv-68) is a gammaherpesvirus which infects murid rodents. previous studies showed that cd8 t cells are important for controlling gamma hv-68 replication during the first 2 weeks of infection and suggested a role for b cells in latent or persistent gamma hv-68 infection. to further define the importance of b cells and cd8 t cells during acute and chronic gamma hv-68 infection, we examined splenic infection in mice with null mutations i ...19968794315
characterization of tumor cell lines derived from murine gammaherpesvirus-68-infected mice.cell lines were derived from mice with murine gammaherpesvirus-68 (mhv-68)-associated lymphoproliferative disease. four were of an ambiguous phenotype and were mhv-68 negative. one, s11, was a b lymphocyte that contained mhv-68 genomes in both linear and episomal forms and released virus. the line was clonable and grew into tumors in nude mice. this is the first naturally occurring mhv-68-positive b-cell line to be generated, and it will be an invaluable tool for the study of mhv-68 latency.19968709292
identification and characterization of murine gammaherpesvirus 68 gp150: a virion membrane glycoprotein.murine gammaherpesvirus 68 (mhv-68) is a naturally occurring virus of murid rodents which displays pathobiological characteristics similar to those of other gammaherpesviruses, including epstein-barr virus (ebv). however, unlike ebv and many other gammaherpesviruses, mhv-68 replicates in epithelial cells in vitro and infects laboratory strains of mice and therefore provides a good model for the study of gammaherpesviruses. studies of sequences around the center of the mhv-68 genome identified a ...19968648686
cytokine production in the immune response to murine gammaherpesvirus 68.cytokine profiles were determined following intranasal infection of c57bl/6j mice with murine gammaherpesvirus 68 (mhv-68). spleen, mediastinal, and cervical lymph node cells from infected mice produced high levels of interleukin 6 (il-6) and gamma interferon (ifn-gamma) and lower levels of il-2 and il-10 following in vitro restimulation. little or no il-4 or il-5 was detected. cytokine production was generally maximal at 10 days after infection, correlating with viral clearance from the lung, a ...19968627809
complete sequence and genomic analysis of murine gammaherpesvirus 68.murine gammaherpesvirus 68 (gammahv68) infects mice, thus providing a tractable small-animal model for analysis of the acute and chronic pathogenesis of gammaherpesviruses. to facilitate molecular analysis of gammahv68 pathogenesis, we have sequenced the gammahv68 genome. the genome contains 118,237 bp of unique sequence flanked by multiple copies of a 1,213-bp terminal repeat. the gc content of the unique portion of the genome is 46%, while the gc content of the terminal repeat is 78%. the uniq ...19979223479
genetic content and preliminary transcriptional analysis of a representative region of murine gammaherpesvirus 68.murine gammaherpesvirus 68 (mhv-68) is a relatively recently discovered pathogen of wild rodents and provides a unique opportunity to explore in detail the interactions of a gammaherpesvirus with its natural host. it may also provide a much needed small animal model for human gammaherpesviruses. as a step in the detailed analysis of virus gene structure and expression we have sequenced over 20 kb of the mhv-68 genome and mapped gene transcripts by northern blot hybridization. the region we chose ...19979191940
identification of ovine herpesvirus-2 infection in sheep.a polymerase chain reaction test for the detection of ovine herpesvirus-2 (ohv-2) dna was used to identify sites of ohv-2 infection in peri-natal lambs and in adult sheep. ohv-2 was detected in the nasal secretions from all lambs within a period of two months following birth. subsequently, ohv-2 dna was identified in a number of epithelial tissues including the cornea, turbinates and pharynx. in addition, ohv-2 dna was detected exclusively in b-lymphocytes from six of ten adult sheep tested. an ...19979170507
pathological changes in the spleens of gamma interferon receptor-deficient mice infected with murine gammaherpesvirus: a role for cd8 t cells.murine gammaherpesvirus is a natural rodent pathogen which causes a primary infection in the lungs and establishes a persistent infection in b lymphocytes. during the primary infection, large amounts of gamma interferon (ifn-gamma) are produced by spleen, mediastinal, and cervical lymph node cells. to investigate the role of ifn-gamma in control of the virus infection, mice lacking the cellular receptor for ifn-gamma (ifn-gamma r-/- mice) were infected with murine gammaherpesvirus 68 (mhv68). if ...19979151815
gamma interferon is not essential for recovery from acute infection with murine gammaherpesvirus 68.murine gammaherpesvirus 68 (mhv-68) when administered intranasally induces high levels of gamma interferon (ifn-gamma) in the lymphoid tissues of infected mice. in order to investigate the role of this cytokine in the immune response to mhv-68, mice which were congenitally deficient in the ifn-gamma gene (ifn-gamma knockout mice) were infected with the virus. comparison of the courses of the disease in wild-type control and ifn-gamma knockout mice revealed surprisingly little difference. both gr ...19979094668
glycoprotein b of bovine herpesvirus 4 is a major component of the virion, unlike that of two other gammaherpesviruses, epstein-barr virus and murine gammaherpesvirus 68.this study reports that in bovine herpesvirus 4, glycoprotein b (gb) is a heterodimer and a major component of the virion, unlike gbs of epstein-barr virus (gp110) and murine gammaherpesvirus 68, two other gammaherpesviruses. these are new characteristics with regard to the general features of gb in the gammaherpesvirinae subfamily.19979060705
murine gammaherpesvirus 68 encodes trna-like sequences which are expressed during latency.murine gammaherpesvirus 68 (mhv-68) is a virus of wild rodents and is a convenient small animal model for studies of gammaherpesvirus pathogenesis. we have sequenced 6162 bp at the left end of the mhv-68 genome and identified two unique open reading frames (orfs) (orf2 and orf3) and an orf (orf1) which displays similarity to poxvirus members of the serpin family. interspersed with the orfs is a family of eight novel trna-like sequences sharing trna-like predicted secondary structures and rna pol ...19979225045
