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The 5' Leader Sequence of Mouse Mammary Tumor Virus Enhances Expression of the Envelope and Reporter Genes.Mouse mammary tumor virus (MMTV) is a complex betaretrovirus, which utilizes a Rev-like auxiliary protein Rem to export the unspliced viral RNA from the nucleus. MMTV env mRNA appears to be exported via a distinct, Rem-independent, mechanism. Here, we analyzed the effect of an extensively folded region coinciding with the 5' leader sequence on env gene expression. We found that the presence of the 5' leader stimulates expression of the envelope protein. Enhanced Env production was accompanied b ...201122113011
Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses.ABSTRACT:201122067224
single residues in the surface subunits of oncogenic sheep retrovirus envelopes distinguish receptor-mediated triggering for fusion at low ph and infection.jaagsiekte sheep retrovirus (jsrv) and enzootic nasal tumor virus (entv) are two closely related oncogenic retroviruses that share the same cellular receptor yet exhibit distinct fusogenicity and infectivity. here, we find that the low fusogenicity of entv envelope protein (env) is not because of receptor binding, but lies in its intrinsic insensitivity to receptor-mediated triggering for fusion at low ph. distinct from jsrv, shedding of entv surface (su) subunit into culture medium was not enha ...201122018783
PBC: Animal Models of Cholangiopathies and Possible Endogenous Viral Infections.Primary Biliary Cirrhosis (PBC) is considered an autoimmune disease characterized by immune-mediated destruction of the intrahepatic bile ducts and its characteristic serologic marker, the anti-mitochondrial antibody (AMA). Several factors were proposed to clarify the pathological and immunological mechanisms of PBC. Immunological reaction with a bacterial or a viral association was identified in the previous report, and it seems probable that PBC was thought to have such an etiology. The majori ...201222007316
simultaneous detection of antibodies to five simian viruses in nonhuman primates using recombinant viral protein based multiplex microbead immunoassays.routine screening for infectious agents is critical in establishing and maintaining specific pathogen free (spf) nonhuman primate (nhp) colonies. more efficient, higher throughput, less costly reagent, and reduced sample consumption multiplex microbead immunoassays (mmias) using purified viral lysates have been developed previously to address some disadvantages of the traditional individual enzyme-linked immunosorbent assay (elisa) methods. to overcome some of the technical and biosafety difficu ...201121945221
[regulatory t cell depletion increases the number of cd8 cells during mouse mammary tumor virus infection.]mouse mammary tumor virus (mmtv) is a milk-borne betaretrovirus that has developed strategies to exploit and subvert the host immune system. we have shown in a natural model of mmtv infection that the virus causes early and progressive increases in superantigen (sag)-specific cd4+ cd25+ foxp3+ regulatory t cells (treg) in peyer's patches. herein, we evaluated whether the depletion of treg cells affects the cd8+ population during milk-borne mmtv infection. at day 6 of infection, the depletion of ...201121745773
clathrin facilitates the morphogenesis of retrovirus particles.the morphogenesis of retroviral particles is driven by gag and gagpol proteins that provide the major structural component and enzymatic activities required for particle assembly and maturation. in addition, a number of cellular proteins are found in retrovirus particles; some of these are important for viral replication, but many lack a known functional role. one such protein is clathrin, which is assumed to be passively incorporated into virions due to its abundance at the plasma membrane. we ...201121738476
ensuring the safety of vaccine cell substrates by massively parallel sequencing of the transcriptome.massively parallel, deep, sequencing of the transcriptome coupled with algorithmic analysis to identify adventitious agents (mp-seq™) is an important adjunct in ensuring the safety of cells used in vaccine production. such cells may harbour novel viruses whose sequences are unknown or latent viruses that are only expressed following stress to the cells. mp-seq is an unbiased and comprehensive method to identify such viruses and other adventitious agents without prior knowledge of the nature of t ...201121651935
the signal peptide of a recently integrated endogenous sheep betaretrovirus envelope plays a major role in eluding gag-mediated late restriction.the exogenous and pathogenic jaagsiekte sheep retrovirus (jsrv) co-exists with highly related and biologically active endogenous retroviruses (enjsrvs). the endogenous enjs56a1 locus possesses a defective gag polyprotein which blocks the late replication steps of related exogenous and endogenous retroviruses by a mechanism known as jsrv late restriction (jlr). conversely, enjsrv-26, which most likely integrated into the sheep genome less than 200 years ago, is able to escape jlr. in this study, ...201121593182
chemical induction of endogenous retrovirus particles from the vero cell line of african green monkeys.endogenous retroviral sequences are present in high copy number in the genomes of all species and may be expressed as rnas, however, the majority are defective for virus production. although virus has been isolated from various old world monkey and new world monkey species, there has been no report of endogenous retroviruses produced from african green monkey (agm) tissues or cell lines. we have recently developed a step-wise approach for evaluating the presence of latent viruses by chemical ind ...201121543506
mouse mammary tumor virus in anti-mitochondrial antibody producing mouse models.a human betaretrovirus resembling the mouse mammary tumor virus (mmtv) has been characterized in primary biliary cirrhosis (pbc) and associated with aberrant pyruvate dehydrogenase complex (pdc)-e2-like expression. as mmtv is prevalent in mice as either an exogenous or endogenous infection, we tested the hypothesis that mmtv is linked with anti-mitochondrial antibody (ama) production in models with severe immune dysfunction.201121334408
differential sensitivities of retroviruses to integrase strand transfer inhibitors.integrase inhibitors are emerging anti-human immunodeficiency virus (hiv) drugs, and multiple retroviruses and transposable elements were evaluated here for susceptibilities to raltegravir (ral) and elvitegravir (evg). all viruses, including primate and nonprimate lentiviruses, a betaretrovirus, a gammaretrovirus, and the alpharetrovirus rous sarcoma virus (rsv), were susceptible to inhibition by ral. evg potently inhibited all lentiviruses and intermediately inhibited betaretrovirus and gammare ...201121270168
killing two birds with one stone. 201121195252
the evidence supports a viral aetiology for primary biliary cirrhosis. 201021147183
