Chimeric Ad5 Vectors Expressing the Short Fiber of Ad41 Show Reduced Affinity for Human Intestinal Epithelium

Kesisoglou, Filippos; Chamberlain, Joel R.; Schmiedlin-Ren, Phyllissa; Kaz, Andrew M.; Fleisher, David; Roessler, Blake J.

doi:10.1021/mp0498897

Cited by 9 publications

(3 citation statements)

References 32 publications

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“…Furthermore, the SF of enteric HAdVs have been suggested to be responsible for the restricted intestinal tropism since these viruses were shown to be more resistant to acidic pH than other HAdV types [29,30]. This claim was refuted by another study describing that a recombinant HAdV-C5 vector carrying the 41SFs showed reduced affinity for enterocytes [57]. The latter study, however, did not subject the virions to acidic pH, which could have affected their results and interpretations.…”

Section: Discussionmentioning

confidence: 99%

Heparan Sulfate Is a Cellular Receptor for Enteric Human Adenoviruses

Rajan

Palm

Trulsson

et al. 2021

Viruses

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Human adenovirus (HAdV)-F40 and -F41 are leading causes of diarrhea and diarrhea-associated mortality in children under the age of five, but the mechanisms by which they infect host cells are poorly understood. HAdVs initiate infection through interactions between the knob domain of the fiber capsid protein and host cell receptors. Unlike most other HAdVs, HAdV-F40 and -F41 possess two different fiber proteins—a long fiber and a short fiber. Whereas the long fiber binds to the Coxsackievirus and adenovirus receptor (CAR), no binding partners have been identified for the short fiber. In this study, we identified heparan sulfate (HS) as an interaction partner for the short fiber of enteric HAdVs. We demonstrate that exposure to acidic pH, which mimics the environment of the stomach, inactivates the interaction of enteric adenovirus with CAR. However, the short fiber:HS interaction is resistant to and even enhanced by acidic pH, which allows attachment to host cells. Our results suggest a switch in receptor usage of enteric HAdVs after exposure to acidic pH and add to the understanding of the function of the short fibers. These results may also be useful for antiviral drug development and the utilization of enteric HAdVs for clinical applications such as vaccine development.

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Section: Discussionmentioning

confidence: 99%

Heparan Sulfate Is a Cellular Receptor for Enteric Human Adenoviruses

Rajan

Palm

Trulsson

et al. 2021

Viruses

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“…However, the incorporation of a 7-lysine-residue motif at the C-terminal end of the Ad40 short fiber in Ad5/40S recovered the transduction efficiencies. The chimeric Ad5SHORT that carries the Ad5 genome and Ad41 short fiber exhibited decreased transduction of human intestinal epithelial cells [148]. Therefore, Ad5/40S and Ad5SHORT are good candidates to employ bispecific conjugates to link the viral capsid and different target cancer cells, while avoiding the transduction of cells expressing the CAR receptor [149].…”

Section: Construction and Evaluation Of Chimeric Oncolytic Adenovirusesmentioning

confidence: 99%

Expanding the Spectrum of Adenoviral Vectors for Cancer Therapy

Gao

Zhang

Ehrhardt

2020

Cancers

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Adenoviral vectors (AdVs) have attracted much attention in the fields of vaccine development and treatment for diseases such as genetic disorders and cancer. In this review, we discuss the utility of AdVs in cancer therapies. In recent years, AdVs were modified as oncolytic AdVs (OAs) that possess the characteristics of cancer cell-specific replication and killing. Different carriers such as diverse cells and extracellular vesicles are being explored for delivering OAs into cancer sites after systemic administration. In addition, there are also various strategies to improve cancer-specific replication of OAs, mainly through modifying the early region 1 (E1) of the virus genome. It has been documented that oncolytic viruses (OVs) function through stimulating the immune system, resulting in the inhibition of cancer progression and, in combination with classical immune modulators, the anti-cancer effect of OAs can be even further enforced. To enhance the cancer treatment efficacy, OAs are also combined with other standard treatments, including surgery, chemotherapy and radiotherapy. Adenovirus type 5 (Ad5) has mainly been explored to develop vectors for cancer treatment with different modulations. Only a limited number of the more than 100 identified AdV types were converted into OAs and, therefore, the construction of an adenovirus library for the screening of potential novel OA candidates is essential. Here, we provide a state-of-the-art overview of currently performed and completed clinic trials with OAs and an adenovirus library, providing novel possibilities for developing innovative adenoviral vectors for cancer treatment.

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“…In this regard, the generation of chimeric Ad5/40S mutants (Ad5 capsid with the F40S protein) has shown to ablate CAR binding while conferring a novel tropism to Ad5 viral vectors, and thus, intravenous administration of Ad5/40S vectors resulted mainly in liver and spleen transduction, as shown by the presence of viral DNA and transgene expression in these organs, while the virus was hardly detected in the intestine [15]. However, and contrary to the reduced affinity of Ad5/41S vectors for human intestinal epithelium [19], when given directly into the gastrointestinal tract by rectal administration in vivo, chimeric Ad5/40S vectors mantain the enteric tropism [20].…”

Section: Introductionmentioning

confidence: 99%

Efficient Amplification of Chimeric Adenovirus 5/40S Vectors Carrying the Short Fiber Protein of Ad40 in Suspension Cell Cultures

et al. 2012

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The human adenovirus 40 (Ad40) is a promising tool for gene therapy of intestinal diseases. Since the production of Ad40 in vitro is extremely inefficient, chimeric Adenovirus 5/40S vectors carrying the Ad40 short fiber on the Ad5 capsid have been developed. However, Ad5/40S productivity is low. We hypothesized that low productivity was a result of inefficient viral entry into producer cells during amplification. To this end, we have developed a production strategy based on using 211B cells (expressing Ad5 fiber) during amplification steps, while Ad5/40S infectivity is further improved by adding polybrene during infections. In addition, the optimal harvesting time was determined by evaluating the Ad5/40S viral cycle. The developed production strategy significantly reduces the number of amplification cycles and duration of the process. Finally, to further facilitate Ad5/40S production, 211B cells were adapted to suspension thus allowing to easily upscale the production process in bioreactors.

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Chimeric Ad5 Vectors Expressing the Short Fiber of Ad41 Show Reduced Affinity for Human Intestinal Epithelium

Cited by 9 publications

References 32 publications

Heparan Sulfate Is a Cellular Receptor for Enteric Human Adenoviruses

Heparan Sulfate Is a Cellular Receptor for Enteric Human Adenoviruses

Expanding the Spectrum of Adenoviral Vectors for Cancer Therapy

Efficient Amplification of Chimeric Adenovirus 5/40S Vectors Carrying the Short Fiber Protein of Ad40 in Suspension Cell Cultures

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