four trna-like sequences and a serpin homologue encoded by murine gammaherpesvirus 68 are dispensable for lytic replication in vitro and latency in vivo.experimental infection of inbred strains of laboratory mice with murine herpesvirus 68 (mhv-68), a natural pathogen of wild rodents, results in acute productive infection of the lung followed by a latent infection of b lymphocytes. we have previously shown that mhv-68 encodes an open reading frame with similarity to poxvirus serpins, designated orf1, and eight novel trna-like sequences. the latter are processed into mature, uncharged trnas and are abundantly expressed during both lytic and laten ...19989460936
kinetic analysis of the specific host response to a murine gammaherpesvirus.respiratory infection of balb/c mice with the murine gammaherpesvirus 68 (mhv-68) induces the clonal expansion of virus-specific cytotoxic t-lymphocyte (ctl) precursors (ctlp) in the regional, mediastinal lymph nodes (mln). some of these ctlps differentiate to become fully functional ctl effectors, which can be detected in both the lymphoid tissue and in the site of pathology in the lung. though the lymph nodes and spleen harbor substantial populations of latently infected b cells for life, the ...19989444986
pathogenesis of murine gammaherpesvirus-68 infection in interleukin-6-deficient mice.murine gammaherpesvirus-68 (mhv-68) induces high levels of interleukin (il)-6 production in both naive and primed lymphocyte populations. mice that are homozygous (-/-) for deletion of the il-6 gene were used to investigate the role of this cytokine in mhv-68 infection. the results showed that il-6 is not essential for clearance of infectious mhv-68 from the lung or for the establishment, or control, of viral latency. both il-6 +/+ and -/- mice eliminated replicating virus from the respiratory t ...19989791027
murine gammaherpesvirus 68: a model for the study of gammaherpesvirus pathogenesis.murine gammaherpesvirus 68 (mhv-68) is a naturally occurring herpesvirus of wild rodents and is genetically related to human herpesvirus 8 and epstein-barr virus. the ability of mhv-68 to establish acute and persistent infection within laboratory mice offers a unique opportunity to investigate immunological and virological aspects of gammaherpesvirus pathogenesis.19989717216
lung epithelial cells are a major site of murine gammaherpesvirus persistence.it is currently believed that latently infected, resting b lymphocytes are central to gammaherpesvirus persistence, whereas mucosal epithelial cells are considered nonessential. we have readdressed the question of nonlymphoid persistence using murine gammaherpesvirus 68 (mhv-68). to dissect lymphoid from nonlymphoid persistence, we used micromt transgenic mice that are defective in b cells. mhv-68 dna persisted in the lungs of intact and b cell-deficient mice. both episomal and linear forms of t ...19989625754
lymphoproliferative disease induced by murine herpesvirus-68. 199810090040
quantitative analysis of the acute and long-term cd4(+) t-cell response to a persistent gammaherpesvirus.the murine gammaherpesvirus 68 (mhv-68) replicates in respiratory epithelial cells, where it establishes a persistent, latent infection limited predominantly to b lymphocytes. the virus-specific cd4(+) t-cell response in c57bl/6 mice challenged intranasally with mhv-68 is detected first in the mediastinal lymph nodes and then in the cervical lymph nodes and the spleen. the numbers of mhv-68-specific cd4(+) t cells generated in congenic mice homozygous for disruption of the beta2-microglobulin ge ...199910196325
b cells regulate murine gammaherpesvirus 68 latency.the dynamics of the establishment of, and reactivation from, gammaherpesviruses latency has not been quantitatively analyzed in the natural host. gammaherpesvirus 68 (gammahv68) is a murine gammaherpesvirus genetically related to primate gammaherpesviruses that establishes a latent infection in infected mice. we used limiting dilution reactivation (frequency of cells reactivating gammahv68 in vitro) and limiting dilution pcr (frequency of cells carrying gammahv68 genome) assays to compare gammah ...199910233924
the murine gammaherpesvirus 68 v-cyclin gene is an oncogene that promotes cell cycle progression in primary lymphocytes.several gammaherpesviruses contain open reading frames encoding proteins homologous to mammalian d-type cyclins. in this study, we analyzed the expression and function of the murine gammaherpesvirus 68 (gammahv68) viral cyclin (v-cyclin). the gammahv68 v-cyclin gene was expressed in lytically infected fibroblasts as a leaky-late mrna of approximately 0.9 kb encoding a protein of approximately 25 kda. to evaluate the effect of the gammahv68 v-cyclin on cell cycle progression in primary lymphocyte ...199910233974
lytic cycle t cell epitopes are expressed in two distinct phases during mhv-68 infection.murine herpesvirus-68 (mhv-68) is a type 2 gamma herpesvirus that productively infects alveolar epithelial cells during the acute infection and establishes long-term latency in b cells and lung epithelial cells. in c57bl/6 mice, t cells specific for lytic cycle mhv-68 epitope p56/db dominate the acute phase of the infection, whereas t cells specific for another lytic cycle epitope, p79/kb, dominate later phases of infection. to further understand this response, we analyzed the kinetics of ag pre ...199910395681
murine gammaherpesvirus 68 encodes a functional regulator of complement activation.sequence analysis of the murine gammaherpesvirus 68 (gammahv68) genome revealed an open reading frame (gene 4) which is homologous to a family of proteins known as the regulators of complement activation (rca proteins) (h. w. virgin, p. latreille, p. wamsley, k. hallsworth, k. e. weck, a. j. dal canto, and s. h. speck, j. virol. 71:5894-5904, 1997). the predicted gene 4 product has homology to other virally encoded rca homologs, as well as to the complement-regulatory proteins decay-accelerating ...199910438856
turnover of t cells in murine gammaherpesvirus 68-infected mice.respiratory challenge of c57bl/6 mice with murine gammaherpesvirus 68 induces proliferation of t lymphocytes early after infection, as evidenced by incorporation of the dna precursor bromodeoxyuridine. using pulse-chase analysis, splenic and peripheral blood activated t lymphocytes were found to continue dividing for at least a month after the initial virus challenge. the results are in accord with the idea that t cells are stimulated for a substantial time after the acute, lytic phase of virus ...199910438881
