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Query: UMLS:C0001486 (Adenovirus)
 3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenovirus binds to its receptor via the head domain of its fiber protein. We have crystallized the adenovirus serotype 2 (subgroup C) receptor binding domain and solved the structure at 1.5 A resolution by the molecular replacement technique using the known adenovirus type 5 head structure. Included in the high-resolution model are 306 water molecules, five alternative side chain conformations, and individual anisotropic temperature factors for each atom. The overall structure of the serotype 2 head is very similar to its serotype 5 homologue, apart from differences in some of the flexible loops. All but subgroup B adenoviruses are believed to use the recently identified protein CAR (Coxsackievirus and adenovirus receptor) as receptor. By comparison of the two structures and sequence alignment of CAR binding and non-CAR binding serotype fiber heads, we discuss possible receptor binding sites and propose a receptor binding site in a crevice between two monomers on the side of the trimer. The structural basis of the extraordinary stability of the fiber head trimer is also discussed.
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PMID:Structure of the human adenovirus serotype 2 fiber head domain at 1.5 A resolution. 1050 12

Adenovirus infection requires that the virus attach to cells and be internalized. Interaction between the viral fiber protein and specific cell surface receptors, such as the 46-kDa coxsackievirus and adenovirus receptor (CAR), is responsible for attachment; a second interaction between the viral penton base and cell surface integrins facilitates virus internalization. Expression of receptors may determine whether tissues are susceptible to adenovirus infection and adenovirus-mediated gene delivery.
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PMID:Receptors mediating adenovirus attachment and internalization. 1079 67

Adenovirus vectors have been used to transfer genes into both hematopoietic progenitor cells and tumor cells, including carcinoma cells that have metastasized to bone marrow (BM). However, the relative susceptibility of different subsets of hematopoietic cells is unknown. In permissive cells adenoviral-mediated gene transfer is mediated by the coxsackievirus and adenovirus receptor (CAR) protein and alpha(v) integrins expressed on the cell surface of the target cells. This prompted us to investigate the expression of CAR on subpopulations of hematopoietic cells, determine whether this protein played a role in adenovirus-mediated gene transfer of hematopoietic cells and whether we could modulate CAR to enhance gene transfer efficiency. In this report we show that CAR is expressed on approximately 40% of all human BM cells, including erythroid and myeloid cells, but not lymphoid cells. Of the CD34(+) cells, 10%-15% expressed CAR, but this did not include most colony-forming progenitor cells, nor the most primitive CD38(-) subpopulation. The presence of CAR correlated well with gene transfer efficiency, but we were unable to induce CAR expression on immature, noncommitted progenitor cells. In conclusion, our results show that primitive hematopoietic progenitor cells lack CAR expression, but that expression is acquired during erythroid and myeloid differentiation.
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PMID:Maturation and lineage-specific expression of the coxsackie and adenovirus receptor in hematopoietic cells. 1084 70

Recombinant adenovirus is used as a competent vector in a wide spectrum of cancer gene therapies. Adenovirus infection depends on coxsackievirus and adenovirus receptor (CAR)-mediated virus attachment to the cell surface. However, the expression levels of CAR and the efficiency of adenoviral gene transduction in musculoskeletal tumors have not been systematically investigated. To study the feasibility of gene therapy in musculoskeletal tumors, the expression levels of CAR and the antiproliferative effect of an adenovirally transduced wild-type p53 tumor suppressor gene were examined in 15 distinct musculoskeletal tumor cell lines, 19 tumor tissue samples, and the corresponding pathologically unremarkable mesenchymal tissues. The expression levels of the CAR gene were significantly higher in six of seven osteosarcoma cell lines and two of five osteosarcoma tissue samples than in the other cell lines, musculoskeletal tumors, and mesenchymal tissues. CAR expression levels were closely correlated with adenoviral gene transduction efficiency and the antiproliferative effect of a transduced adenoviral p53 gene in the tested cell lines. In addition, an immunocytochemical study confirmed that transfected green fluorescent protein (GFP) borne by Ad-CAG-GFP was expressed at the cell surface of CAR-positive cells. These results indicate that CAR expression is a critical determinant of transduction efficiency in adenovirus-based gene therapy. Most osteosarcomas appeared to express high levels of CAR, and thus adenovirus-mediated p53 gene therapy is likely to be suitable for the treatment of such tumors.
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PMID:Expression of the coxsackievirus and adenovirus receptor in musculoskeletal tumors and mesenchymal tissues: efficacy of adenoviral gene therapy for osteosarcoma. 1270 77

