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PubMed1996

Adenovirus-vector-mediated cytokine gene transfer to lung tissue.

In summary, we have been able to demonstrate that adenovirus vectors are valuable tools in examining the roles played by individual cytokines in lung responses and inflammation. These viral vectors have marked trophism for the epithelial cells of the lung and are highly efficient in transferring the genes into these lining cells. This results in significant expression of cytokines both within the lumen and the parenchyma of the lung. As a result of an individual cytokine being overexpressed, there are cytokine-specific changes seen-IL-6 resulting in lymphocytosis, MIP2 resulting in neutrophil accumulation, RANTES resulting in monocyte accumulation, TGF beta resulting in monocytosis but no fibrosis, and GM-CSF most surprisingly resulting in tissue eosinophilia, granuloma formation, and subsequently the onset of fibrosis. These vectors have helped pinpoint the role of a number of the cytokines in inducing chronic inflammatory changes to the lung and imply that a single cytokine may not be the only trigger resulting in chronic changes within the lung parenchyma.

Adenoviridae↗
PubMed1996

In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector.

A retroviral vector system based on the human immunodeficiency virus (HIV) was developed that, in contrast to a murine leukemia virus-based counterpart, transduced heterologous sequences into HeLa cells and rat fibroblasts blocked in the cell cycle, as well as into human primary macrophages. Additionally, the HIV vector could mediate stable in vivo gene transfer into terminally differentiated neurons. The ability of HIV-based viral vectors to deliver genes in vivo into nondividing cells could increase the applicability of retroviral vectors in human gene therapy.

Amino Acid Sequence↗
PubMed1998

The prospects of hepatic drug delivery and gene therapy.

Liver targeted therapy is designed to deliver a substance preferentially to the organ in order to increase the accumulation, improve the therapeutic effect and reduce toxicity to other organs. The aim of selective targeting is to deliver a substance to a specific cell type in the liver. A variety of vehicles have been designed and further modified for selective targeting of therapeutics to the liver. The targeting properties and strategies of commonly used agents, such as liposomes, microspheres and recombinant chylomicrons, are discussed. Viral and non-viral vectors, such as cationic liposomes, reconstituted chylomicron remnants, adenoviruses, adeno-associated viruses, retroviruses, and SV-40, are currently being evaluated for the delivery of DNA to the liver. New developments in improving the targeting efficiency of the available vectors while avoiding their disadvantages have made their use in clinical trials of various genetic disorders possible. For viral hepatitis, antisense and ribozyme techniques are being employed with selective targeting approaches. A commonly employed current strategy for targeting hepatocellular carcinoma cells is to make the tumour cells convert non-toxic 'prodrugs' to toxic metabolites in situ, achieving a high concentration of the toxic product in the local milieu, while avoiding systemic toxicity. Although gene therapy itself is in its infancy, some encouraging results have been developed in studies of familial hypercholesterolaemia, haemophilia, alpha1-antitrypsin deficiency and Crigler-Najjar syndrome. The potential strengths as well as the problems with these studies are discussed.

Journal Article↗
PubMed2005

Ligand-directed gene targeting to mammalian cells by pseudotype baculoviruses.

The baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) can infect a variety of mammalian cells, as well as insect cells, facilitating its use as a viral vector for gene delivery into mammalian cells. Glycoprotein gp64, a major component of the budded AcMNPV envelope, is involved in viral entry into cells by receptor-mediated endocytosis and subsequent membrane fusion. We examined the potential production of pseudotype baculovirus particles transiently carrying ligands of interest in place of gp64 as a method of ligand-directed gene delivery into target cells. During amplification of a gp64-null pseudotype baculovirus carrying a green fluorescent protein gene in gp64-expressing insect cells, however, we observed the high-frequency appearance of a replication-competent virus incorporating the gp64 gene into the viral genome. To avoid generation of replication-competent revertants, we prepared pseudotype baculoviruses by transfection with recombinant bacmids without further amplification in the gp64-expressing cells. We constructed gp64-null recombinant bacmids carrying cDNAs encoding either vesicular stomatitis virus G protein (VSVG) or measles virus receptors (CD46 or SLAM). The VSVG pseudotype baculovirus efficiently transduced a reporter gene into a variety of mammalian cell lines, while CD46 and SLAM pseudotype baculoviruses allowed ligand-receptor-directed reporter gene transduction into target cells expressing measles virus envelope glycoproteins. Gene transduction mediated by the pseudotype baculoviruses could be inhibited by pretreatment with specific antibodies. These results indicate the possible application of pseudotype baculoviruses in ligand-directed gene delivery into target cells.