immunological control of a murine gammaherpesvirus independent of cd8+ t cells.adult thymectomized c57 bl/6j mice were depleted of t cell subsets by mab treatment either prior to, or after, respiratory challenge with murine gammaherpesvirus-68. protection against acute infection was maintained when either the cd4+ or the cd8+ t cell population was greatly diminished, whereas the concurrent removal of both t cell subsets proved invariably fatal. the same depletions had little effect on mice with established infection. the results indicate firstly that both cd4+ and cd8+ t c ...199910073710
identification and initial characterization of the murine gammaherpesvirus 68 gene m3, encoding an abundantly secreted protein.several viruses, including members of the gammaherpesvirus family, encode proteins that are secreted into the extracellular environment. we have identified an abundant 44-kda secreted protein that is present in the supernatant of fibroblasts infected with murine gammaherpesvirus 68 (gammahv68; also referred to as mhv-68) but not in that of uninfected fibroblasts. sequence analysis of the amino terminus and of internal peptides revealed that this protein is encoded by the gammahv68 m3 open readin ...199910196360
murine gammaherpesvirus m2 gene is latency-associated and its protein a target for cd8(+) t lymphocytes.murine gammaherpesvirus 68 (mhv-68) infection of mice is a potential model with which to address fundamental aspects of the pathobiology and host control of gammaherpesvirus latency. control of mhv-68 infection, like that of epstein-barr virus, is strongly dependent on the cellular immune system. however, the molecular biology of mhv-68 latency is largely undefined. a screen of the mhv-68 genome for potential latency-associated mrnas revealed that the region encompassing and flanking the genomic ...199910377445
type i interferons and irf-1 play a critical role in the control of a gammaherpesvirus infection.the murine gammaherpesvirus 68 (mhv-68) is an ideal model system for the study of interactions between gammaherpesviruses and their hosts. intranasal infection of mice with mhv-68 results in replication of the virus in the lung epithelium followed by latent infection of b cells. resolution of productive mhv-68 infection depends on the adaptive immune system, but little is known about the role of innate immune mechanisms and the early interaction between the host and the virus. in this report, we ...199910497103
requirement for cd40 ligand, cd4(+) t cells, and b cells in an infectious mononucleosis-like syndrome.respiratory challenge with the murine gammaherpesvirus 68 (gammahv-68) results in productive infection of the lung, the establishment of latency in b lymphocytes and other cell types, transient splenomegaly, and prolonged clonal expansion of activated cd8(+) cd62l(lo) t cells, particularly a vbeta4(+) cd8(+) population that is found in mice with different major histocompatibility complex (mhc) haplotypes. aspects of the cd8(+)-t-cell response are substantially modified in mice that lack b cells, ...199910516078
t-cell vaccination alters the course of murine herpesvirus 68 infection and the establishment of viral latency in mice.diseases caused by gammaherpesviruses such as epstein-barr virus are a major health concern, and there is significant interest in developing vaccines against this class of viral infections. however, the requirements for effective control of gammaherpesvirus infection are only poorly understood. the recent development of the murine herpesvirus mhv-68 model provides an experimental tool to dissect the immune response to gammaherpesvirus infections. in this study, we investigated the impact of prim ...199910559297
kinetic and phenotypic changes in murine lymphocytes infected with murine gammaherpesvirus-68 in vitro.primary infection with murine gammaherpesvirus-68 (mhv-68), as with other members of the gammaherpesvirus subfamily, is characterized by a lymphoproliferative phase. mhv-68 causes acute splenomegaly and an infectious mononucleosis-like syndrome in which there is expansion of the cd8+ t cell subset. in long-term infections, mhv-68 is associated with lymphoma development. in order to elucidate the mechanisms underlying the proliferative processes, the events following infection of murine splenocyt ...199910573167
the murine gammaherpesvirus-68 m11 protein inhibits fas- and tnf-induced apoptosis.the murine gammaherpesvirus-68 (mhv-68) m11 gene encodes a protein predicted to have limited homology to the bcl-2 family of proteins. unlike most of the other viral bcl-2 homologues, which have both bh1 and bh2 domains conserved with respect to bcl-2, the m11 protein has a bh1 domain, but apparently lacks a bh2 domain. transfection of hela cells with an epitope-tagged mhv-68 m11 construct showed that the protein is predominantly located in the cytoplasm of cells. in hela cells, m11 inhibited ap ...199910573168
in vivo models for epstein-barr virus (ebv)-associated b cell lymphoproliferative disease (blpd).ebv infects b lymphocytes in vivo and establishes a life-long persistent infection in the host. the latent infection is controlled by ebv-specific mhc class 1-restricted ctl. immunosuppression reduces ctl activity, and this facilitates outgrowth of ebv+ve b cell lymphoproliferative disease (blpd). blpd are aggressive lesions with high mortality. this review presents some key facets in the development of ebv-associated blpd and in vivo studies on its pathogenesis. the animal models used to date i ...199910578121
analysis of murine gammaherpesvirus-68 transcription during lytic and latent infection.murine gammaherpesvirus-68 (mhv-68) is a gamma2-herpesvirus that upon experimental infection of laboratory mice establishes a latent infection in b lymphocytes. to date, no virus-encoded gene products have been reported to be expressed during latent infection. in this study, viral transcription has been analysed in a persistently infected b-cell line and abundant and preferential transcription of open reading frame m3 has been identified. significantly, in situ hybridization analysis of latently ...19999934687
three distinct regions of the murine gammaherpesvirus 68 genome are transcriptionally active in latently infected mice.the program(s) of gene expression operating during murine gammaherpesvirus 68 (gammahv68) latency is undefined, as is the relationship between gammahv68 latency and latency of primate gammaherpesviruses. we used a nested reverse transcriptase pcr strategy (sensitive to approximately one copy of gammahv68 genome for each genomic region tested) to screen for the presence of viral transcripts in latently infected mice. based on the positions of known latency-associated genes in other gammaherpesvir ...19999971815