anti-infective activities of pelargonium sidoides (eps® 7630): effects of induced no production on leishmania major in infected macrophages and antiviral effects as assessed in a fibroblast-virus protection assay.eps® 7630 is an aqueous-ethanolic extract of the roots of pelargonium sidoides, employed in the treatment of upper respiratory tract infections. its anti-infective activity is supposed to be associated with the activation of the nonspecific immune system. using leishmania major gfp-infected murine bmmφ, the no production of eps® 7630-activated macrophages was correlated with the reduction of the gfp signal measured at single cell levels using flow cytometry. the anti-infectious effect of eps® 76 ...201021104606
identification of novel endogenous betaretroviruses which are transcribed in the bovine placenta.sequences of retroviral origin occupy approximately 10% of mammalian genomes. various infectious endogenous retroviruses (ervs) and functional retroviral elements have been reported for several mammals but not cattle. here, we identified two proviruses, designated bovine endogenous retrovirus k1 (berv-k1) and berv-k2, containing full-length envelope (env) genes in the bovine genome. phylogenetic analysis revealed that they belong to the genus betaretrovirus. by reverse transcription (rt)-pcr, bo ...201021084469
absence of markers of betaretrovirus infection in human pulmonary adenocarcinoma.a proportion of human pulmonary adenocarcinomas has been shown previously to express an antigen related to the gag protein of a betaretrovirus, jaagsiekte sheep retrovirus, that causes ovine pulmonary adenocarcinoma. to investigate further the hypothesis that a retrovirus might be present in human lung adenocarcinoma, we examined specimens from patients with lung cancer for evidence of retroviral infection by immunohistochemistry, reverse transcriptase-polymerase chain reaction, immunoblotting a ...201020825971
increases in iga(+) b cells in peyer's patches during milk-borne mouse mammary tumor virus infection are influenced by toll-like receptor 4 and are completely dependent on the superantigen response.mouse mammary tumor virus (mmtv) is a milk-borne betaretrovirus that has developed strategies to exploit and subvert the host immune system. although mammary glands are the final target of infection, peyer's patches (pp) are the entry site of the virus. herein, we show that the infection induces increases in the number of pp iga(+) b cells and higher expression of the α circular transcript, which is a specific marker of the switch to iga. in addition, iga(+) b-cell increases correlated with high ...201020685932
human mammary tumor virus in inflammatory breast cancer.the authors have found that retroviral sequences with 85% to 95% homology to the mouse mammary tumor virus were present in 40% of the sporadic breast cancers of american women. these sequences were not found in normal breasts or other tumors. a whole proviral structure was detected in 2 tumors. breast cancer cells in culture were shown to contain and shed betaretroviral particles. this virus was designated human mammary tumor virus (hmtv). the authors have investigated the presence of hmtv seque ...201020503403
cyclosporine a inhibits in vitro replication of betaretrovirus associated with primary biliary cirrhosis.up to one-third of patients with primary biliary cirrhosis (pbc) experience recurrent disease following liver transplantation, which is associated with earlier and more severe recurrence in patients treated with tacrolimus as compared with cyclosporine a (csa). as the latter has known antiviral activity, we hypothesized that csa has the ability to inhibit the betaretrovirus characterized from patients with pbc.201020492501
an updated review of simian betaretrovirus (srv) in macaque hosts.this review is an updated summary of nearly 30 years of srv history and provides new and critical findings of original research accomplished in the last 5 years including, but not limited to, the pathogenetic mechanisms underlying the origin of hematopoietic abnormalities observed in infected hosts and proposed new srv serotypes. despite major advances in the understanding and control of srv disease, much more remains to be learned and srv continues to be an exciting and attractive primate model ...201020412379
full-length genome sequence analysis of enzootic nasal tumor virus reveals an unusually high degree of genetic stability.enzootic nasal tumor virus (entv) is a betaretrovirus of sheep (entv-1) and goats (entv-2) associated with neoplastic transformation of epithelial cells of the ethmoid turbinate. confirmation of the role of entv in the pathogenesis of enzootic nasal adenocarcinoma (ena) has yet to be resolved due to the lack of an infectious molecular clone and the inability to culture the virus. very little is known about the prevalence of this disease, particularly in north america, and only one full-length se ...201020398709
simian betaretrovirus infection in a colony of cynomolgus monkeys (macaca fascicularis).of the 419 laboratory-bred cynomolgus macaques (macaca fascicularis) in a breeding colony at our institution, 397 (95%) exhibited antibodies or viral rna (or both) specific for simian betaretrovirus (srv) in plasma. pregnant monkeys (n= 95) and their offspring were tested to evaluate maternal-infant infection with srv. at parturition, the first group of pregnant monkeys (n = 76) was antibody-positive but rna-negative, the second group (n = 14 monkeys) was positive for both antibody and rna, and ...201020158949
detection of human mammary tumor virus proteins in human breast cancer cells.mouse mammary tumor virus (mmtv) has been proven to induce mammary cancer in mice. mmtv-like env gene sequences have been detected in one-third of the human breast tumors studied. the whole proviral structure with 95% homology to mmtv was found in two human breast tumors and was designated as human mammary tumor virus (hmtv). hmtv viral particles with betaretroviral features have been isolated. in addition, a retrovirus called human betaretrovirus (hbrv), homologous to the mentioned retroviruses ...201019781575
identification and mutational analysis of a rej response element in jaagsiekte sheep retrovirus rna.jaagsiekte sheep retrovirus (jsrv) is a simple betaretrovirus causing a contagious lung cancer of sheep. jsrv encodes unspliced and spliced viral rnas, among which unspliced rna encodes gag and pol proteins and a singly spliced mrna encodes env protein. in another study we found that jsrv encodes a regulatory protein, rej, that is responsible for synthesis of gag polyprotein from unspliced viral rna. rej is encoded in the 5' end of env, and it enhances nuclear export or accumulation of cytoplasm ...200919776134
jaagsiekte sheep retrovirus encodes a regulatory factor, rej, required for synthesis of gag protein.retroviruses express gag and pol proteins by translation of unspliced genome-length viral rna. for some retroviruses, transport of unspliced viral rna to the cytoplasm is mediated by small regulatory proteins such as human immunodeficiency virus rev, while other retroviruses contain constitutive transport elements in their rnas that allow transport without splicing. in this study, we found that the betaretrovirus jaagsiekte sheep retrovirus (jsrv) encodes within the env gene a trans-acting facto ...200919776124
