Publications

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envelope variation as a primary determinant of lentiviral vaccine efficacy.lentiviral envelope antigenic variation and associated immune evasion are believed to present major obstacles to effective vaccine development. although this perception is widely assumed by the scientific community, there is, to date, no rigorous experimental data assessing the effect of increasing levels of lentiviral env variation on vaccine efficacy. it is our working hypothesis that env is, in fact, a primary determinant of vaccine effectiveness. we previously reported that a successful expe ...200717846425
comparative requirements for the restriction of retrovirus infection by trim5alpha and trimcyp.the restriction factors, trim5alpha in most primates and trimcyp in owl monkeys, block infection of various retroviruses soon after virus entry into the host cell. rhesus monkey trim5alpha (trim5alpha rh) inhibits human immunodeficiency virus (hiv-1) and feline immunodeficiency virus (fiv) more potently than human trim5alpha (trim5alpha hu). trimcyp restricts infection of hiv-1, simian immunodeficiency virus of african green monkeys (siv agm) and fiv. early after infection, trimcyp, like trim5al ...200717920096
development of photoreceptor-specific promoters and their utility to investigate eiav lentiviral vector mediated gene transfer to photoreceptors.we wanted to investigate the ability of recombinant equine infectious anemia virus (eiav) vectors to transduce photoreceptor cells by developing a series of photoreceptor-specific promoters that drive strong gene expression in photoreceptor cells.200717963276
long terminal repeats are not the sole determinants of virulence for equine infectious anemia virus.the long terminal repeats (ltrs) of equine infectious anemia virus donkey leukocyte-attenuated virus (eiav-dla) were substituted with those of the wild-type eiav-l (wt eiav-l, the parent virus of eiav-dla). the resulting chimeric plasmid was designated pok-ltr dla/l. purified pok-ltr dla/l was transfected into monocyte-derived macrophage (mdm) cultures prepared from eiav-negative, heparinized whole blood from a donkey. eighth-passage cell cultures developed the typical cytopathogenic effects (cp ...200716932982
[establishment of a 293-cell line containing luciferase reporter for eiav receptor and ltr functions].to accurately and conveniently detect neutralizing antibodies and receptor binding affinities of different equine infectious anemia virus (eiav) strains, the cdna of eiav receptor, elr1, was cloned and inserted in an eukaryotic expression vector pcdna3.1(+). this recombinant plasmid was designated as pelr1. the 293 cell line was transiently transfected with pelr1 and the expression of elr1 on transfected cells was verified by western blot and indirect immunofluorescence assay (ifa). furthermore, ...200718271266
development and characterization of an equine infectious anemia virus env-pseudotyped reporter virus.we developed a replication-defective reporter virus pseudotyped with the envelope glycoprotein of equine infectious anemia virus (eiav). the in vitro host range and neutralization phenotype of eiav env-pseudotyped virus were similar to those of replication-competent virus. an eiav env pseudovirus will improve antigenic characterization of viral variants and evaluation of lentivirus vaccines.200818448619
correction of the disease phenotype in the mouse model of stargardt disease by lentiviral gene therapy.autosomal recessive stargardt disease (stgd1) is a macular dystrophy caused by mutations in the abca4 (abcr) gene. the disease phenotype that is most recognized in stgd1 patients, and also in the abca4-/- mouse (a disease model), is lipofuscin accumulation in retinal pigment epithelium. here, we tested whether delivery of the normal (wt) human abca4 gene to the subretinal space of the abca4 -/- mice via lentiviral vectors would correct the disease phenotype; that is, reduce accumulation of the l ...200818463687
analysis of the eiav rev-responsive element (rre) reveals a conserved rna motif required for high affinity rev binding in both hiv-1 and eiav.a cis-acting rna regulatory element, the rev-responsive element (rre), has essential roles in replication of lentiviruses, including human immunodeficiency virus (hiv-1) and equine infection anemia virus (eiav). the rre binds the viral trans-acting regulatory protein, rev, to mediate nucleocytoplasmic transport of incompletely spliced mrnas encoding viral structural genes and genomic rna. because of its potential as a clinical target, rre-rev interactions have been well studied in hiv-1; however ...200818523581