macrophages are the major reservoir of latent murine gammaherpesvirus 68 in peritoneal cells.b cells have previously been identified as the major hematopoietic cell type harboring latent gammaherpesvirus 68 (gammahv68) (n. p. sunil-chandra, s. efstathiou, and a. a. nash, j. gen. virol. 73:3275-3279, 1992). however, we have shown that gammahv68 efficiently establishes latency in b-cell-deficient mice (k. e. weck, m. l. barkon, l. i. yoo, s. h. speck, and h. w. virgin, j. virol. 70:6775-6780, 1996), demonstrating that b cells are not required for gammahv68 latency. to understand this dich ...199910074181
requirement for cd4+ t cells in v beta 4+cd8+ t cell activation associated with latent murine gammaherpesvirus infection.a cd8+ t cell lymphocytosis in the peripheral blood is associated with the establishment of latency following intranasal infection with murine gammaherpesvirus-68. remarkably, a large percentage of the activated cd8+ t cells of mice expressing different mhc haplotypes express v beta 4+ tcr. identification of the ligand driving the v beta 4+cd8+ t cell activation remains elusive, but there is a general correlation between v beta 4+cd8+ t cell stimulatory activity and establishment of latency in t ...199910477611
disruption of the murine gammaherpesvirus 68 m1 open reading frame leads to enhanced reactivation from latency.murine gammaherpesvirus 68 (gammahv68, or mhv-68) is a genetically tractable, small animal model for the analysis of gammaherpesvirus pathogenesis. the gammahv68 genome is colinear with the genomes of other sequence gammaherpesviruses, containing large blocks of conserved genes interspersed by a number of putative genes without clear homologs in the other gammaherpesviruses. one of these putative unique genes, the m1 open reading frame (orf), exhibits sequence homology to a poxvirus serine prote ...200010644370
infection of intestinal epithelial cells and development of systemic disease following gastric instillation of murine gammaherpesvirus-68.murine gammaherpesvirus-68 (gammahv-68) induces a lymphocytosis in mice and establishes a latent infection of b lymphocytes following intranasal administration in anaesthetized animals. because gammahv-68 is a gammaherpesvirus, it has been used as a model to understand the pathogenesis of epstein-barr virus (ebv) and human herpesvirus-8 (hhv-8) infections. in this study, we investigated the unlikely possibility that gammahv-68 could survive the harsh gastrointestinal environment to efficiently i ...200010644841
analysis of the virus-specific and nonspecific b cell response to a persistent b-lymphotropic gammaherpesvirus.respiratory challenge of mice with murine gammaherpesvirus 68 (gammahv68) results in acute replication in respiratory epithelial cells and persistent, latent infection of b cells and macrophages. gammahv68 elicits virus-specific ab, and also nonspecifically activates b cells to ab production through a cd4+ t cell-dependent process. the current analysis characterizes virus-specific and nonspecific ab production at the single cell level and investigates the requirements and nature of the nonspecif ...200010657630
a broad spectrum secreted chemokine binding protein encoded by a herpesvirus.chemokines are a family of small proteins that interact with seven-transmembrane domain receptors and modulate the migration of immune cells into sites of inflammation and infection. the murine gammaherpesvirus 68 m3 gene encodes a secreted 44-kd protein with no sequence similarity to known chemokine receptors. we show that m3 binds a broad range of chemokines, including cc, cxc, c, and cx(3)c chemokines, but does not bind human b cell-specific nor mouse neutrophil-specific cxc chemokines. this ...200010662803
lymphotoxin-alpha-deficient mice can clear a productive infection with murine gammaherpesvirus 68 but fail to develop splenomegaly or lymphocytosis.respiratory challenge with murine gammaherpesvirus 68 (mhv-68) leads to an acute productive infection of the lung and a persistent latent infection in b lymphocytes, epithelia, and macrophages. the virus also induces splenomegaly and an increase in the number of activated cd8 t cells in the circulation. lymphotoxin- alpha-deficient (ltalpha(-/-)) mice have no lymph nodes and have disrupted splenic architecture. surprisingly, in spite of the severe defect in secondary lymphoid tissue, ltalpha(-/- ...200010684295
rta of murine gammaherpesvirus 68 reactivates the complete lytic cycle from latency.herpesviruses are characterized as having two distinct life cycle phases: lytic replication and latency. the mechanisms of latency establishment and maintenance, as well as the switch from latency to lytic replication, are poorly understood. human gammaherpesviruses, including epstein-barr virus (ebv) and human herpesvirus-8 (hhv-8), also known as kaposi's sarcoma-associated herpesvirus (kshv), are associated with lymphoproliferative diseases and several human tumors. unfortunately, the lack of ...200010729142
absence of herpesvirus dna sequences in the 5t murine model of human multiple myeloma.kaposi's sarcoma-associated herpesvirus (kshv, also known as hhv-8) has been found in patients with multiple myeloma (mm) and postulated to be aetiologically associated with the development of this common plasma cell malignancy. a murine model of mm was previously established in which intravenous transfer of 5t myeloma cells into c57bl/kalwrij mice resulted in characteristic features of human mm. in the present study, we sought to identify herpesvirus dna sequences in this murine model of mm thr ...200010848833
cloning and mutagenesis of the murine gammaherpesvirus 68 genome as an infectious bacterial artificial chromosome.gammaherpesviruses cause important infections of humans, in particular in immunocompromised patients. recently, murine gammaherpesvirus 68 (mhv-68) infection of mice has been developed as a small animal model of gammaherpesvirus pathogenesis. efficient generation of mutants of mhv-68 would significantly contribute to the understanding of viral gene functions in virus-host interaction, thereby further enhancing the potential of this model. to this end, we cloned the mhv-68 genome as a bacterial a ...200010888635