unintended spread of a biosafety level 2 recombinant retrovirus.contamination of vertebrate cell lines with animal retroviruses has been documented repeatedly before. although such viral contaminants can be easily identified with high sensitivity by pcr, it is impossible to screen for all potential contaminants. therefore, we explored two novel methods to identify viral contaminations in cell lines without prior knowledge of the kind of contaminant.200919772602
conformational changes of the n-terminal part of mason-pfizer monkey virus p12 protein during multimerization.the mason-pfizer monkey virus is a prototype betaretrovirus with the defining characteristic that it assembles spherical immature particles from gag-related polyprotein precursors within the cytoplasm of the infected cell. it was shown previously that the n-terminal part of the gag p12 domain (wt-np12) is required for efficient assembly. however, the precise role for p12 in mediating gag-gag interaction is still poorly understood. in this study we employed detailed circular dichroism spectroscop ...200919699504
development of a generic real-time pcr assay for simultaneous detection of proviral dna of simian betaretrovirus serotypes 1, 2, 3, 4 and 5 and secondary uniplex assays for specific serotype identification.simian betaretroviruses (formerly type d retroviruses; srv) are a group of closely related retroviruses for which the natural host species are asian monkeys of the genus macaca. five serotypes have been identified by classical neutralization assays and three additional untyped variants have been reported (srv(tsukuba), srv-6, srv-7). these viruses may be significant pathogens in macaque colonies, causing a broad spectrum of clinical disease secondary to viral-induced immune suppression. undetect ...200919664660
nmr structure of the n-terminal domain of capsid protein from the mason-pfizer monkey virus.the high-resolution structure of the n-terminal domain (ntd) of the retroviral capsid protein (ca) of mason-pfizer monkey virus (m-pmv), a member of the betaretrovirus family, has been determined by nmr. the m-pmv ntd ca structure is similar to the other retroviral capsid structures and is characterized by a six alpha-helix bundle and an n-terminal beta-hairpin, stabilized by an interaction of highly conserved residues, pro1 and asp57. since the role of the beta-hairpin has been shown to be crit ...200919527730
premature processing of mouse mammary tumor virus gag polyprotein impairs intracellular capsid assembly.mouse mammary tumor virus (mmtv) is the prototypical member of the betaretrovirus genus, but the processes of its morphogenesis are poorly characterized. in this report, we describe an unusual intracellular processing of mmtv gag polyprotein in human 293t cells transiently expressing mmtv from heterologous promoter. the same specific cleavage products of the viral protease were seen for the wild type as well as for nonmyristylated mutant of mmtv gag polyprotein completely defective in the partic ...200919046754
broad-spectrum inhibition of retroviral and filoviral particle release by tetherin.the expression of many putative antiviral genes is upregulated when cells encounter type i interferon (ifn), but the actual mechanisms by which many ifn-induced gene products inhibit virus replication are poorly understood. a recently identified ifn-induced antiretroviral protein, termed tetherin (previously known as bst-2 or cd317), blocks the release of nascent human immunodeficiency virus type 1 (hiv-1) particles from infected cells, and an hiv-1 accessory protein, vpu, acts as a viral antago ...200919036818
structure of the capsid amino-terminal domain from the betaretrovirus, jaagsiekte sheep retrovirus.jaagsiekte sheep retrovirus is a betaretrovirus and the causative agent of pulmonary adenocarcinoma, a transmissible lung tumour of sheep. here we report the crystal structure of the capsid amino-terminal domain and examine the self-association properties of jaagsiekte sheep retrovirus capsid. we find that the structure is remarkably similar to the amino-terminal domain of the alpharetrovirus, avian leukosis virus, revealing a previously undetected evolutionary similarity. examination of capsid ...200919007792
coevolution of endogenous betaretroviruses of sheep and their host.sheep betaretroviruses offer a unique model system to study the complex interaction between retroviruses and their host. jaagsiekte sheep retrovirus (jsrv) is a pathogenic exogenous retrovirus and the causative agent of ovine pulmonary adenocarcinoma. the sheep genome contains at least 27 copies of endogenous retroviruses (enjsrvs) highly related to jsrv. enjsrvs have played several roles in the evolution of the domestic sheep as they are able to block the jsrv replication cycle and play a criti ...200818818869
identification of postentry restrictions to mason-pfizer monkey virus infection in new world monkey cells.trim5alpha has been shown to be a major postentry determinant of the host range for gammaretroviruses and lentiviruses and, more recently, spumaviruses. however, the restrictive potential of trim5alpha against other retroviruses has been largely unexplored. we sought to determine whether or not mason-pfizer monkey virus (m-pmv), a prototype betaretrovirus isolated from rhesus macaques, was sensitive to restriction by trim5alpha. cell lines from both old world and new world primate species were s ...200818799582
mouse apobec3 restricts friend leukemia virus infection and pathogenesis in vivo.several members of the apolipoprotein b mrna-editing enzyme catalytic polypeptide-like complex 3 (apobec3) family in primates act as potent inhibitors of retroviral replication. however, lentiviruses have evolved mechanisms to specifically evade host apobec3. likewise, murine leukemia viruses (mulv) exclude mouse apobec3 from the virions and cleave virion-incorporated apobec3. although the betaretrovirus mouse mammary tumor virus has been shown to be susceptible to mouse apobec3, it is not known ...200818786991
establishment of a lacz marker rescue assay to detect infectious rd114 virus.cats have an infectious endogenous retrovirus, named rd114 virus, and there is a possibility that rd114 virus has contaminated live attenuated vaccines, for which feline cells are used as a substrate. to monitor infectious rd114 virus in vaccines for cats, we developed a lacz marker rescue assay to detect infectious rd114 virus. among four human cell lines examined, te671 cells (human rhabdomyosarcoma) were most susceptible to rd114 virus and supported rd114 replication efficiently. infection wa ...200818772552
enzootic nasal tumor virus envelope requires a very acidic ph for fusion activation and infection.enzootic nasal tumor virus (entv) is a close relative of jaagsiekte sheep retrovirus (jsrv), and the two viruses use the same receptor, hyaluronidase 2 (hyal2), for cell entry. we report here that, unlike the jsrv envelope (env) protein, the entv env protein does not induce cell fusion at phs of 5.0 and above but requires a much lower ph (4.0 to 4.5) for fusion to occur. the entry of entv env pseudovirions was substantially inhibited by bafilomycin a1 (bafa1) but was surprisingly enhanced by lys ...200818632865