biochemical characterization of a recombinant trim5alpha protein that restricts human immunodeficiency virus type 1 replication.the rhesus monkey intrinsic immunity factor trim5alpha(rh) recognizes incoming capsids from a variety of retroviruses, including human immunodeficiency virus type 1 (hiv-1) and equine infectious anemia virus (eiav), and inhibits the accumulation of viral reverse transcripts. however, direct interactions between restricting trim5alpha proteins and retroviral capsids have not previously been demonstrated using pure recombinant proteins. to facilitate structural and mechanistic studies of retrovira ...200818799573
effect of two synthetic peptides mimicking conserved regions of equine infectious anemia virus proteins gp90 and gp45 upon cytokine mrna expression.gp90 and gp45 synthetic peptides, which mimic conserved sequences of native viral proteins, are recognized by antibodies to equine infectious anemia virus (eiav) in asymptomatic carrier horses and generate humoral and cellular responses in immunized mice. cytokine mrna levels were evaluated in equine peripheral blood mononuclear cells (pbmcs) after in vitro stimulation with gp90 and gp45 with the aim of determining the cytokine profile associated with the proliferative response. stimulation inde ...200818825485
eiav vector-mediated co-delivery of endostatin and angiostatin driven by the rpe-specific vmd2 promoter inhibits choroidal neovascularization.equine infectious anemia virus (eiav) is a non-primate lentivirus that does not cause human disease. subretinal injection in mice of a recombinant eiav lentiviral vector in which lacz is driven by a cmv promoter (eiav cmv lacz) resulted in rapid and strong expression of lacz in retinal pigmented epithelial (rpe) cells and some other cells including ganglion cells resulting in x-gal within the optic nerve. substitution of the rpe-specific vmd2 promoter for the cmv promoter resulted in prolonged ( ...200818840069
structural insights into the cyclin t1-tat-tar rna transcription activation complex from eiav.the replication of many retroviruses is mediated by a transcriptional activator protein, tat, which activates rna polymerase ii at the level of transcription elongation. tat interacts with cyclin t1 of the positive transcription-elongation factor p-tefb to recruit the transactivation-response tar rna, which acts as a promoter element in the transcribed 5' end of the viral long terminal repeat. here we present the structure of the cyclin box domain of cyclin t1 in complex with the tat protein fro ...200819029897
[comparison of proviral genomes between the chinese eiav donkey leukocyte-attenuated vaccine and its parental virulent strain].the donkey leukocyte-attenuated vaccine of equine infectious anemia virus (eiav) was the first lentiviral vaccine that induced solid protection from the infection of virulent strains. to elucidate the mechanism of increased immunogenicity and attenuated virulence of the vaccine, the proviral genomic dna of an eiav vaccine strain, eiav(dlv121) was analyzed and compared with the genome of a parental virulent strain eiav(dv117). full length viral genomic dnas were amplified as two segments by la-pc ...200819226953
structural and functional studies of alix interactions with ypx(n)l late domains of hiv-1 and eiav.retrovirus budding requires short peptide motifs (late domains) located within the viral gag protein that function by recruiting cellular factors. the ypx(n)l late domains of hiv and other lentiviruses recruit the protein alix (also known as aip1), which also functions in vesicle formation at the multivesicular body and in the abscission stage of cytokinesis. here, we report the crystal structures of alix in complex with the ypx(n)l late domains from hiv-1 and eiav. the two distinct late domains ...200818066081
[equine infectious anemia (eia)].equine infectious anemia (eia) is a reportable, eradicable epizootic disease caused by the equine lentivirus of the retrovirus family which affects equids only and occurs worldwide. the virus is transmitted by blood, mainly by sanguivorous insects. the main symptoms of the disease are pyrexia, apathy, loss of body condition and weight, anemia, edema and petechia. however, infected horses can also be inapparent carriers without any overt signs. the disease is diagnosed by serological tests like t ...200919333901