Antigens, CD↗
PubMed2006

Differences and similarities in viral life cycle progression and host cell physiology after infection of human dendritic cells with modified vaccinia virus Ankara and vaccinia virus.

Modified vaccinia virus Ankara (MVA) is an attenuated strain of vaccinia virus (VV) that has attracted significant attention as a candidate viral vector vaccine for immunization against infectious diseases and treatment of malignancies. Although MVA is unable to replicate in most nonavian cells, vaccination with MVA elicits immune responses that approximate those seen after the administration of replication-competent strains of VV. However, the mechanisms by which these viruses elicit immune responses and the determinants of their relative immunogenicity are incompletely understood. Studying the interactions of VV and MVA with cells of the human immune system may elucidate these mechanisms, as well as provide a rational basis for the further enhancement of the immunogenicity of recombinant MVA vectors. Toward this end, we investigated the consequences of MVA or VV infection of human dendritic cells (DCs), key professional antigen-presenting cells essential for the generation of immune responses. We determined that a block to the formation of intracellular viral replication centers results in abortive infection of DCs with both VV and MVA. MVA inhibited cellular protein synthesis more rapidly than VV and displayed a distinct pattern of viral protein expression in infected DCs. MVA also induced apoptosis in DCs more rapidly than VV, and DC apoptosis after MVA infection was associated with an accelerated decline in the levels of intracellular Bcl-2 and Bcl-X(L). These findings suggest that antigen presentation pathways may contribute differentially to the immunogenicity of VV and MVA and that targeted modifications of virus-induced DC apoptosis may further increase the immunogenicity of MVA-vectored vaccines.

Apoptosis↗
PubMedDate not supplied

[Nonviral methods of gene transfer in gene therapy].

A number of viral and non-viral vector systems have been developed nowadays for gene therapy applications. The advantages and shortcomings of the following non-viral methods of transfection are discussed in this review: calcium phosphate technique, ballistic transfection using "gene gun", electroporation, microinjection into the nucleus, receptor-mediated gene transfer, and artificial macromolecular complexes (polycations, hydrophobic polycations, polymers, cationic and neutral liposomes). Special attention is paid to methods of lipofection based on the usage of cationic and neutral liposomes as well as targeted gene delivery with the emphasis on the works which were out in author's laboratories.

Animals↗
PubMed2003

Acute meningitis due to Toscana virus infection among patients from both the Spanish Mediterranean region and the region of Madrid.

Toscana virus (TOSV) is a member of the genus Phlebovirus that is transmitted to humans by two different species of sand fly and causes acute aseptic meningitis (AAM) and meningoencephalitis in Central Italy. Fifteen cases of AAM due to TOSV have been found at the Spanish province of Granada, but no data regarding the presence of TOSV-related disease in other regions of Spain have been still reported. A collection of 88 serum and 53 cerebrospinal fluid (CSF) samples taken from 81 selected patients with AAM of unknown aetiology, residing at Madrid or at the southern Mediterranean coast of Spain, was retrospectively studied for presence of TOSV-specific antibodies from both IgG and IgM classes. Anti-TOSV IgG was also investigated in 457 serum samples from healthy individuals, aged 2-60 years, residing at the south of the Region of Madrid. Specific IgM in serum and/or intrathecally produced anti-TOSV IgG were detected in seven patients, three residents from the Mediterranean region and the remainder four from the Region of Madrid. The overall prevalence of anti-TOSV among the healthy population studied was 5%. These results confirm the role of TOSV as an agent causing AAM in the Spanish Mediterranean coast, extend these findings to the central region of the country and suggest that TOSV might be producing infection and neurological disease in every area of Spain harbouring significant populations of the viral vectors.

Adolescent↗
PubMed1996

Autonomous parvovirus transduction of a gene under control of tissue-specific or inducible promoters.