clinical trial: randomized controlled trial of zidovudine and lamivudine for patients with primary biliary cirrhosis stabilized on ursodiol.background: a human betaretrovirus has been characterized in patients with primary biliary cirrhosis (pbc). uncontrolled studies using combination anti-retroviral therapy have reported significant biochemical and histological improvement. our aim was to conduct a double blind, randomized controlled trial as a proof of principal to link infection with pbc. methods: 59 patients with an alkaline phosphatase level > 1.5 upper limits of normal stabilized on ursodeoxycholic acid therapy were randomize ...200818627363
structural characterization of the genome of berv gamma4, the most abundant endogenous retrovirus family in cattle.the genome of replication-competent berv gamma4 provirus, which is the most abundant erv family in the bovine genome, was characterized in detail. the berv gamma4 genome showed that berv gamma4 harbors 8576 nucleotides and has the typical 5'-long terminal repeat (ltr)-gag-pro-pol-env-ltr-3' retroviral organization with a long leader region positioned before the gag open reading frame. multiple sequences analysis showed that the nucleotide difference between 5' and 3' ltrs was 4.2% (mean value 0. ...200818612240
development of real-time pcr assays for quantitation of simian betaretrovirus serotype-1, -2, -3, and -5 viral dna in asian monkeys.simian betaretroviruses (srv), formerly known as simian type d retroviruses, are endemic in many populations of asian monkeys of the genus macaca. asian monkeys have been used extensively as animal models for preclinical hiv vaccine development, therapeutics, and other biomedical studies. srv infection can sometimes lead to immune deficiency disease, which complicates such studies; thus, it is important to screen for srv infection and remove infected animals from test populations. real-time pcr ...200818597861
early increases in superantigen-specific foxp3+ regulatory t cells during mouse mammary tumor virus infection.mouse mammary tumor virus (mmtv) is a milk-borne betaretrovirus that has developed strategies to exploit and subvert the host immune system. here, we show in a natural model of mmtv infection that the virus causes early and progressive increases in superantigen (sag)-specific foxp3(+) regulatory t cells (t(reg)) in peyer's patches (pp). these increases were shown to be dependent on the presence of dendritic cells. cd4(+) cd25(+) t cells from the pp of infected mice preferentially suppress the pr ...200818495774
other potential medical therapies: the use of antiviral agents to investigate and treat primary ciliary cirrhosis.a human betaretrovirus has been characterized in patients with primary biliary cirrhosis (pbc) and the related mouse mammary tumor virus linked with autoimmune biliary disease in the nod.c3c4 mouse model. translational studies have been performed in patients who have pbc to investigate the role of viral infection in disease. patients treated with combivir experienced significant improvements in hepatic biochemistry, clinical symptoms, and histology with evidence of reversal of ductopenia. prelim ...200818456190
convergence on chromatin of non-genomic and genomic pathways of hormone signaling.gene regulation by steroid hormones involves genomic and non-genomic signaling pathways and the relationship between these two pathways is unknown. genomic actions are often mediated by binding of the ligand-activated hormone receptors to hormone responsive elements (hres) followed by recruitment of co-regulators, remodeling of chromatin and formation of the transcription initiation complex. the non-genomic effects of steroid hormones involve the rapid and transient activation of several kinase ...200818417338
characterization of the bovine endogenous retrovirus beta3 genome.we recently used degenerate pcr and locus-specific pcr methods to identify the endogenous retroviruses (erv) in the bovine genome. using the ovine erv classification system, the bovine ervs (bervs) could be classified into four families. here, we searched the most recently released bovine genome database with the partial nucleotide sequence of the pro/pol region of the berv beta3 family. this allowed us to obtain and analyze the complete genome of berv beta3. the berv beta3 genome is 7666 nucleo ...200818319627
signal transduction pathways utilized by enzootic nasal tumor virus (entv-1) envelope protein in transformation of rat epithelial cells resemble those used by jaagsiekte sheep retrovirus.the ovine beta-retroviruses enzootic nasal tumor virus (entv) and jaagsiekte sheep retrovirus (jsrv) are the causative agent of enzootic nasal adenocarcinoma (ena) and ovine pulmonary adenocarcinoma (opa), respectively, characterized by neoplastic transformation of secretory epithelial cells. the envelope (env) proteins of these related betaretroviruses act as oncogenes, in that they can transform fibroblast and epithelial cell lines in culture. in addition, viral vector-mediated expression of t ...200818176837
variable transcriptional activity of endogenous retroviruses in human breast cancer.human endogenous retroviruses (hervs) account for up to 9% of the human genome and include more than 800 elements related to betaretroviruses. while mouse mammary tumor virus (mmtv) is the accepted etiological agent of mammary tumors in mice, the role of retroviral elements in human breast cancer remains elusive. here, we performed a comprehensive microarray-based analysis of overall retroviral transcriptional activities in 46 mammary gland tissue specimens representing pairs of nonmalignant and ...200818077721
replication of beta- and gammaretroviruses is restricted in i/lnj mice via the same genetic mechanism.mice of the i/lnj inbred strain are unique in their ability to mount a robust and sustained humoral immune response capable of neutralizing infection with a betaretrovirus, mouse mammary tumor virus (mmtv). virus-neutralizing antibodies (abs) coat mmtv virions secreted by infected cells, preventing virus spread and hence the formation of mammary tumors. to investigate whether i/lnj mice resist infection with other retroviruses besides mmtv, the animals were infected with murine leukemia virus (m ...200818057254
conservation of inner domain modules in the surface envelope glycoproteins of an ancient rabbit lentivirus and extant lentiviruses and betaretroviruses.the consensus sequence of endogenous lentiviral elements in the genome of european rabbits (relik) was used to extend a model of conserved lentiviral and betaretroviral surface envelope glycoprotein (su) inner domain structures. here it is shown that nearly all the inner domain elements of human and simian immunodeficiency virus gp120 mediating conformational changes upon cd4 binding were conserved in the su of relik. many of these inner domain elements and a carboxy-terminal region outside the ...200818037464