in vivo evolution of the gp90 gene and consistently low plasma viral load during transient immune suppression demonstrate the safety of an attenuated equine infectious anemia virus (eiav) vaccine.to study the in vivo evolution of the attenuated chinese equine infectious anemia virus (eiav) vaccine, viral gp90 gene variation and virus replication in immunosuppressed hosts were investigated. the results showed that after vaccination, the gp90 gene followed an evolutionary trend of declining diversity. the trend coincided with the maturation of immunity to eiav, and eventually, the gp90 gene became highly homologous. the sequences of these predominant quasispecies were consistently detected ...200919363668
viral load and clinical disease enhancement associated with a lentivirus cytotoxic t lymphocyte vaccine regimen.effective dna-based vaccines against lentiviruses will likely induce ctl against conserved viral proteins. equine infectious anemia virus (eiav) infects horses worldwide, and serves as a useful model for lentiviral immune control. although attenuated live eiav vaccines have induced protective immune responses, dna-based vaccines have not. in particular, dna-based vaccines have had limited success in inducing ctl responses against intracellular pathogens in the horse. we hypothesized that priming ...200919368787
defects in cellular sorting and retroviral assembly induced by gga overexpression.we previously demonstrated that overexpression of golgi-localized, gamma-ear containing, arf-binding (gga) proteins inhibits retrovirus assembly and release by disrupting the function of endogenous adp ribosylation factors (arfs). gga overexpression led to the formation of large, swollen vacuolar compartments, which in the case of gga1 sequestered hiv-1 gag.200919788741
[receptors for animal retroviruses].diseases caused by animal retroviruses have been recognized since 19th century in veterinary field. most livestock and companion animals have own retroviruses. to disclose the receptors for these retroviruses will be useful for understanding retroviral pathogenesis, developments of anti-retroviral drugs and vectors for human and animal gene therapies. of retroviruses in veterinary field, receptors for the following viruses have been identified; equine infectious anemia virus, feline immunodefici ...200920218331
equine infectious anemia viral vector-mediated codelivery of endostatin and angiostatin driven by retinal pigmented epithelium-specific vmd2 promoter inhibits choroidal neovascularization.equine infectious anemia virus (eiav) is a nonprimate lentivirus that does not cause human disease. subretinal injection into mice of a recombinant eiav lentiviral vector in which lacz is driven by a cmv promoter (eiav cmv lacz) resulted in rapid and strong expression of lacz in retinal pigmented epithelial (rpe) cells and some other cells including ganglion cells, resulting in the presence of 5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside within the optic nerve. substitution of the rpe-spe ...200920377369
replication of equine infectious anemia virus in engineered mouse nih 3t3 cells.we employed the equine lentivirus equine infectious anemia virus (eiav) to investigate the cellular restrictions for lentivirus replication in murine nih 3t3 cells. the results of these studies demonstrate that nih 3t3 cells expressing the eiav receptor elr1 and equine cyclin t1 supported productive replication of eiav and produced infectious virions at levels similar to those found in a reference permissive equine cell line. the studies presented here demonstrate, for the first time, differenti ...200919073738
genetic variation in the long terminal repeat associated with the transition of chinese equine infectious anemia virus from virulence to avirulence.a highly virulent strain of equine infectious anemia virus (eiav) lost its fatal virulence but retained the desired antigens during serial passage over 130 generations in leukocytes in vitro. we compared the long terminal repeat (ltr) sequences of the different generations and found that three stable genetic variations occurred in the transcriptional start site, the initial base of tar, and the pre-mrna cleavage site at the r-u5 boundary, respectively. these three mutations happened at the infle ...200919130201
hiv-1 exploits importin 7 to maximize nuclear import of its dna genome.nuclear import of the hiv-1 reverse transcription complex (rtc) is critical for infection of non dividing cells, and importin 7 (imp7) has been implicated in this process. to further characterize the function of imp7 in hiv-1 replication we generated cell lines stably depleted for imp7 and used them in conjunction with infection, cellular fractionation and pull-down assays.200919193229