murine gammaherpesvirus 68 cyclin d homologue is required for efficient reactivation from latency.murine gammaherpesvirus 68 (mhv68) is a gammaherpesvirus that was first isolated from murid rodents. mhv68 establishes a latent infection in the spleen and other lymphoid organs. several gammaherpesviruses, including herpesvirus saimiri, human herpesvirus 8, and mhv68, encode proteins with extensive homology to the d-type cyclins. to study the function of the cyclin homologue, a recombinant mhv68 has been constructed that lacks the cyclin homologue and expresses beta-galactosidase as a marker (m ...200010888640
analysis of gene expression in a human cell line stably transduced with herpesvirus saimiri.herpesvirus saimiri (hvs) is the prototype gamma-2 herpesvirus; it has significant homology to the human gammaherpesviruses kaposi's sarcoma-associated virus and epstein-barr virus and the murine gammaherpesvirus murine herpesvirus 68. hvs causes a persistent asymptomatic infection in its natural host, the squirrel monkey. both subgroups a and c possess the ability to immortalize common marmoset t lymphocytes to interleukin-2-independent proliferation. however, only subgroup c is capable of tran ...200010906186
the murine gammaherpesvirus 68 v-cyclin is a critical regulator of reactivation from latency.gamma-2 herpesviruses encode a homolog of mammalian d-type cyclins. the v-cyclin encoded by murine gammaherpesvirus 68 (gammahv68) induces cell cycle progression and is an oncogene (l. f. van dyk, j. l. hess, j. d. katz, m. jacoby, s. h. speck, and h. w. virgin iv, j. virol. 73:5110-5122, 1999). however, the role of the pro-proliferative v-cyclins in gamma-2 herpesvirus pathogenesis is not known. here we report the generation and characterization of a gammahv68 v-cyclin mutant (v-cyclin.lacz) th ...200010906198
generation of monoclonal antibodies directed against the immunogenic glycoprotein k8.1 of human herpesvirus 8.human herpesvirus 8 (hhv-8) is clearly associated with kaposi's sarcoma (ks), body cavity-based lymphomas (bcbl), and certain forms of multifocal castleman's disease (mcd). it appears to be the sexually transmissible agent involved in the development of aids-associated ks. hhv-8 genomes are invariably present in bcbl-derived cell lines where lytic replication of the virus can be induced by phorbol esters (pe). first-generation hhv-8 serological assays were based on these cell lines. more recentl ...200011001401
murine gammaherpesvirus-68 infection of and persistence in the central nervous system.murine gammaherpesvirus-68 (mhv-68) was originally isolated from a bank vole by passage through mouse brain. given its ability to replicate in mouse brain and its subsequent reisolation from trigeminal ganglia, it was originally considered to be an alphaherpesvirus. molecular studies have now firmly established mhv-68 to be a gammaherpesvirus. other gammaherpesviruses have been suggested to cause and in some cases shown to cause neurological disease. given the isolation history of mhv-68, we hav ...200011038374
a murine gammaherpesvirus.in 1976, within a project on isolation of herpesviruses from small rodents in former czechoslovakia, the mouse herpesvirus strain 68 (mhv-68) was isolated (blaskovic et al., 1980). this virus was accepted by the international committee on taxonomy of viruses (ictv) as a new, so far unassigned species (member) of the gammaherpesvirinae subfamily of the herpesviridae family (murphy et al., 1995). besides mhv-68, four more isolates (mhv-60, mhv-72, mhv-76, and mhv-78) similar to mhv-68 were obtaine ...200011155368
characterization of gammaherpesvirus 68 gene 50 transcription.gene 50 is the only immediate-early gene that appears to be conserved among the characterized gammaherpesviruses. it has recently been demonstrated for the human viruses epstein-barr virus (ebv) and kaposi's sarcoma-associated herpesvirus (kshv) that ectopic expression of the gene 50-encoded product in some latently infected cell lines can lead to the induction of virus replication, indicating that gene 50 is likely to play a pivotal role in regulating gammaherpesvirus reactivation. here we demo ...200010644377
antiapoptotic herpesvirus bcl-2 homologs escape caspase-mediated conversion to proapoptotic proteins.the antiapoptotic bcl-2 and bcl-x(l) proteins of mammals are converted into potent proapoptotic factors when they are cleaved by caspases, a family of apoptosis-inducing proteases (e. h.-y. cheng, d. g. kirsch, r. j. clem, r. ravi, m. b. kastan, a. bedi, k. ueno, and j. m. hardwick, science 278:1966-1968, 1997; r. j. clem, e. h.-y. cheng, c. l. karp, d. g. kirsch, k. ueno, a. takahashi, m. b. kastan, d. e. griffin, w. c. earnshaw, m. a. veliuona, and j. m. hardwick, proc. natl. acad. sci. usa 95 ...200010799576
historical background.the persisting ancient view of cancer as a contagious disease ended with 19th century scientific investigations which seemed to show it was not. the resulting dogma against an infectious cause for cancer produced great prejudice in the scientific community against the first report of an oncogenic virus by rous early in the 20th century and, even in the 1950s, against gross's finding of a murine leukaemia virus and a murine virus causing solid tumours. the lucké frog renal carcinoma virus was the ...200111313002
regression of a murine gammaherpesvirus 68-positive b-cell lymphoma mediated by cd4 t lymphocytes.murine gammaherpesvirus 68-infected s11 cells were injected subcutaneously into nude mice. adoptively transferred restimulated lymphocytes consistently elicited the regression of s11 tumors. cd4 t lymphocytes were most effective in preventing tumor formation, and immunohistochemistry highlighted populations of cd4 t cells in regressing tumors.200111238875
virus-specific and bystander cd8+ t-cell proliferation in the acute and persistent phases of a gammaherpesvirus infection.the cycling characteristics of cd8+ t cells specific for two lytic-phase epitopes of murine gammaherpesvirus 68 (gammahv68) have been analyzed for mice with high or low levels of virus persistence. the extent of cell division is generally reflective of the antigen load and suggests that gammahv68 may be regularly reactivating from latency for some months after the resolution of the acute phase of the infectious process. although gammahv68 infection is also associated with massive proliferation o ...200111287596