jaagsiekte sheep retrovirus is not detected in human lung adenocarcinomas expressing antigens related to the gag polyprotein of betaretroviruses.a proportion of human lung adenocarcinomas (hlacs) express an antigen related to the major capsid protein (ca) of jaagsiekte sheep retrovirus (jsrv), a betaretrovirus that causes a transmissible lung cancer in sheep. in this study, we have investigated whether jsrv or related betaretroviruses are expressed in hlacs. results obtained indicate that jsrv is not associated with human lung adenocarcinomas. however, a proportion of hlacs reacted positively in immunohistochemistry with antibodies speci ...200717889995
reverse transcriptase activity in patients with primary biliary cirrhosis and other autoimmune liver disorders.patients with biliary disease make retroviral antibodies and the human betaretrovirus has been characterized in patients with primary biliary cirrhosis.200717661762
search for dna of exogenous mouse mammary tumor virus-related virus in human breast cancer samples.earlier reports of a human exogenous retrovirus (hmtv) related closely to mouse mammary tumor virus (mmtv) led us to search for these viral sequences in breast cancer tissues and normal tissues. a real-time pcr was developed based on mmtv and published hmtv envelope sequences. the real-time pcr method can detect one to ten copies of mmtv target dna. tissue samples were collected prospectively from 18 breast cancer patients and 11 non-malignant control cases, as well as peripheral blood leukocyte ...200717485542
critical role of dendritic cells in mouse mammary tumor virus in vivo infection.mouse mammary tumor virus (mmtv) is a milk-transmitted betaretrovirus that causes mammary tumors in mice. although mammary epithelial cells are the ultimate targets of mmtv, the virus utilizes components of the host immune system to establish infection. previous studies indicated that dendritic cells play a role in mmtv infection. here we show that dendritic cells are the first cells to be infected by mmtv in vivo and that they are capable of producing infectious virus that can be transmitted to ...200717267484
jaagsiekte sheep retrovirus (jsrv): from virus to lung cancer in sheep.jaagsiekte sheep retrovirus (jsrv) is a betaretrovirus infecting sheep. this virus is responsible for a pulmonary adenocarcinoma, by transformation of epithelial cells from the bronchioli and alveoli. this animal cancer is similar to human bronchioloalveolar cancer (bac), a specific form of human lung cancer for which a viral aetiology has not yet been identified. jsrv interacts with target cells through the membrane receptor hyal2. the jsrv genome is simple and contains no recognised oncogene. ...200717257570
flexible segments modulate co-folding of dutpase and nucleocapsid proteins.the homotrimeric fusion protein nucleocapsid (nc)-dutpase combines domains that participate in rna/dna folding, reverse transcription, and dna repair in mason-pfizer monkey betaretrovirus infected cells. the structural organization of the fusion protein remained obscured by the n- and c-terminal flexible segments of dutpase and the linker region connecting the two domains that are invisible in electron density maps. small-angle x-ray scattering reveals that upon oligonucleotide binding the nc do ...200717169987
ledgf/p75 interacts with divergent lentiviral integrases and modulates their enzymatic activity in vitro.transcriptional co-activator ledgf/p75 is the major cellular interactor of hiv-1 integrase (in), critical to efficient viral replication. in this work, a series of ins from the betaretrovirus, gammaretrovirus, deltaretrovirus, spumavirus and lentivirus retroviral genera were tested for interaction with the host factor. none of the non-lentiviral ins possessed detectable affinity for ledgf in either pull-down or yeast two-hybrid assays. in contrast, all lentiviral ins examined, including those fr ...200717158150
murine musd retrotransposon: structure and molecular evolution of an "intracellularized" retrovirus.we had previously identified active autonomous copies of the musd long terminal repeat-retrotransposon family, which have retained transpositional activity. these elements are closely related to betaretroviruses but lack an envelope (env) gene. here we show that these elements encode strictly intracellular virus-like particles that can unambiguously be identified by electron microscopy. we demonstrate intracellular maturation of the particles, with a significant proportion of densely packed core ...200717151128
the betaretrovirus mason-pfizer monkey virus selectively excludes simian apobec3g from virion particles.the apobec3 protein family can constitute a potent barrier to the successful infection of mammalian species by retroviruses. therefore, any retrovirus that has evolved the ability to replicate in a given animal must have developed mechanisms that allow it to avoid or inhibit the apobec3 proteins expressed in that animal. here, we demonstrate that mason-pfizer monkey virus (mpmv) is resistant to inhibition by the apobec3g protein expressed in its normal host, the rhesus macaque, but highly suscep ...200617035335
differentiation-induced cleavage of cutl1/cdp generates a novel dominant-negative isoform that regulates mammary gene expression.cutl1/ccaat displacement protein (cdp) is a transcriptional repressor of mouse mammary tumor virus (mmtv), a betaretrovirus that is a paradigm for mammary-specific gene regulation. virgin mammary glands have high levels of full-length cdp (200 kda) that binds to negative regulatory elements (nres) to repress mmtv transcription. during late pregnancy, full-length cdp levels decline, and a 150-kda form of cdp (cdp150) appears concomitantly with a decline in dna-binding activity for the mmtv nres a ...200617015474
development of real-time pcrs for detection and quantitation of human mmtv-like (hml) sequences hml expression in human tissues.the human genome contains around 1000 betaretrovirus-like copies, human mouse mammary tumour virus (mmtv)-like (hml) groups 1-10, also referred to as human endogenous retrovirus "herv-k". despite many efforts, it is not established whether betaretroviruses, exo- or endogenous, are involved in the etiology of breast cancer, or other cancer diseases, in humans. quantitative real-time pcr (qpcr) taqman-based assays for hml groups 1-7, targeting the conserved reverse transcriptase (rt) and integrase ...200616713632
the pp24 phosphoprotein of mason-pfizer monkey virus contributes to viral genome packaging.the gag protein of mason-pfizer monkey virus, a betaretrovirus, contains a phosphoprotein that is cleaved into the np24 protein and the phosphoprotein pp16/18 during virus maturation. previous studies by yasuda and hunter (j. virology. 1998. 72:4095-4103) have demonstrated that pp16/18 contains a viral late domain required for budding and that the np24 protein plays a role during the virus life cycle since deletion of this n-terminal domain blocked virus replication. the function of the np24 dom ...200516274484
evolution and distribution of class ii-related endogenous retroviruses.endogenous retroviruses (ervs) are widespread in vertebrate genomes and have been loosely grouped into "classes" on the basis of their phylogenetic relatedness to the established genera of exogenous retroviruses. four of these genera-the lentiviruses, alpharetroviruses, betaretroviruses, and deltaretroviruses-form a well-supported clade in retroviral phylogenies, and ervs that group with these genera have been termed class ii ervs. we used pcr amplification and sequencing of retroviral fragments ...200515858031