an lypsl late domain in the gag protein contributes to the efficient release and replication of rous sarcoma virus.the efficient release of newly assembled retrovirus particles from the plasma membrane requires the recruitment of a network of cellular proteins (escrt machinery) normally involved in the biogenesis of multivesicular bodies and in cytokinesis. retroviruses and other enveloped viruses recruit the escrt machinery through three classes of short amino acid consensus sequences termed late domains: pt/sap, ppxy, and lypx(n)l. the major late domain of rous sarcoma virus (rsv) has been mapped to a pppy ...201020392845
[infectious anemia in belgium]. 201020415032
lentiviral vif degrades the apobec3z3/apobec3h protein of its mammalian host and is capable of cross-species activity.all lentiviruses except equine infectious anemia virus (eiav) use the small accessory protein vif to counteract the restriction activity of the relevant apobec3 (a3) proteins of their host species. prior studies have suggested that the vif-a3 interaction is species specific. here, using the apobec3h (z3)-type proteins from five distinct mammals, we report that this is generally not the case: some lentiviral vif proteins are capable of triggering the degradation of both the a3z3-type protein of t ...201020519393
molecular detection, epidemiology, and genetic characterization of novel european field isolates of equine infectious anemia virus.the application of molecular diagnostic techniques along with nucleotide sequence determination to permit contemporary phylogenetic analysis of european field isolates of equine infectious anemia virus (eiav) has not been widely reported. as a result, of extensive testing instigated following the 2006 outbreak of equine infectious anemia in italy, 24 farms with a history of exposure to this disease were included in this study. new pcr-based methods were developed, which, especially in the case o ...201021084503
dynamics of escrt protein recruitment during retroviral assembly.the escrt (endosomal sorting complex required for transport) complexes and associated proteins mediate membrane scission reactions, such as multivesicular body formation, the terminal stages of cytokinesis and retroviral particle release. these proteins are believed to be sequentially recruited to the site of membrane scission, and then complexes are disassembled by the atpase vps4a. however, these events have never been observed in living cells, and their dynamics are unknown. by quantifying th ...201121394083
protective effects of broadly neutralizing immunoglobulin against homologous and heterologous equine infectious anemia virus infection in horses with severe combined immunodeficiency.using the equine infectious anemia virus (eiav) lentivirus model system, we previously demonstrated protective effects of broadly neutralizing immune plasma in young horses (foals) with severe combined immunodeficiency (scid). however, in vivo selection of a neutralization-resistant envelope variant occurred. here, we determined the protective effects of purified immunoglobulin with more potent broadly neutralizing activity. overall, protection correlated with the breadth and potency of neutrali ...201121543497
equine infectious anemia prevalence in feral donkeys from northeast brazil.equine infectious anemia virus (eiav) is an important cause of morbidity and mortality throughout the world. although the virus infects all members of the equidae the vast majority of studies have been conducted in horses (equus caballus) with comparatively little information available for other equid species. brazil has one of the most abundant donkey (e. asinus) populations of any nation although the economic importance of these animals is declining as transportation becomes increasingly mecha ...201728460747
host and viral traits predict zoonotic spillover from mammals.the majority of human emerging infectious diseases are zoonotic, with viruses that originate in wild mammals of particular concern (for example, hiv, ebola and sars). understanding patterns of viral diversity in wildlife and determinants of successful cross-species transmission, or spillover, are therefore key goals for pandemic surveillance programs. however, few analytical tools exist to identify which host species are likely to harbour the next human virus, or which viruses can cross species ...201728636590
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