characterization of the murine gammaherpesvirus 68 orf74 product: a novel oncogenic g protein-coupled receptor.murine gammaherpesvirus (mhv-68) is well established as a small animal model for the study of gammaherpesviruses. the mhv-68 genome contains an open reading frame (orf74) that has significant sequence homology with mammalian g-protein coupled receptors (gpcrs) and the gpcr from the related kaposi's sarcoma-associated herpesvirus (kshv). here we show that the mhv-68 orf74 is predicted to encode a gpcr since it has seven potential transmembrane helices and that it has other sequence motifs in comm ...200111297694
kinetics of murine gammaherpesvirus 68 gene expression following infection of murine cells in culture and in mice.a model system to study the pathogenesis of gammaherpesvirus infections is the infection of mice with murine gammaherpesvirus 68 (mhv-68). to define the kinetics of infection, we developed an rnase protection assay to quantitate gene expression from lytic (k3, rta, m8, dna polymerase [dna pol], and gb) and candidate latency (m2, m3, m9, m11, orf73, and orf74) genes. all candidate latency genes were expressed during lytic infection of 3t3 cells. four kinetic classes of transcripts were observed f ...200111333874
virus reconstituted from infectious bacterial artificial chromosome (bac)-cloned murine gammaherpesvirus 68 acquires wild-type properties in vivo only after excision of bac vector sequences.we studied the in vivo biological properties of viruses reconstituted from the genome of murine gammaherpesvirus 68 (mhv-68) cloned as an infectious bacterial artificial chromosome (bac). recombinant virus rgammahv68a98.01, containing bac vector sequences, is attenuated in vivo as determined by (i) viral titers in the lungs during the acute phase of infection, (ii) the extent of splenomegaly, and (iii) the number of latently infected spleen cells reactivating virus in an ex vivo reactivation ass ...200111356978
human herpesvirus 8 envelope-associated glycoprotein b interacts with heparan sulfate-like moieties.cell-surface heparan sulfate (hs) serves as an initial attachment receptor for several herpesviruses. the gamma2-human herpesvirus-8 (hhv-8) or kaposi's sarcoma associated herpesvirus dna and transcripts have been detected in b cells, endothelial cells, macrophages, and epithelial cells. hhv-8 infects a variety of human and animal cell lines leading to latent or abortive infection. our studies showed that this broad cellular tropism may be in part due to hhv-8's interaction with the ubiquitous h ...200111384223
murine gammaherpesvirus-68 infection causes multi-organ fibrosis and alters leukocyte trafficking in interferon-gamma receptor knockout mice.murine gammaherpesvirus-68 (mhv-68) infection in interferon-gamma receptor knockout mice (ifn-gammar(-)/(-)) results in splenic fibrosis and excessive loss of splenocytes. in our present study we found that mhv-68 infection in ifn-gammar(-)/(-) mice also resulted in fibrosis and atrophy of the mediastinal lymph nodes, interstitial pulmonary fibrosis and fibrotic changes in the liver. atrophy and cellular depletion of the spleen in ifn-gammar(-)/(-) was not the result of increased cell death. the ...200111395389
perforin and fas in murine gammaherpesvirus-specific cd8(+) t cell control and morbidity.the immune system uses both virus-specific t cells and b cells to control the acute and latent phases of respiratory infection with the murine gammaherpesvirus 68 (gammahv-68). we sought to further define the important effector mechanisms for cd8(+) t cells. first, depletion of the cd4(+) t cells resulted in a failure of most animals to drive the virus into latency, although lytic virus in the lung was reduced by approximately 1000-fold from its peak. second, the absence of either perforin or fa ...200111458005
analysis of virus-specific cd4(+) t cells during long-term gammaherpesvirus infection.major histocompatibility complex class ii-mediated antigen presentation after intranasal infection with murine gammaherpesvirus 68 differs in mediastinal lymph nodes and spleen. evidence that virus-specific cd4(+) t cells were being stimulated was found as late as 6 to 8 months after infection, and cells specific for the viral gp150(67-83) and orf11(168-180) peptides were maintained as a fairly stable proportion of the total response.200111462049
a secreted chemokine binding protein encoded by murine gammaherpesvirus-68 is necessary for the establishment of a normal latent load.herpesviruses encode a variety of proteins with the potential to disrupt chemokine signaling, and hence immune organization. however, little is known of how these might function in vivo. the b cell-tropic murine gammaherpesvirus-68 (mhv-68) is related to the kaposi's sarcoma-associated herpesvirus (kshv), but whereas kshv expresses small chemokine homologues, mhv-68 encodes a broad spectrum chemokine binding protein (m3). here we have analyzed the effect on viral pathogenesis of a targeted disru ...200111489949
function of rta is essential for lytic replication of murine gammaherpesvirus 68.rta, encoded primarily by open reading frame 50, is well conserved among gammaherpesviruses. it has been shown that the rta proteins of epstein barr virus (ebv), kaposi's sarcoma-associated herpesvirus (kshv, or hhv-8), and murine gammaherpesvirus 68 (mhv-68; also referred to as gamma hv68) play an important role in viral reactivation from latency. however, the role of rta during productive de novo infection has not been characterized in gammaherpesviruses. since there are cell lines that can su ...200111533188
vaccination against murine gamma-herpesvirus infection.the gamma-herpesviruses establish life-long latency in the host and are important human pathogens. t cells play a major role in controlling the initial acute infection and subsequently maintaining the virus in a quiescent state. however, the nature of the t-cell response to gamma-herpesvirus infection and the requirements for effective vaccination are poorly understood. the recent development of a murine gamma-herpesvirus (murine herpesvirus-68 [mhv-68]) has made it possible to analyze t-cell re ...200111572633
murine gammaherpesvirus-68-induced interleukin-10 increases viral burden, but limits virus-induced splenomegaly and leukocytosis.based on its genomic sequence and its pathogenesis, murine gammaherpesvirus-68 (gammahv-68) has been established as a tractable model for the study of viral infections caused by the human gammaherpesviruses, epstein-barr virus or human herpesvirus-8. despite significant advances, the mechanisms responsible for gammahv-68-induced alterations in the protective host response, and the accompanying virus-induced leukocytosis, are not clear. in the present study, we questioned whether viral infection ...200111576228