variable regions 1 and 2 (vr1 and vr2) in jsrv gag are not responsible for the endogenous jsrv particle release defect.jaagsiekte sheep retrovirus (jsrv) is a betaretrovirus causing ovine pulmonary adenocarcinoma, a transmissible lung tumor of sheep. a very closely related endogenous retrovirus (enjsrv) occurs as 15 to 20 copies in the genome of all sheep, and is not known to be linked to pathogenesis. we previously localized a particle release defect of the full-length endogenous-derived expression construct pcmv2enjs56a1 to the amino-terminal region of gag that incorporates the two variable regions vr1 and vr2 ...200515744563
isolation and characterization of a new simian retrovirus type d subtype from monkeys at the tsukuba primate center, japan.exogenous type d simian retroviruses (srv/d) are prevalent in captive and feral populations of various macaque monkeys. thus far, five subtypes of srv/ds have been reported, three of which (srv-1, -2 and -3) have been molecularly characterized. two srv/d strains (n27 and t150) were isolated from seropositive cynomolgus macaques at the tsukuba primate center (tpc) in japan, showing clinical signs of srv/d infection, including anemia and persistent unresponsive diarrhea. electron microscopy demons ...200415716073
[lymphadenopathy of the neck in children]. 200415699993
localization of self-interacting domains within betaretrovirus gag polyproteins.the betaretrovirus genus is characterized by the ability to preassemble immature capsids within the cytoplasm. for mason-pfizer monkey virus (m-pmv) this ability depends in part upon the unique internal scaffold domain (isd) within the p12 region of gag. in this study, we have further characterized the ability of m-pmv p12 to promote gag-gag interaction and have examined the gag polyprotein of the related mouse mammary tumor virus (mmtv) to potentially identify a region with equivalent function. ...200515680431
proof of principal studies to assess the role of the human betaretrovirus in patients with primary biliary cirrhosis. 200415571601
pilot studies of single and combination antiretroviral therapy in patients with primary biliary cirrhosis.preliminary reports suggest that patients with primary biliary cirrhosis (pbc) have evidence of human betaretrovirus infection. the aim of this study was to determine whether antiviral therapy impacts on the disease process.200415571581
proteinases of betaretroviruses bind single-stranded nucleic acids through a novel interaction module, the g-patch.retroviral proteinases (prs) are essential for retrovirus infectivity but the mechanism of their activity regulation is poorly understood. we investigated possible involvement in this process of the c-terminal domain (ctd) of betaretroviral prs. we found that the presence of ctd attenuates proteolytic activity of mason-pfizer monkey virus pr, while it does not significantly affect the activity of mouse intracisternal a-particle retrovirus pr. however, both prs bind single-stranded nucleic acids ...200415474050
detection and characterization of betaretroviral sequences, related to sheep jaagsiekte virus, in africans from nigeria and cameroon.jaagsiekte retrovirus (jsrv) causes ovine pulmonary adenomatosis (opa) that resembles bronchioloalveolar carcinoma (bac) in humans. to test the possible role of jsrv in human diseases, dna specimens from 103 individuals either healthy or suffering from lung carcinomas were analyzed for jsrv sequences. orf-x sequences were detected in 19 of 64 samples and gag-prt sequences in 4 of 38 samples, predominantly in individuals from africa. sequences obtained from orf-x amplimers varied in-between each ...200415351203
human endogenous retrovirus family herv-k(hml-5): status, evolution, and reconstruction of an ancient betaretrovirus in the human genome.the human genome harbors numerous distinct families of so-called human endogenous retroviruses (herv) which are remnants of exogenous retroviruses that entered the germ line millions of years ago. we describe here the hitherto little-characterized betaretrovirus herv-k(hml-5) family (named hervk22 in repbase) in greater detail. out of 139 proviruses, only a few loci represent full-length proviruses, and many lack gag protease and/or env gene regions. we generated a consensus sequence from multip ...200415280487
multiple groups of endogenous betaretroviruses in mice, rats, and other mammals.betaretroviruses exist in endogenous and exogenous forms in hosts that are widely distributed and evolutionarily distantly related. here we report the discovery and characterization of several previously unknown betaretrovirus groups in the genomes of mus musculus and rattus norvegicus. each group contains both mouse and rat elements, and several of the groups are more closely related to previously known betaretroviruses from nonmurine hosts. some of the groups also include members from hosts wh ...200415140976
biodistribution of the rd114/mammalian type d retrovirus receptor, rdr.the limited expression of viral receptors on target cells is a recognized barrier to therapeutic gene transfer. previous analysis of receptor expression has been performed using indirect methods due to a lack of receptor-specific antibodies.200415026986
cryoelectron microscopy of mouse mammary tumor virus.cryoelectron microscopy of mouse mammary tumor virus, a betaretrovirus, provided information about glycoprotein structure and core formation. the virions showed the broad range of diameters typical of retroviruses. betaretroviruses assemble cytoplasmically, so the broad size range cannot reflect the use of the plasma membrane as a platform for assembly.200414963166
cloning the human betaretrovirus proviral genome from patients with primary biliary cirrhosis.patients with primary biliary cirrhosis (pbc) have both serologic and tissue evidence of infection. a recently identified human betaretrovirus was originally cloned from the biliary epithelium cdna library of a patient with pbc. by conducting a blastn search, the initial partial pol gene fragment was found to have 95% to 97% nucleotide homology with mouse mammary tumor virus (mmtv) and with retrovirus sequences derived from human breast cancer samples. using an anti-p27(ca) mmtv antibody, viral ...200414752833
retrovirus infection as a trigger for primary biliary cirrhosis? 200414751695
endogenous betaretroviruses of sheep: teaching new lessons in retroviral interference and adaptation.the endogenous betaretroviruses of small ruminants offer an excellent model to investigate the biological relevance of endogenous retroviruses (ervs). approximately twenty copies of endogenous betaretroviruses (enjsrvs) are present in the genome of sheep and goats. enjsrvs are highly related to jaagsiekte sheep retrovirus (jsrv) and the enzootic nasal tumour virus (entv), the causative agents of naturally occurring carcinomas of the respiratory tract of sheep. enjsrvs interact/interfere at diffe ...200414718613
