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Different modulation of cellular transcription by Adenovirus 5, DeltaE1/E3 Adenovirus and helper-dependent vectors.

One problem encountered in the use of adenoviral vectors for gene therapy is their toxicity. Although many studies have analyzed this question in vivo, few researches have investigated Adenovirus vector effects at the cellular level using a large-scale approach. In particular, no such data are available for helper-dependent Adenovirus vectors (HD), which are promising Adenovirus vectors for clinical applications since they are devoid of all viral genes and can host large transgene cassettes. The present study used gene chips to examine (Affymetrix HG-U95Av2 interrogating 12,626 unique human transcripts) the effect on liver cells of HD vectors versus that of DeltaE1/E3 Adenovirus vector and wild type Adenovirus (Ad5). The effects of the DeltaE1/E3 Adenovirus and of HD vectors were comparable, and significantly milder than that of Ad5. Interestingly the expression signatures of DeltaE1/E3 Adenovirus and HD vectors were non-overlapping both at the single gene and the pathway level, suggesting specific and different interactions between the host cell and the two gene therapy vectors.

Different modulation of cellular transcription by Adenovirus 5, ΔE1/E3 Adenovirus and helper-dependent vectors

One problem encountered in the use of adenoviral vectors for gene therapy is their toxicity. Although many studies have analyzed this question in vivo, few researches have investigated Adenovirus vector effects at the cellular level using a large-scale approach. In particular, no such data are available for helper-dependent Adenovirus vectors (HD), which are promising Adenovirus vectors for clinical applications since they are devoid of all viral genes and can host large transgene cassettes. The present study used gene chips to examine (Affymetrix HG-U95Av2 interrogating 12,626 unique human transcripts) the effect on liver cells of HD vectors versus that of ΔE1/E3 Adenovirus vector and wild type Adenovirus (Ad5). The effects of the ΔE1/E3 Adenovirus and of HD vectors were comparable, and significantly milder than that of Ad5. Interestingly the expression signatures of ΔE1/E3 Adenovirus and HD vectors were non-overlapping both at the single gene and the pathway level, suggesting specific and different interactions between the host cell and the two gene therapy vectors.

combined cd8 and cd4 Adenovirus hexon specific t cells associated with viral clearance after stem cell transplantation as treatment for Adenovirus infection

Background Human Adenovirus can cause morbidity and mortality in immunocompromised patients after allogeneic stem cell transplantation. Reconstitution of Adenovirus-specific CD4+ T cells has been reported to be associated with sustained protection from Adenovirus disease, but epitope specificity of these responses has not been characterized. Since mainly CD4+ T cells and no CD8+ T cells specific for Adenovirus have been detected after allogeneic stem cell transplantation, the relative contribution of Adenovirus-specific CD4+ and CD8+ T cells in protection from Adenovirus disease remains to be elucidated.

Design and Methods The presence of human Adenovirus hexon-specific T cells was investigated in peripheral blood of pediatric and adult allogeneic stem cell transplant recipients, who showed spontaneous resolution of disseminated Adenovirus infection. Subsequently, a clinical grade method was developed for rapid generation of Adenovirus-specific T-cell lines for adoptive immunotherapy.

Results Clearance of human Adenovirus viremia coincided with emergence of a coordinated CD8+ and CD4+ T-cell response against Adenovirus hexon epitopes in patients after allogeneic stem cell transplantation. Activation of Adenovirus hexon-specific CD8+ and CD4+ T cells with a hexon protein-spanning peptide pool followed by interferon-γ-based isolation allowed rapid expansion of highly specific T-cell lines from healthy adults, including donors with very low frequencies of Adenovirus hexon-specific T cells. Adenovirus-specific T-cell lines recognized multiple MHC class I and II restricted epitopes, including known and novel epitopes, and efficiently lysed human Adenovirus-infected target cells.

Conclusions This study provides a rationale and strategy for the adoptive transfer of donor-derived human Adenovirus hexon-specific CD8+ and CD4+ T cells for the treatment of disseminated Adenovirus infection after allogeneic stem cell transplantation.

cd46 is a cellular receptor for all species b Adenoviruses except types 3 and 7

The 51 human Adenovirus serotypes are divided into six species (A to F). Adenovirus serotypes from all species except species B utilize the coxsackie-Adenovirus receptor for attachment to host cells in vitro. Species B Adenoviruses primarily cause ocular and respiratory tract infections, but certain serotypes are also associated with renal disease. We have previously demonstrated that Adenovirus type 11 (species B) uses CD46 (membrane cofactor protein) as a cellular receptor instead of the coxsackie-Adenovirus receptor (A. Segerman et al., J. Virol. 77:9183-9191, 2003). In the present study, we found that transfection with human CD46 cDNA rendered poorly permissive Chinese hamster ovary cells more permissive to infection by all species B Adenovirus serotypes except Adenovirus types 3 and 7. Moreover, rabbit antiserum against human CD46 blocked or efficiently inhibited all species B serotypes except Adenovirus types 3 and 7 from infecting human A549 cells. We also sequenced the gene encoding the fiber protein of Adenovirus type 50 (species B) and compared it with the corresponding amino acid sequences from selected serotypes, including all other serotypes of species B. From the results obtained, we conclude that CD46 is a major cellular receptor on A549 cells for all species B Adenoviruses except types 3 and 7.