Several classes of viruses are in use, or are being developed, as gene therapy vectors. Viruses with small genomes containing few essential genes have the advantage of requiring only simple complementation systems to allow packaging of foreign DNA, substituted for the entire viral coding sequences. Retroviruses and the dependent parvovirus AAV (adeno-associated virus) have been used in this way, and both possess an efficient integration mechanism which should allow long-term expression of transduced genes. In some situations, however, long-term persistence may be undesirable and there is a need for small, non-integrating viral vectors. Autonomous parvoviruses, such as LuIII, have potential as such vectors for short-term expression of therapeutic genes. We previously described recombinants of LuIII that transduced reporter genes, expressed using the viral constitutive promoter, P4. We have now generated several recombinants containing regulated promoters. A virus including a liver-specific enhancer directed 10- to 20-fold preferential expression of the luciferase reporter in transduced human hepatoma (HepG2) versus HeLa cells. In additional LuIII recombinants, the luciferase reporter was linked with chimeric promoters containing binding sequences for either the yeast GAL4 protein or the bacterial tetracycline repressor. Luciferase expression was strongly activated when these viruses were used to infect cells containing a cognate trans-activator (GAL4 or tTA, a tetracycline repressor fusion with VP16 of herpes simplex), introduced by transfection. The response to tTA could be abolished, or reduced in a graded manner, by exposure of the infected cells to tetracycline. Further results suggested that an increase in basal expression, apparently mediated by the viral left terminal inverted repeat, could be minimized by interposing polyadenylation signals between this sequence and the promoter. These results confirm that appropriate transcriptional regulation can be achieved for genes transduced by an autonomous parvovirus vector. Such vectors therefore show promise for the delivery of therapeutic genes in situations requiring cell-specific, short-term expression, eg in targeting suicide genes for ablation of cancer cells.

Cell Line↗
PubMed1992

Retroviruses that express different ras mutants cause different types of tumors in chickens.

We have used replication-competent retroviral vectors to express avian and murine ras genes in cultured chick embryo fibroblasts (CEF) and in chickens. Since the viral vectors are identical, it is possible to compare the oncogenic potential of the ras genes directly. The normal (12 gly) form of chicken c-Ha-ras is not oncogenic in vivo, nor does high-level expression transform CEF. Expression of murine v-ras or modified forms of chicken c-Ha-ras with either lysine or glutamine at position 12 transforms CEF and causes tumors in birds. However, the oncogenic potential of the transforming ras genes is different; the viruses that express the genes with lysine and glutamine at position 12 cause a distinct spectrum of tumors.

Animals↗
PubMed2001

Gene transfer into neurons from hippocampal slices: comparison of recombinant Semliki Forest Virus, adenovirus, adeno-associated virus, lentivirus, and measles virus.

Viral vectors are useful for transferring genes into neurons. Here, we characterized recombinant Semliki Forest virus (SFV), adenovirus type 5 (Ad5), adeno-associated virus type 2 (AAV), lentivirus, and measles virus (MV) by their expression of green fluorescent protein (GFP) in rat hippocampal slice cultures. SFV infected more neurons (>90% of all GFP-positive cells) than AAV, lentivirus, and MV (71, 69, and 62%, respectively), whereas no infected neurons were identified with Ad5. AAV-mediated GFP expression was neuron-specific when the platelet-derived growth factor beta-chain promoter rather than cytomegalovirus promoter was used. Transgene expression occurred rapidly but transiently for SFV, increased slowly but remained stable with AAV and lentivirus, and was fast with MV. Resting membrane potential and conductance, action potentials, firing accommodation, and H-current appeared normal in infected CA1 pyramidal cells. Thus, SFV is useful for short-term and AAV and lentivirus for long-term transduction of hippocampal slices, while MV constitutes a novel vector.

Adenoviridae↗
PubMed2000

Genetic engineering of herpes simplex virus and vector genomes carrying loxP sites in cells expressing Cre recombinase.