the endogenous langur type d retrovirus po-1-lu and its exogenous counterparts in macaque and langur monkeys.po-1-lu, the endogenous type d retrovirus of langurs (trachypithecus obscurus) has previously been considered a progenitor to the prototype type d retrovirus, mason pfizer monkey virus (m-pmv/srv-3), that became established in macaque monkeys (macaca spp.) following a zoonosis. this study reevaluates this hypothesis to include other exogenous srvs. new sequence information from the gp70(su)-encoding region of po-1-lu shows striking similarity to the newly identified exogenous langur retrovirus, ...200314585330
identification of the receptor binding domain of the mouse mammary tumor virus envelope protein.mouse mammary tumor virus (mmtv) is a betaretrovirus that infects rodent cells and uses mouse transferrin receptor 1 for cell entry. to characterize the interaction of mmtv with its receptor, we aligned the mmtv envelope surface (su) protein with that of friend murine leukemia virus (f-mlv) and identified a putative receptor-binding domain (rbd) that included a receptor binding sequence (rbs) of five amino acids and a heparin-binding domain (hbd). mutation of the hbd reduced virus infectivity, a ...200312970432
understanding xenotransplantation risks from nonhuman primate retroviruses.significant progress in making animal-to-human transplantation a viable adjunct to human organ donation will require a greater understanding of the intricacies of immunologic rejection. recent success in generating cloned knockout piglets increases the possibility that xenotransplantation may find its way into the clinics. nonhuman primates' organs have been used for human transplants in the past and there is reason to believe that if ethical considerations and inherent problems with supply were ...200312934943
dutpase and nucleocapsid polypeptides of the mason-pfizer monkey virus form a fusion protein in the virion with homotrimeric organization and low catalytic efficiency.betaretroviruses encode dutpase, an essential factor in dna metabolism and repair, in the pro open reading frame located between gag and pol. ribosomal frame-shifts during expression of retroviral proteins provide a unique possibility for covalent joining of nucleocapsid (nc) and dutpase within gag-pro polyproteins. by developing an antibody against the prototype betaretrovirus mason-pfizer monkey virus dutpase, we demonstrate that i) the nc-dutpase fusion protein exists both within the virions ...200312869552
does a betaretrovirus infection trigger primary biliary cirrhosis?patients with primary biliary cirrhosis develop progressive ductopenia associated with the production of antimitochondrial antibodies that react with a protein aberrantly expressed on biliary epithelial cells and peri-hepatic lymph nodes. although no specific microbe has been identified, it is thought that an infectious agent triggers this autoimmune liver disease in genetically predisposed individuals. previous serologic studies have provided evidence to suggest a viral association with primary ...200312832623
putative phosphatidylinositol 3-kinase (pi3k) binding motifs in ovine betaretrovirus env proteins are not essential for rodent fibroblast transformation and pi3k/akt activation.jaagsiekte sheep retrovirus (jsrv) and enzootic nasal tumor virus (entv) are simple betaretroviruses that cause epithelial cell tumors in the lower and upper airways of sheep and goats. the envelope (env) glycoproteins of both viruses can transform rodent and chicken fibroblasts, indicating that they play an essential role in oncogenesis. previous studies found that a yxxm motif in the env cytoplasmic tail, a putative docking site for phosphatidylinositol 3-kinase (pi3k) after tyrosine phosphory ...200312829832
prevalence of antibodies to selected viruses in a long-term closed breeding colony of rhesus macaques (macaca mulatta) in brazil.the rhesus macaque breeding colony of the oswaldo cruz foundation (fiocruz) was established in 1932 from a founding stock of 100 animals. this population has remained closed to new animal introductions for almost 70 years. a serologic survey was performed to determine the prevalence of antibodies to selected viruses as a first approach to identifying viral pathogens endemic in this population. banked serum samples were tested for antibodies to simian immunodeficiency virus (siv), simian t-lympho ...200312619046
pathology of human bronchioloalveolar carcinoma and its relationship to the ovine disease.lung cancer is a leading cause of cancer with a poor prognosis. bronchioloalveolar carcinoma (bac) is a rare tumor that has always intrigued physicians. since the last world health organization classification the pathology has been clarified; bac per se is an adenocarcinoma with a pure bronchioloalveolar growth pattern and appears as an in situ alveolar adenocarcinoma. more usually bac is a clinically recognizable entity presenting as multi-focal nodules evolving towards pneumonia associated wit ...200312596901
pathology of ovine pulmonary adenocarcinoma.clinical, gross pathology, histopathology and electron microscopy of the ovine pulmonary adenocarcinoma (opa, jaagsiekte) either natural or experimentally induced in sheep, goat and moufflon are described. opa is caused by an oncogenic betaretrovirus,jaagsiekte sheep retrovirus (jsrv). most natural cases of opa appear in animals 1-4 years old. there is no evidence of sex or breed susceptibility. sheep affected by opa show an afebrile respiratory illness associated with loss of weight. a very cha ...200312596894
a history of ovine pulmonary adenocarcinoma (jaagsiekte) and experiments leading to the deduction of the jsrv nucleotide sequence.jaagsiekte (js), a contagious cancer affecting the lungs of sheep has been called many names over the years. at a recent workshop in missilac, france it was agreed that the disease would be called ovine pulmonary adenocarcinoma (opa). the disease is caused by an infectious retrovirus called jaagsiekte sheep retrovirus (jsrv). this chapter focuses on the early research that led up to the isolation, cloning and sequencing of the exogenous infectious form of jsrv and the demonstration that it has a ...200312596893
role of virus receptor hyal2 in oncogenic transformation of rodent fibroblasts by sheep betaretrovirus env proteins.the ovine betaretroviruses jaagsiekte sheep retrovirus (jsrv) and enzootic nasal tumor virus (entv) cause contagious cancers in the lungs and upper airways of sheep and goats. oncogenic transformation assays using mouse and rat fibroblasts have localized the transforming activity to the env proteins encoded by these viruses, which require the putative lung and breast cancer tumor suppressor hyaluronidase 2 (hyal2) to promote virus entry into cells. these results suggested the hypothesis that the ...200312584308
receptor usage and fetal expression of ovine endogenous betaretroviruses: implications for coevolution of endogenous and exogenous retroviruses.betaretroviruses of sheep include two exogenous viruses, jaagsiekte sheep retrovirus (jsrv) and enzootic nasal tumor virus (entv), and a group of endogenous viruses known as enjsrvs. the exogenous jsrv and entv are the etiological agents of ovine pulmonary adenocarcinoma (opa) and enzootic nasal tumor (ent), respectively. sheep affected by opa or ent do not show an appreciable antibody response to jsrv or entv. consequently, it is conceivable that enjsrv expression in the fetal lamb tolerizes sh ...200312477881
