Molecular basis of the inflammatory response to adenovirus vectors

Liu, Q; Muruve, Daniel A.

doi:10.1038/sj.gt.3302036

Cited by 391 publications

(291 citation statements)

References 49 publications

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“…10 A large body of evidence suggests that virus capsid proteins alone are responsible for induction of the acute phase of the immune response. 11 The second phase of the immune response begins 5-7 days after administration of vector and is directed against newly transduced cells. Adenovirusspecific major histocompatibility complex (MHC) class I-restricted CD8 + T cells directed against cells expressing viral genes and transgene products are generated.…”

Section: Introductionmentioning

confidence: 99%

PEGylated helper-dependent adenoviral vectors: highly efficient vectors with an enhanced safety profile

et al. 2005

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Transgene expression from helper-dependent adenoviral (HD-Ad) vectors is effective and long lasting, but not permanent. Their use is also limited by the host response against capsid proteins that precludes successful gene expression upon readministration. In this report, we test the hypothesis that PEGylation of HD-Ad reduces its toxicity and promotes transgene expression upon readministration. PEGylation did not compromise transduction efficiency in vitro and in vivo and reduced peak serum IL-6 levels two-fold. IL-12 and TNF-a levels were reduced three-and sevenfold, respectively. Thrombocytopenia was not detected in mice treated with the PEGylated vector. Serum transaminases were not significantly elevated in mice treated with either vector. Mice immunized with 1 Â 10 11 particles of unmodified HD-Ad expressing human alpha-1 antitrypsin (hA1AT) were rechallenged 28 days later with 8 Â 10 10 particles of unmodified or PEG-conjugated vector expressing beta-galactosidase. Trace levels of beta-galactosidase (52.23719.2 pg/mg protein) were detected in liver homogenates of mice that received two doses of unmodified HDAd. Mice rechallenged with PEGylated HD-Ad produced significant levels of beta-galactosidase (5.170.4 Â 10 5 pg/mg protein, P ¼ 0.0001). This suggests that PEGylation of HD-Ad vectors may be appropriate for their safe and efficient use in the clinic. Gene Therapy (2005) 12, 579-587.

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Section: Introductionmentioning

confidence: 99%

PEGylated helper-dependent adenoviral vectors: highly efficient vectors with an enhanced safety profile

et al. 2005

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“…The underlying reasons for this will require further investigation, but it is possible that the ability of adenovirus type-5 vectors to elicit potent innate immune responses and local inflammatory reactions, which are essential in initiating primary immune responses, plays a role in this process [64][65][66].…”

Section: Discussionmentioning

confidence: 99%

HSV-1 amplicon vectors elicit polyfunctional T cell responses to HIV-1 Env, and strongly boost responses to an adenovirus prime

Duke

Maguire

Keefer

et al. 2007

Vaccine

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HSV-1 amplicon vectors elicit strong T-cell responses to encoded antigens but the qualitative nature of these responses is poorly understood. Antigen-specific CD4 + and CD8 + T-cell responses to amplicon and adenovirus (rAd5) vectors encoding HIV-1 gp120 were assessed following immunization of mice, by performing intracellular cytokine staining for IFNγ, IL-2 and TNFα, following stimulation of splenocytes with a HIV-1 Env peptide pool. The quality of the primary Tcell response to amplicon and rAd5 vectors was strikingly similar, but there were qualitative differences in responses to amplicon vectors that incorporated different promoters upstream of gp120 -suggesting that promoters can significantly influence immune response quality. When prime-boost combinations were studied, a rAd5 prime and amplicon boost elicited the highest T-cell response. Furthermore, protocols that incorporated a rAd5 prime consistently elicited a greater proportion of polyfunctional CD4 + T-cells -regardless of boost. This suggests that initial priming can shape immune response quality after a boost. Overall, these findings provide insight into effective vector combinations for HIV-1 vaccine development.

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“…This finding may have important implications for in vivo applications of adenoviral vectors, given that antivector immune response has been a major obstacle for adenoviral gene therapy. 6,7 Furthermore, the enhanced gene expression will only take place in tissue exposed to light, and thus the light treatment increases the specificity of the virus improving the therapeutic index. The PCI technology has already been implemented in animal models, and promising results have been obtained combining photochemical treatment with gelonin, a type I ribosomal-inactivating protein, 43 implying that the combination of adenoviral vectors and photochemical treatment has the potential to be successful in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…However, clinical studies have revealed that limiting factors are immune response in humans and the large number of viral particles needed to obtain therapeutic effect. 6,7 A major concern is therefore that the adenovirus dose necessary to achieve therapeutic effectiveness, may be difficult to obtain with acceptable systemic toxicity. A multimodality treatment combining adenoviral gene therapy with other therapeutic approaches such as radiation, 8 immunotherapy or photochemical treatment, as described in this paper, may be critical in achieving clinical success.…”

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confidence: 99%

PCI-enhanced adenoviral transduction employs the known uptake mechanism of adenoviral particles

et al. 2005

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The development of methods for efficient and specific delivery of therapeutic genes into target tissues is an important issue for further development of in vivo gene therapy. In the present study, the physical targeting technique, photochemical internalization (PCI), has been used together with adenovirus. The combination of PCI and adenoviral transduction has previously been shown to be favorable compared to adenovirus used alone, and the aim of this study was to verify the role of the adenoviral receptors and identify the uptake pathway used by adenoviral particles in photochemically treated cells. All examined cell lines showed augmented transduction efficiency after PCI-treatment, with a maximum of 13-fold increase in transgene expression compared to conventionally infected cells. Blocking of CAR induced a complete inhibition of PCI-enhanced transgene expression. However, photochemical treatment managed to enhance the transduction efficiency of the retargeted virus AdRGD-GFP showing also that the virus-CAR interaction is not vital for obtaining a photochemical effect on adenoviral transduction. Blocking the a V -integrins reduced the gene expression significantly in photochemically treated cells. Subjecting HeLa cells expressing negative mutant-dynamin to light treatment after infection gave no significant increase in gene transfer, while the gene transfer were enhanced seven-fold in cells with wild-type dynamin. Furthermore, chlorpromazine inhibited photochemical transduction in a dose-dependent manner, whereas Filipin III had no effect on the gene transfer. In summary, the data presented imply that adenoviral receptor binding is important and clathrin-mediated endocytosis is the predominant uptake mechanism for adenoviral particles in photochemically treated cells.

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Molecular basis of the inflammatory response to adenovirus vectors

Cited by 391 publications

References 49 publications

PEGylated helper-dependent adenoviral vectors: highly efficient vectors with an enhanced safety profile

PEGylated helper-dependent adenoviral vectors: highly efficient vectors with an enhanced safety profile

HSV-1 amplicon vectors elicit polyfunctional T cell responses to HIV-1 Env, and strongly boost responses to an adenovirus prime

PCI-enhanced adenoviral transduction employs the known uptake mechanism of adenoviral particles

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