analysis of a novel strain of murine gammaherpesvirus reveals a genomic locus important for acute pathogenesis.infection of mice by murine gammaherpesvirus 68 (mhv-68) is an excellent small-animal model of gammaherpesvirus pathogenesis in a natural host. we have carried out comparative studies of another herpesvirus, murine herpesvirus 76 (mhv-76), which was isolated at the same time as mhv-68 but from a different murid host, the yellow-necked mouse (apodemus flavicollis). molecular analyses revealed that the mhv-76 genome is essentially identical to that of mhv-68, except for deletion of 9,538 bp at the ...200111333912
antigen expression during murine gamma-herpesvirus infection.gammaherpesviruses (gammahv) establish a life-long latency in the host and are associated with a number of malignant human diseases. it is generally believed that t cells play a major role in controlling the initial acute infection and subsequently maintaining the virus in a quiescent state. however, the nature of the t cell response to gamma-herpesvirus infections is poorly understood. in the current report we took advantage of a mouse model of gammahv infection (murine herpesvirus-68, mhv-68) ...200111846230
chemokine induction and leukocyte trafficking to the lungs during murine gammaherpesvirus 68 (mhv-68) infection.murine gammaherpesvirus 68 replicates in the alveolar epithelium and induces an inflammatory infiltrate in the lung, following intranasal challenge, and is cleared 10 and 13 days after infection by a t-cell-dependent mechanism. in order to understand the development of the immune response to this virus and how leukocyte trafficking to the lung is regulated, chemokine expression during mhv-68 infection was examined in lung tissue using an rnase protection assay. expression of rantes, eotaxin, mip ...200211853399
cd28(-/-) mice show defects in cellular and humoral immunity but are able to control infection with murine gammaherpesvirus 68.the role of cd28-dependent costimulatory interactions in the development and maintenance of antiviral immune responses was investigated in a mouse model of gammaherpesvirus infection. cd28(-/-) mice could clear a productive infection with murine gammaherpesvirus 68 (mhv-68), although early lung viral titers were significantly increased. both cd28(-/-) and cd28(+/+) mice maintained effective long-term control of mhv-68. gamma interferon responses appeared to develop more slowly in cd28(-/-) mice, ...200211861872
gammaherpesvirus lytic gene expression as characterized by dna array.gammaherpesviruses are associated with a number of diseases including lymphomas and other malignancies. murine gammaherpesvirus 68 (mhv-68) constitutes the most amenable animal model for this family of pathogens. however experimental characterization of gammaherpesvirus gene expression, at either the protein or rna level, lags behind that of other, better-studied alpha- and beta-herpesviruses. we have developed a cdna array to globally characterize mhv-68 gene expression profiles, thus providing ...200212021358
characterization of a spontaneous 9.5-kilobase-deletion mutant of murine gammaherpesvirus 68 reveals tissue-specific genetic requirements for latency.murine gammaherpesvirus 68 (gammahv68 [also known as mhv-68]) establishes a latent infection in mice, providing a small-animal model with which to identify host and viral factors that regulate gammaherpesvirus latency. while gammahv68 establishes a latent infection in multiple tissues, including splenocytes and peritoneal cells, the requirements for latent infection within these tissues are poorly defined. here we report the characterization of a spontaneous 9.5-kb-deletion mutant of gammahv68 t ...200212050366
a new approach to epitope confirmation by sampling effector/memory t cells migrating to the lung.the identification of t cell epitopes that elicit a weak t cell response is technically challenging due to the relatively low resolution of many available screening assays. peptide immunization can confirm the immunogenicity of a given peptide, however, this also often induces a low frequency response in lymphoid organs. in this report, we use the murine gammaherpesvirus-68 model system to describe a novel technique to enrich for antigen-experienced t cells in vivo as an aid to epitope mapping. ...200212133630
immunophenotyping of leukocytes in peripheral blood of balb/c mice infected with mouse herpesvirus isolate 72.we characterized leukocytes in peripheral blood of balb/c mice infected with mouse herpesvirus isolate 72 (mhv-72) representing an isolate of mouse herpesvirus strain 68 (mhv-68, species murid herpesvirus 4, genus rhadinovirus, subfamily gammaherpesvirinae, family herpesviridae) (van regenmortel et al., 2000). in acute infection (up to day 30 post infection (p.i.)) the number of cd8+ t cells increased, reaching a maximum at day 11 p.i. this increase correlated with that of cd4+ t, activated cd 1 ...200212197630
elevated chemokine responses are maintained in lungs after clearance of viral infection.we observed two patterns of chemokine expression in the lungs of mice infected with murine gammaherpesvirus 68: peaks of chemokine expression correlated with or occurred after the peak of viral gene expression. chemokine expression remained elevated through 29 days postinfection.200212239330
murine gammaherpes virus as a cofactor in the development of pulmonary fibrosis in bleomycin resistant mice.studies of human tissue have suggested an association between productive epstein barr virus and idiopathic pulmonary fibrosis (ipf). however, a pathogenic role for the virus has not been established. this study was undertaken to develop an animal model, which would explore the association between viral infection and pulmonary fibrosis. balb/c mice (n=30), resistant to bleomycin, were primed with murine gammaherpesvirus 68 and then given intraperitoneal bleomycin. the mice were sacrificed at 28 d ...200212449178