infection of simian b lymphoblastoid cells with simian immunodeficiency virus is associated with upregulation of cd23 and cd40 cell surface markers.simian immunodeficiency virus (siv) as well as human immunodeficiency virus (hiv) induce polyclonal b-cell activation and are associated with the appearance of lymphomas in their respective hosts in either the presence or the absence of other co-infecting viruses such as epstein-barr virus (ebv). however, the pathogenic role of these retroviruses in the development of lymphoproliferative disorders remains poorly understood. to explore the virus-b-cell interactions, two immortalized lymphoblastoi ...200212210440
envelope-induced cell transformation by ovine betaretroviruses.ovine betaretroviruses include jaagsiekte sheep retrovirus (jsrv) and enzootic nasal tumor virus (entv). jsrv and entv represent a unique class of oncogenic retroviruses that induce tumors of the respiratory tract. jsrv and entv are highly related but induce different diseases. expression of the jsrv envelope (env) induces transformation of rodent fibroblasts in vitro and phosphorylation of akt, a central player in the phosphatidylinositol 3-kinase (pi-3k)/akt signal transduction pathway. howeve ...200211991967
selection for c-myc integration sites in polyclonal t-cell lymphomas.type b leukemogenic virus (tblv) is highly related to mouse mammary tumor virus but induces rapidly appearing t-cell lymphomas in mice. unlike other t-cell tumors induced by retroviruses, only 5 to 10% of tblv-induced lymphomas have detectable viral integrations near c-myc by southern blotting, whereas northern blotting has shown that most tumors have two- to sixfold overexpression of c-myc rna. in this report, pcr was used to demonstrate that at least 30% of these lymphomas have tblv insertions ...200211836386
expression of endogenous betaretroviruses in the ovine uterus: effects of neonatal age, estrous cycle, pregnancy, and progesterone.the ovine genome contains 15 to 20 copies of endogenous retroviruses (enjsrvs) highly related to the oncogenic jaagsiekte sheep retrovirus (jsrv) and enzootic nasal tumor virus. enjsrvs are highly expressed in the endometrial lumenal epithelia (le) and glandular epithelia (ge) of the ovine uterus. the effects of neonatal age, estrous cycle, pregnancy, and progesterone on expression of enjsrvs in the ovine uterus were determined. expression of enjsrv rnas was absent from the uterus of ewes at bir ...200111689612
a pcr primer system for detecting oncoretroviruses based on conserved dna sequence motifs of animal retroviruses and its application to human leukaemias and lymphomas.many c- and d-type retroviruses are known to cause a broad spectrum of malignant diseases in animals. certain genome regions of these animal retroviruses are highly conserved between different animal species. it should be possible to detect new members of the retrovirus family with consensus pcr primers derived from these conserved sequence motifs. the consensus pcr primers developed in this study are generic enough to detect nearly all known oncogenic mammalian and avian exogenous c- and d-type ...200111514731
mapping the functional domains of hap95, a protein that binds rna helicase a and activates the constitutive transport element of type d retroviruses.the complex retroviruses such as human immunodeficiency virus, type 1, employ a virally encoded protein, rev, to mediate the nuclear export of unspliced and partially spliced mrna. in contrast, the simian type d retroviruses act through a cis-acting constitutive transport element (cte) that presumably interacts directly with cellular export proteins. we first reported that rna helicase a (rha) is a shuttle protein that binds to functional cte in vitro and in vivo. recently, we isolated a novel p ...200111402034
retroviral constitutive transport element evolved from cellular tap(nxf1)-binding sequences.the constitutive transport element (cte) of type d retroviruses serves as a signal of nuclear export of unspliced viral rnas. the human tap(nxf1) protein, a cellular mrna export factor, directly binds to cte and mediates nuclear export of cte-containing rnas. here, we use genomic selex (systematic evolution of ligands by exponential enrichment) to show that the human genome encodes a family of high-affinity tap ligands. these tap-binding elements (tbe) are 15-bp minisatellite repeats that are ho ...200111356964
comparison of replication-competent molecular clones of porcine endogenous retrovirus class a and class b derived from pig and human cells.vertically transmitted endogenous retroviruses pose an infectious risk in the course of pig-to-human transplantation of cells, tissues, and organs. two classes of polytropic type c porcine endogenous retroviruses (perv) which are infectious for human cells in vitro are known. recently, we described the cloning and characterization of replication-competent perv-b sequences from productively infected human cells (f. czauderna, n. fischer, k. boller, r. kurth, and r. r. tönjes, j. virol. 74:4028-40 ...200111356953
identification of novel porcine endogenous betaretrovirus sequences in miniature swine.pcr amplification of genomic dna from miniature swine peripheral blood lymphocytes, using primers corresponding to highly conserved regions of the polymerase (pol) gene, allowed the identification of two novel porcine endogenous retrovirus (perv) sequences, pmsn-1 and pmsn-4. phylogenetic analyses of the nucleotide sequences of pmsn-1 and pmsn-4 revealed them to be most closely related to betaretroviruses. the identification of pervs belonging to the betaretrovirus genus shows that endogenous re ...200111222699
endogenous type d retrovirus in a marsupial, the common brushtail possum (trichosurus vulpecula).we have sequenced and characterized an endogenous type d retrovirus, which we have named tverv(d), from the genome of an australian marsupial, the common brushtail possum (trichosurus vulpecula). intact tverv(d) gag, pro, pol, and env open reading frames were detected in the possum genome. tverv(d) was classified as a type d retrovirus, most closely related to those of old world monkeys, new world monkeys, and mice, based on phylogenetic analyses and genetic organization. approximately 30 tverv( ...200111160757
conservation of human immunodeficiency virus type 1 gp120 inner-domain sequences in lentivirus and type a and b retrovirus envelope surface glycoproteins.we recently described a sequence similarity between the small ruminant lentivirus surface unit glycoprotein (su) gp135 and the second conserved region (c2) of the primate lentivirus gp120 which indicates a structural similarity between gp135 and the inner proximal domain of the human immunodeficiency virus type 1 gp120 (i. hötzel and w. p. cheevers, virus res. 69:47-54, 2000). here we found that the seven-amino-acid sequence of the gp120 strand beta 25 in the c5 region, which is also part of the ...200111160703
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