The prokaryotic Cre-loxP recombination system is a powerful tool that enables in vitro and in vivo site-specific manipulations of the genome of eukaryotic cells as well as of DNA viruses and their derived vectors. This system, however, has not yet been exploited in the context of herpes simplex virus type 1 (HSV-1) infected cells, perhaps because this virus encodes several functions that induce a strong shutoff of cellular protein synthesis, a fact that could preclude expression of cellular-encoded Cre recombinase. In the present study, we show that efficient site-specific recombination can take place in cell lines expressing Cre, even in the context of HSV-1 infection, as evidenced by the engineering of an HSV-1 recombinant virus and several viral vectors carrying one or two loxP sequences. More precisely, we have used this system to induce an irreversible switch in the expression of a viral complex transcription unit encoding two different open reading frames and allowing consecutive expression of two reporter genes. Furthermore Cre recombinations were also used to induce the decatenation of the genomic concatemers harbored by amplicon particles upon infection of cells under nonreplicative conditions, thus enabling the rescue of many independent plasmids corresponding to the original amplicon plasmid used to generate the vectors. Thus the Cre-loxP recombination system can successfully be used for engineering the genome of HSV-1 or HSV-1-based vectors in cultured cells.

Animals↗
PubMed2001

Assessment of recombinants that arise from the use of a TMV-based transient expression vector.

A potential use of virus-based transient expression vectors is the large-scale production of commercial specialty products, which would require the inoculation of many acres of plants with the viral vector. However, there are several concerns about the widespread use of virus-based vectors. Among these are the spread of the engineered virus to susceptible plants and the generation and persistence of recombinant viruses in the environment. Using a Tobacco mosaic virus (TMV)-based transient gene expression vector, 30B, which expresses the jellyfish green fluorescent protein (30B-GFP), we describe the predominant types of hybrid viruses that developed in plants. In general, the recombinants deleted the foreign gene and repeated sequences, retaining only those sequences required for optimal replication and movement. In pathogenicity studies and challenge experiments designed to make a comparative assessment of the competitiveness of the recombinants with the parent virus, the recombinants had reduced vigor and were less competitive and pathogenic than TMV, a virus which is already present in the areas where tobacco is grown.

Animals↗
PubMedDate not supplied

Endothelium-specific expression of an E-selectin promoter recombinant adenoviral vector.

BACKGROUND: E-selectin expression is very low in normal adult blood vessels, but is significantly elevated in newly formed tumor capillaries. We hypothesized that a viral vector which has transcriptional specificity for the tumor vasculature may be a tool for angiogenesis-targeted gene therapy. We therefore designed an adenoviral vector which would only be expressed in cells that transcribe the E-selectin gene. MATERIALS AND METHODS: The E-selectin promoter was inserted into an adenoviral vector driven by the luciferase reporter gene. The resulting AdV-Esel-Luc vector was then used to transduce endothelial cells as well as other cell types, and luciferase activity measured with a luminometric assay. RESULTS: Exposure of transduced endothelial cells to TNF-alpha (tumor necrosis factor-alpha), a known inducer of the E-selectin promoter, generated a 30-fold increase in luciferase expression compared to untreated cells (p = 0.01). Endothelial cells cultured in tumor conditioned media as an in vitro recreation of the tumor environment resulted in even higher induction of luciferase (p = 0.0001). Furthermore, many non-endothelial cell lines expressed minimal levels of luciferase when transduced with the AdV-Esel-Luc vector under identical conditions. CONCLUSIONS: We conclude that the E-selectin promoter can be used in order to confer transcriptional specificity to an adenoviral vector. This transcriptional specificity may in the future enable us to deliver the specific expression of therapeutic genes to the tumor vasculature.

Adenoviridae↗
PubMed2001

Isolation, characterization, and recovery of small peptide phage display epitopes selected against viable malignant glioma cells.

Phage display techniques rely on nearly random oligonucleotide sequences inserted into the protein III filament binding protein of an Escherichia coli filamentous phage M13 to generate a library of phage that express more than 10(7) different peptides. Phage that expresses a sequence having high affinity for a specific molecule, cell, or tissue can then be isolated through selective binding and recovery. Selected phage cannot only be used as gene transfer vectors in themselves, but the small peptide epitopes can be sequenced and potentially recombined into the attachment proteins of viral vectors, or used by themselves to target other therapeutic agents and diagnostic imaging radiolabels. Most phage display selections are carried out against purified and/or fixed protein targets, raising concerns as to the relevance of the selected epitopes. We have selected phage from the CMTI library against viable U87-MG human malignant glioma cells using a derivation of biopanning. The library, which initially contained phage expressing 2x10(7) different epitope sequences, collapsed after four rounds of selection such that 42% of recovered clones expressed a consensus sequence. Selective binding to viable adherent U87-MG cells was subsequently demonstrated under physiologic conditions at 167% (+/-27%) unselected phage using a novel, viable enzyme-linked immunosorbent assay technique. In comparison, there was no difference in binding to control 9L rat gliosarcoma, PANC-1 human pancreatic adenocarcinoma, T98-MG human malignant glioma, or AST-4 human malignant glioma cells of selected compared to unselected phage. Using polymerase chain reaction, the epitope was recovered with flanking unique restriction sites for recombination into a herpes simplex virus type-1 vector. This study demonstrates and discusses optimized methodologies for using phage display to target viable cells.