Adenovirus vectors are expected to be a powerful tool for gene therapy to treat severe fractures. Adenovirus invades cells through binding to the coxsackievirus and adenovirus receptor (CAR) on the cell membrane. CAR expression is low in normal adult animals, but it is induced on regenerating cells in some experimental models. We made a rib fracture model in mice and evaluated the histological changes and CAR mRNA expression by RT-PCR 1, 5, 10, 14, and 21 days after the fracture. CAR mRNA was expressed exclusively in the fractured ribs at each time point, but not in the normal ribs. We detected the CAR protein immunohistochemically in fibroblast-like cells in the fracture callus on days 10 and 14 after fracture. In situ hybridization showed that these fibroblast-like cells expressed mRNA of type I collagen and osteopontin, but not osteocalcin, defining the cells as immature osteoblasts. We then transferred small doses (10(4)-10(8) PFU) of lacZ-expressing adenovirus vector into immature osteoblasts on day 14. beta-galactosidase was detected only on the immature osteoblasts at every dose. Immature osteoblasts play an important role in the matrix replacement step in fracture healing. CAR-mediated gene transfer into immature osteoblasts can be reasonable for adenovirus-mediated treatment of fracture healing.
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PMID:Coxsackievirus and adenovirus receptor (CAR)-positive immature osteoblasts as targets of adenovirus-mediated gene transfer for fracture healing. 1290 55

Coxsackievirus B is the most common cause of viral myocarditis and is particularly virulent in neonates and children. Adenovirus is also a leading cause of the disease. The determinant of tropism for both viruses is considered to be the expression of coxsackievirus and adenovirus receptor (CAR) in target organs. However, developmental change and physiological localization of CAR in the heart are unknown. We examined expression levels of CAR in rat hearts by quantitative real-time polymerase chain reaction and Western blot analysis and found that CAR decreased gradually during postnatal development, although CAR was detectable, even in adults. Immunohistochemistry revealed CAR on the whole surface of cardiomyocytes in immature rat hearts. In contrast, CAR was detected predominantly on intercalated disks in the adult heart and was accumulated especially at the contact point between the cultured cardiomyocytes, even though they were prepared from the neonatal rat heart. In conclusion, CAR was expressed abundantly on the whole surface of cardiomyocytes in immature rat hearts. Both the expression level and the localization of CAR are possible determinants of the susceptibility to viral myocarditis of neonates and children.
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PMID:Spatiotemporal changes of coxsackievirus and adenovirus receptor in rat hearts during postnatal development and in cultured cardiomyocytes of neonatal rat. 1462 62

Most adenoviral vectors use in gene therapy protocols derive from species C. However, expression of the primary receptor (human Coxsackievirus and Adenovirus receptor, hCAR) for these AdV is variable on cancer cells. In vivo targeting of a therapeutic gene to specific cells has then become a major issue in gene therapy. The Ad fiber protein largely determines viral tropism through interaction with specific receptors. Hereto, we constructed a set of HAdV5 vectors carrying chimeric fibers with knob domains from nonhuman AdV, namely from the FAdV-1 (Aviadenovirus), DAdV-1, and BAdV-4 (Atadenovirus). Correspondents viruses were produced using an established new HEK293 cell line, which express the HAdV2 fiber. Recombinant HAdV harboring chimeric fibers constituted of the N-terminal domain of HAdV2, and knob domain of bovine adenovirus type 4 (BAdV-4) demonstrated the greatest reduction in fiber-mediated gene transfer into human cells expressing the hCAR. Moreover, this vector infects with a better efficiency than vector with wild-type fiber, the Chinese Hamster Ovarian (CHO) and SKOV3 cell lines, both from ovarian origin, hamster and human, respectively. These studies support the concept that changing the fiber knob domain to ablate hCAR interaction should result in a de- or retargeted adenoviral vector. The adenoviral vector with the chimeric HAdV2/BAdV-4 fiber lacking hCAR interaction and with an ovarian cell tropism could be a nice candidate to elaborate vectors for ovarian tumor therapy.
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PMID:Abolition of hCAR-dependent cell tropism using fiber knobs of Atadenovirus serotypes. 1505 80

