Adenovirus Vector Toxicity

Harmon, Andrew W.; Byrnes, Andrew P.

doi:10.1007/978-3-319-53457-2_3

Cited by 9 publications

(6 citation statements)

References 139 publications

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“…Administration concentrations were established to ensure safety as a high dose of adenoviral vector can induce toxicity by eliciting rapid innate responses. 30 Excessive administration of IFNλ activates the p53 pathway, inhibiting cell growth and suppressing re-epithelialization, which could lead to side effects related to secondary bacterial infections. 31,32 However, the rAd-huIFNλ4 used in this study elicits an antiviral effect at a concentration that does not induce an increase in p53.…”

Section: Discussionmentioning

confidence: 99%

Antiviral activity of adenoviral vector expressing human interferon lambda‐4 against influenza virus

Kim,

Lim

et al. 2024

Journal of Medical Virology

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Interferon lambda (IFNλ), classified as a type III IFN, is a representative cytokine that plays an important role in innate immunity along with type I IFN. IFNλ can elicit antiviral states by inducing peculiar sets of IFN‐stimulated genes (ISGs). In this study, an adenoviral vector expression system with a tetracycline operator system was used to express human IFNλ4 in cells and mice. The formation of recombinant adenovirus (rAd‐huIFNλ4) was confirmed using immunohistochemistry assays and transmission electron microscopy. Its purity was verified by quantifying host cell DNA and host cell proteins, as well as by confirming the absence of the replication‐competent adenovirus. The transduction of rAd‐huIFNλ4 induced ISGs and inhibited four subtypes of the influenza virus in both mouse‐derived (LA‐4) and human‐derived cells (A549). The antiviral state was confirmed in BALB/c mice following intranasal inoculation with 109 PFU of rAd‐huIFNλ4, which led to the inhibition of four subtypes of the influenza virus in mouse lungs, with reduced inflammatory lesions. These results imply that human IFNλ4 could induce antiviral status by modulating ISG expression in mice.

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Section: Discussionmentioning

confidence: 99%

Antiviral activity of adenoviral vector expressing human interferon lambda‐4 against influenza virus

Kim,

Lim

et al. 2024

Journal of Medical Virology

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“…Mammalian species may differ from each other in terms of particular tissue scavengers, which play a dominant role in bloodborne Ad uptake. These differences in RES clearance may explain species-specific toxicity [15]. Thus, it has been shown that in mice, hamsters and non-human primates the main trap for i.v.…”

Section: Trapping Of Ad5 and Ad6 By Scavenger Cells And Hepatocyte Transductionmentioning

confidence: 99%

“…Importantly, activation or damage of LSEC leads to release of von Willebrand factor (vWF), which binds platelets and collagen with high affinity. This binding can induce thrombocytopenia which is broadly observed after Ad5 administration [15,77]. Therefore, further investigation of LSEC role in Ad6 trapping is of great importance.…”

Section: Trapping Of Ad5 and Ad6 By Scavenger Cells And Hepatocyte Transductionmentioning

confidence: 99%

“…Furthermore, the recent discovery of oncolytic viruses facilitating immunogenic cell death, which evokes a local antitumor response, has opened a new avenue for its use in the clinic [14]. Yet, the HAdV-C5-based vectors have been often criticized for a number of drawbacks, mainly for reported liver tropism and immunogenicity, which undoubtedly limit the clinical and commercial value of HAdV-C5 [15]. It is also important to acknowledge HAdV-C5 high seroprevalence, which may result in rapid clearance of adenoviral virions from blood stream by neutralizing antibodies and inability to treat a systemic disease.…”

Section: Introductionmentioning

confidence: 99%

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Adenovirus Type 6: Subtle Structural Distinctions from Adenovirus Type 5 Result in Essential Differences in Properties and Perspectives for Gene Therapy

et al. 2021

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Adenovirus vectors are the most frequently used agents for gene therapy, including oncolytic therapy and vaccine development. It’s hard to overestimate the value of adenoviruses during the COVID-19 pandemic as to date four out of four approved viral vector-based SARS-CoV-2 vaccines are developed on adenovirus platform. The vast majority of adenoviral vectors are based on the most studied human adenovirus type 5 (HAdV-C5), however, its immunogenicity often hampers the clinical translation of HAdV-C5 vectors. The search of less seroprevalent adenovirus types led to another species C adenovirus, Adenovirus type 6 (HAdV-C6). HAdV-C6 possesses high oncolytic efficacy against multiple cancer types and remarkable ability to induce the immune response towards carrying antigens. Being genetically very close to HAdV-C5, HAdV-C6 differs from HAdV-C5 in structure of the most abundant capsid protein, hexon. This leads to the ability of HAdV-C6 to evade the uptake by Kupffer cells as well as to distinct opsonization by immunoglobulins and other blood proteins, influencing the overall biodistribution of HAdV-C6 after systemic administration. This review describes the structural features of HAdV-C6, its interaction with liver cells and blood factors, summarizes the previous experiences using HAdV-C6, and provides the rationale behind the use of HAdV-C6 for vaccine and anticancer drugs developments.

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“…), Ad vectors have the potential to reach any vascularized organ or tumor, but their biodistribution has proven difficult to control. Poor targeting of vectors not only reduces the efficiency of gene therapy but can also increase risks, for example when vectors cause liver damage because of undesired targeting to hepatocytes [ 2 ]. Although vector biodistribution is influenced by the expression pattern of viral receptors, it has become increasingly clear that host blood proteins have an equally important influence on vector biodistribution [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Hexons from adenovirus serotypes 5 and 48 differentially protect adenovirus vectors from neutralization by mouse and human serum

Harmon

Moitra

et al. 2018

PLoS ONE

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Adenovirus vectors are widely used in gene therapy clinical trials, and preclinical studies with these vectors are often conducted in mice. It is therefore critical to understand whether mouse studies adequately predict the behavior of adenovirus vectors in humans. The most commonly-used adenovirus vectors are derived from adenovirus serotype 5 (Ad5). The Ad5 hexon protein can bind coagulation factor X (FX), and binding of FX has a major impact on vector interactions with other blood proteins. In mouse serum, FX protects Ad5 vectors from neutralization by natural antibodies and complement. In the current study, we similarly find that human FX inhibits neutralization of Ad5 vectors by human serum, and this finding is consistent among individual human sera. We show that human IgM and human IgG can each induce complement-mediated neutralization when Ad5 vectors are not protected by FX. Although mouse and human serum had similar effects on Ad5 vectors, we found that this was not true for a chimeric Ad5 vector that incorporated hexon regions from adenovirus serotype 48. Interestingly, this hexon-chimeric vector was neutralized by human serum, but not by mouse serum. These findings indicate that studies in mouse serum accurately predict the behavior of Ad5 vectors in human serum, but mouse serum is not an accurate model system for all adenovirus vectors.

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Adenovirus Vector Toxicity

Cited by 9 publications

References 139 publications

Antiviral activity of adenoviral vector expressing human interferon lambda‐4 against influenza virus

Antiviral activity of adenoviral vector expressing human interferon lambda‐4 against influenza virus

Adenovirus Type 6: Subtle Structural Distinctions from Adenovirus Type 5 Result in Essential Differences in Properties and Perspectives for Gene Therapy

Hexons from adenovirus serotypes 5 and 48 differentially protect adenovirus vectors from neutralization by mouse and human serum

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