Amino Acid Sequence↗
PubMed2002

Induction of cyclo-oxygenase-2 in non-small cell lung cancer cells by infection with DeltaE1, DeltaE3 recombinant adenovirus vectors.

Infection of epithelial-derived cells by adenovirus vectors has myriad effects on cellular behavior and function. Some are relevant to the desired effect of the encoded transgene and therapeutic goals of gene therapy approach. The current experiments describe the induction of COX-2 protein and PGE-2 production by non-small cell lung cancer (NSCLC) cells following infection with a first generation (DeltaE1, DeltaE3) Ad vector. COX-2 overexpression by malignant cells has been shown to enhance cellular invasion, induce angiogenesis, regulate anti-apoptotic cellular defenses and augment immunologic resistance through production of PGE-2. Data show DeltaE1, DeltaE3, Ad5 vector infection induces dose-dependent increases in PGE-2 production by NSCLC cell lines. Data with UV/psoralen inactivated vectors and control vectors show this effect is dependent on Ad vector gene expression, but independent of the transgene expressed. Selective blockade of ERK with PD98029 abrogated induction of PGE-2 by Ad vectors. Consistent with these data, detectable increases in COX-2 protein were seen at 48 h after infection by Western blot that were paralleled by increases in the phosphorylation of ERK-1/2. UV/psoralen-inactivated vector did not induce COX-2 protein or ERK phosphorylation at 48 h. Further, an inhibitor of NF-kappa B (NFkappaB) translocation to the nucleus, SN50, had no effect on PGE-2 levels. In contrast, Ad vector infection did induce NFkappaB activity measured by NFkappaB-luciferase reporter plasmid, transfected into a NSCLC cell line. Collectively the data indicate DeltaE1, DeltaE3, Ad5 vector infection leads to ERK phosphorylation with parallel increases in COX-2 protein and PGE-2 production. These effects appear unrelated to NFkappaB and are dependent on gene expression by the vector. This information may need to be considered when defining targets for cancer gene therapy and/or the choice of viral vector.

Adenoviridae↗
PubMed2000

Transcription factor ERG variants and functional diversification of chondrocytes during limb long bone development.

During limb development, chondrocytes located at the epiphyseal tip of long bone models give rise to articular tissue, whereas the more numerous chondrocytes in the shaft undergo maturation, hypertrophy, and mineralization and are replaced by bone cells. It is not understood how chondrocytes follow these alternative pathways to distinct fates and functions. In this study we describe the cloning of C-1-1, a novel variant of the ets transcription factor ch-ERG. C-1-1 lacks a short 27-amino acid segment located approximately 80 amino acids upstream of the ets DNA binding domain. We found that in chick embryo long bone anlagen, C-1-1 expression characterizes developing articular chondrocytes, whereas ch-ERG expression is particularly prominent in prehypertrophic chondrocytes in the growth plate. To analyze the function of C-1-1 and ch-ERG, viral vectors were used to constitutively express each factor in developing chick leg buds and cultured chondrocytes. We found that virally driven expression of C-1-1 maintained chondrocytes in a stable and immature phenotype, blocked their maturation into hypertrophic cells, and prevented the replacement of cartilage with bone. It also induced synthesis of tenascin-C, an extracellular matrix protein that is a unique product of developing articular chondrocytes. In contrast, virally driven expression of ch-ERG significantly stimulated chondrocyte maturation in culture, as indicated by increases in alkaline phosphatase activity and deposition of a mineralized matrix; however, it had modest effects in vivo. The data show that C-1-1 and ch-ERG have diverse biological properties and distinct expression patterns during skeletogenesis, and are part of molecular mechanisms by which limb chondrocytes follow alternative developmental pathways. C-1-1 is the first transcription factor identified to date that appears to be instrumental in the genesis and function of epiphyseal articular chondrocytes.