Adenovirus and reovirus are nonenveloped viruses that engage cell-surface receptors using filamentous attachment proteins with head-and-tail morphology. The coxsackievirus and adenovirus receptor (CAR) and reovirus receptor junctional adhesion molecule 1 (JAM1) are immunoglobulin superfamily members that form homodimers stabilized by ionic and hydrophobic contacts between their N-terminal immunoglobulin-like domains. Both proteins are expressed at regions of cell-cell contact and contain sequences in their cytoplasmic tails that anchor the proteins to the actin cytoskeleton. Like CAR and JAM1, the attachment proteins of adenovirus and reovirus, fiber and sigma1, respectively, also share key structural features. Both fiber and sigma1 have defined regions of flexibility within the tail, which is constructed in part using an unusual triple beta-spiral motif. The head domains of both proteins are formed by an 8-stranded beta-barrel with identical beta-strand connectivity. Strikingly, both adenovirus fiber and reovirus 1 engage their receptors by interacting with sequences that also mediate formation of receptor homodimers. Therefore, while adenovirus and reovirus belong to different virus families and have few overall properties in common, the observed similarities between the receptors and attachment proteins of these viruses suggest a conserved mechanism of attachment and an evolutionary relationship.
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PMID:Structural similarities in the cellular receptors used by adenovirus and reovirus. 1527 94

Adenovirus-based (Ad) vectors are used widely for experimental gene transfer to the CNS. Ad transduce many cell types including postmitotic neurons. However, their use for CNS gene transfer is limited due to the host immune response elicited. Furthermore, the extensive distribution of the primary cellular receptor for Ad, the coxsackievirus and adenovirus receptor (CAR), allows adenoviral vectors to infect a broad range of host cells which may be disadvantageous in tissues with various different cell types, like the CNS. The use of tissue-specific promoters allows for neuron-restricted gene expression, even though gene expression driven by these promoters is often very weak. Accordingly, increased transgene expression levels from viral transcription units are needed in order to improve the overall performance of Ad vectors. We designed a high-capacity Ad vector (HC-Ad) that allows for high-level, neuron-restricted transgene expression and shows no obvious signs of immunogenicity or toxicity in the mouse brain.
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PMID:Improved high-capacity adenoviral vectors for high-level neuron-restricted gene transfer to the CNS. 1667 63

Adenovirus-mediated gene therapy for hematopoietic malignancies, especially those derived from B cells, is difficult due to systemic nature of these diseases. More importantly, most tumor cells derived from B cell lineage express a very low level of the adenovirus receptor hCAR; thus, warranting the design of adenoviral vectors with high affinity to abundant B cell surface molecules. To mimic this approach and to test the validity of adenoviral vectors in gene therapy of disseminated malignancies, we created an hCAR-expressing follicular lymphoma B cell line. The cell line was generated with the aid of a lentivirus vector carrying a novel fusion gene with EGFP replacing the cytoplasmic domain of hCAR. After verifying that this cell line was expressing the hybrid receptor in a correct manner and enrichment of the bright EGFP positive population, the cells were transduced with adenoviruses expressing the red fluorescent protein DsRed2. It was shown that regular transduction with a low viral dose (1 pfu/cell) increased the gene transfer rate by a factor of 5. Furthermore, experiments with adenovirus vector carrying the HSV-TK-GFP transgene demonstrated that the modified follicular lymphoma B cells became sensitive to ganciclovir while the parental cells remained virtually resistant to this form of gene therapy. In summary, we show here with this simple model system that adenoviral gene therapy of B cell malignancies is possible provided that correct receptors for adenovirus attachment are present on the surface of the target cells. Thus, our results warrant further modifications of adenovirus capsid to obtain vectors with specific affinity to B cell epitopes.
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PMID:hCAR-EGFP fusion receptor in human follicular lymphoma B cells - a model for adenoviral gene therapy for B cell malignancies. 1668 16


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