humoral immune response and protection from viral infection in mice vaccinated with inactivated mhv-68: effects of type i interferon.infection of mice by murine gammaherpesvirus 68 (mhv-68) represents a suitable animal model in which to investigate the immune response against gammaherpesviruses and to test the efficacy of vaccination strategies. in this study, we evaluated the efficacy of heat-inactivated mhv-68 as a vaccine as well as the adjuvant activity of type i interferon (ifn-i) administered together with the vaccine. mice vaccinated with inactivated mhv-68 and subsequently infected with the virus exhibited a significa ...200212513907
pathogenetic characterization of a mouse herpesvirus isolate sumava.balb/c mice inoculated intranasally (i.n.) with the mouse herpesvirus isolate sumava (mhv-sumava) did not show apparent symptoms of illness. however, they showed an increase in the number of leukocytes and appearance of atypical leukocytes in peripheral blood. the infiltration of spleen with atypical cells resulted in splenomegaly. in the course of the infection the virus persisted in lungs, spleen, thymus, bone marrow, mammary glands, peritoneal macrophages and liver. we regard mhv-sumava as on ...200212197633
disruption of the m2 gene of murine gammaherpesvirus 68 alters splenic latency following intranasal, but not intraperitoneal, inoculation.infection of mice with murine gammaherpesvirus 68 (gamma hv68; also referred to as mhv68) provides a tractable small-animal model with which to address the requirements for the establishment and maintenance of gammaherpesvirus infection in vivo. the m2 gene of gamma hv68 is a latency-associated gene that encodes a protein lacking discernible homology to any known viral or cellular proteins. m2 gene transcripts have been detected in latently infected splenocytes (s. m. husain, e. j. usherwood, h. ...200211799175
exacerbation of experimental autoimmune encephalomyelitis in rodents infected with murine gammaherpesvirus-68.viral infections have long been suspected to play a role in the pathogenesis of multiple sclerosis. in the present study, two different rodent models of experimental autoimmune encephalomyelitis (eae) were used to demonstrate the ability of murine gammaherpesvirus-68 (gammahv-68) to exacerbate development of neurological symptoms. sjl mice received uv-inactivated gammahv-68 or intranasalgammahv-68, followed by immunization against proteolipid-protein peptide 139-151. infected mice became moribun ...200312811845
murine gammaherpesvirus 68 lacking thymidine kinase shows severe attenuation of lytic cycle replication in vivo but still establishes latency.the lytic cycle functions of gammaherpesviruses have received relatively little attention to date, at least in part due to the lack of a convenient experimental model. the murine gammaherpesvirus 68 (mhv-68) now provides such a model and allows the roles of individual lytic cycle gammaherpesvirus proteins to be evaluated in vivo. we have used mhv-68 to determine the contribution of a gammaherpesvirus thymidine kinase (tk) to viral lytic replication and latency establishment. mhv-68 mutants with ...200312551978
transcriptome profile of murine gammaherpesvirus-68 lytic infection.the murine gammaherpesvirus-68 genome encodes 73 protein-coding open reading frames with extensive similarities to human gamma(2) herpesviruses, as well as unique genes and cellular homologues. we performed transcriptome analysis of stage-specific viral rna during permissive infection using an oligonucleotide-based microarray. using this approach, m4, k3, orf38, orf50, orf57 and orf73 were designated as immediate-early genes based on cycloheximide treatment. the microarray analysis also identifi ...200312533705
the wood mouse is a natural host for murid herpesvirus 4.infection of laboratory mice by the murid herpesvirus 4 (mhv-4) is a much studied model system for gammaherpesvirus pathogenesis. little, however, is known about its natural host range, epidemiology and pathogenesis outside the laboratory. we have studied mhv-4 infection in free-living murids in the uk. using a combination of serology and pcr analysis, we found that mhv-4 was endemic in wood mice (apodemus sylvaticus) but not in two species of voles (clethrionomys glareolus, microtus agrestis). ...200312533706
effective vaccination against long-term gammaherpesvirus latency.the fundamental question of whether a primed immune system is capable of preventing latent gammaherpesvirus infection remains unanswered. recent studies showing that vaccination can reduce acute replication and short-term latency but cannot alter long-term latency further call into question the possibility of achieving sterilizing immunity against gammaherpesviruses. using the murine gammaherpesvirus 68 (gammahv68) system, we demonstrate that it is possible to effectively vaccinate against long- ...200312551990
absence of a functional defect in cd8+ t cells during primary murine gammaherpesvirus-68 infection of i-a(b-/-) mice.the murine gammaherpesvirus-68 kills i-a(b-/-) mice despite the presence of virus-specific cd8+ cytotoxic t lymphocytes (ctl). this has raised the possibility that these ctl are functionally abnormal. here, no difference was observed between i-a(b-/-) mice and i-a(b+/+) controls in virus-specific ctl function, t cell receptor usage, or surface phenotype. thus ctl immunity was independent of cd4+ t cells in a chronic herpesvirus infection, but was still inadequate to control virus replication.200312560565
inhibition of gammaherpesvirus replication by rna interference.rna interference (rnai) is a conserved mechanism in which double-stranded, small interfering rnas (sirnas) trigger a sequence-specific gene-silencing process. here we describe the inhibition of murine herpesvirus 68 replication by sirnas targeted to sequences encoding rta, an immediate-early protein known as an initiator of the lytic viral gene expression program, and open reading frame 45 (orf 45), a conserved viral protein. our results suggest that rnai can block gammaherpesvirus replication a ...200312584354
murine gammaherpesvirus-68 infects microglia and induces high levels of pro-inflammatory cytokine production.murine gammaherpesvirus-68 (mhv-68) has been established as a tractable model for the study of human herpesvirus infections. recent associations between herpesvirus infections and inflammatory central nervous system (cns) disorders, including multiple sclerosis (ms), have prompted us to investigate the susceptibility of cultured microglia and astrocytes to mhv-68 infection. in the present study, we demonstrate that mhv-68 can infect both cell types. importantly, we show that mhv-68-infected micr ...200312620645
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