Alkaline Phosphatase↗
PubMed2002

Dose-dependent neuroprotective effect of ciliary neurotrophic factor delivered via tetracycline-regulated lentiviral vectors in the quinolinic acid rat model of Huntington's disease.

The ability to regulate gene expression constitutes a prerequisite for the development of gene therapy strategies aimed at the treatment of neurologic disorders. In the present work, we used tetracycline (Tet)-regulated lentiviral vectors to investigate the dose-dependent neuroprotective effect of human ciliary neurotrophic factor (CNTF) in the quinolinic acid (QA) model of Huntington's disease (HD). The Tet system was split in two lentiviruses, the first one containing the CNTF or green fluorescent protein (GFP) cDNAs under the control of the Tet-response element (TRE) and a second vector encoding the transactivator (tTA). Preliminary coinfection study demonstrated that 63.8% +/- 2.0% of infected cells contain at least two viral copies. Adult rats were then injected with CNTF- and GFP-expressing viral vectors followed 3 weeks later by an intrastriatal administration of QA. A significant reduction of apomorphine-induced rotations was observed in the CNTF-on group. In contrast, GFP-treated animals or CNTF-off rats displayed an ipsilateral turning behavior in response to apomorphine. A selective sparing of DARPP-32-, choline acetyltransferase (ChAT)-, and NADPH-d-positive neurons was observed in the striatum of CNTF-on rats compared to GFP animals and CNTF-off group. Enzyme-linked immunosorbent assay (ELISA) performed on striatal samples of rats sacrificed at the same time point indicated that this neuroprotective effect was associated with the production of 15.5 +/- 4.7 ng CNTF per milligram of protein whereas the residual CNTF expression in the off state (0.54 +/- 0.02 ng/mg of protein) was not sufficient to protect against QA toxicity. These results establish the proof of principle of neurotrophic factor dosing for neurodegenerative diseases and demonstrate the feasibility of lentiviral-mediated tetracycline-regulated gene transfer in the brain.

Animals↗
PubMed1996

Cytokine production by cultured human bronchial epithelial cells infected with a replication-deficient adenoviral gene transfer vector or wild-type adenovirus type 5.

Exposure of animals to adenoviral gene transfer vectors has been associated with respiratory tract inflammation. The pathogenesis of this inflammation is unclear. One hypothesis is that viral vectors directly induce production of inflammatory cytokines by host cells in the airways. We exposed cultured human lung cells to an adenovirus-5--based vector containing the cytomegalovirus promoter and lacZ reporter gene (Ad.CMV.lacZ) and to wild-type adenovirus 5 (wtAd5) and measured subsequent release of cytokines into cell culture supernatants. Inoculation of human bronchial epithelial (HBE) cells with Ad.CMV. lacZ at 10(1) to 10(4) plaque-forming units (pfu)/cell resulted in dose-related expression of lacZ by both X-gal staining and immunohistochemistry but did not increase release of interleukin (IL)-8 or IL-6 at 24, 48, or 96 h after inoculation. In the same cultures, tumor necrosis factor-alpha induced marked increases in release of both IL-8 and IL-6 at 24 and 48 h after stimulation. Similar data were observed in the BEAS-2B HBE cell line. HBE cells incubated with wtAd5 at doses of 10(1) to 10(3) pfu/cell did not release increased amounts of IL-6 or IL-8 up to 48 h after inoculation, though wild-type respiratory syncytial virus (3 pfu/HBE cell) infection resulted in increases in both cytokines. Human alveolar macrophages obtained by bronchoalveolar lavage also showed no increases in cytokine release after incubation with Ad.CMV.lacZ, though relatively little gene transfer occurred in macrophages. These data do not support a role for direct induction of airway epithelial or alveolar macrophage inflammatory cytokines in the pathogenesis of inflammation associated with exposure of airways to adenovirus or to adenoviral gene transfer vectors.

Adenoviruses, Human↗