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Research and Clinical Application of Adenovirus (AdV)

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (15 April 2023) | Viewed by 22525

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Dr. Julia Davydova

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Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
Interests: gene therapy approaches for cancer and non-malignant diseases; oncolytic adenovirus for cancer therapy and imaging; combination of virotherapy with radiation and chemotherapy; adenovirus-mediated immunotherapy for cancer; viral vectors as a tool for gene delivery
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Dear Colleagues,

The concept behind using viruses to fight human diseases is very straightforward: for millions of years, they have been delivering their genes to different types of mammalian and human cells. Indeed, virus-based gene therapy is a growing area of modern medicine as viruses have the potential to overcome limitations of conventional therapeutic approaches.

Adenovirus (AdV) is one of the most versatile viral backbones with applications ranging from gene delivery and treatment of monogenic diseases to vaccination and cancer therapy. Adenoviruses can target a broad spectrum of both dividing and non-dividing cells, do not integrate into host DNA, have high in vivo transduction capacity, and are well characterized, thereby allowing for countless modifications of their genetic structure. The first AdV-based therapy took place in 1956, when 30 patients with cervical carcinoma were treated with adenoidal–pharyngeal–conjunctival virus, now known as an adenovirus. After a turbulent past full of both medical achievements and failures, the stigma related to adenovirus has been gradually replaced by the wide acceptance of feasibility and safety of AdV-based therapeutics. It is difficult to overestimate the value of AdV during the COVID-19 pandemic as, to date, AdV represents the most effective viral vector platform for anti-SARS-CoV-2 vaccines. The recent clinical successes have also demonstrated the promise of tumor-selective, infectivity-improved oncolytic adenoviruses for cancer gene therapy and highlighted their role in inducing anticancer immunity. In this Special Issue, we will discuss the most recent advances in adenovirus research and how AdV can be used to treat human diseases.

Dr. Julia Davydova
Guest Editor

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Keywords

adenovirus
gene
therapy
cancer
oncolytic
vaccine
delivery

Published Papers (10 papers)

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Research

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10 pages, 1258 KiB

Open AccessArticle

Viral Shedding in Mice following Intravenous Adenovirus Injection: Impact on Biosafety Classification

by Christopher J. LaRocca, Kari L. Jacobsen, Kazuho Inoko, Stanislav O. Zakharkin, Masato Yamamoto and Julia Davydova

Viruses 2023, 15(7), 1495; https://doi.org/10.3390/v15071495 - 01 Jul 2023

Cited by 2 | Viewed by 1448

Abstract

There have been numerous advances in gene therapy and oncolytic virotherapy in recent years, especially with respect to cutting-edge animal models to test these novel therapeutics. With all of these advances, it is important to understand the biosafety risks of testing these vectors in animals. We performed adenovirus-based viral shedding studies in murine models to ascertain when it is appropriate to downgrade the animals from Biosafety Level (BSL) 2 to BSL 1 for experimental handling and transport. We utilized intravenous injections of a replication-competent adenovirus and analyzed viral shedding via the collection of buccal and dermal swabs from each animal, in addition to obtaining urine and stool samples. The adenovirus hexon copy number was determined by qPCR, and plaque formation was analyzed to assess the biologic activity of viral particles. Our results demonstrate that after 72 h following viral inoculation, there is no significant quantity of biologically active virus shedding from the animals. This observation suggests that on day 4 following adenovirus injection, mice can be safely downgraded to BSL 1 for the remainder of the experiment with no concern for hazardous exposure to laboratory personnel. Full article

(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV))

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15 pages, 10124 KiB

Open AccessArticle

Generation and Characterization of a Replication-Competent Human Adenovirus Type 55 Encoding EGFP

by Wei Li, Yuehong Chen, Ye Feng, Jing Li, Xiaoping Kang, Sen Zhang, Yuchang Li, Zhiyan Zhao, Wenguang Yang, Lu Zhao, Huiyao Wang and Tao Jiang

Viruses 2023, 15(5), 1192; https://doi.org/10.3390/v15051192 - 18 May 2023

Cited by 1 | Viewed by 1413

Abstract

Human adenovirus 55 (HAdV-55) has recently caused outbreaks of acute respiratory disease (ARD), posing a significant public threat to civilians and military trainees. Efforts to develop antiviral inhibitors and quantify neutralizing antibodies require an experimental system to rapidly monitor viral infections, which can be achieved through the use of a plasmid that can produce an infectious virus. Here, we used a bacteria-mediated recombination approach to construct a full-length infectious cDNA clone, pAd55-FL, containing the whole genome of HadV-55. Then, the green fluorescent protein expression cassette was assembled into pAd55-FL to replace the E3 region to obtain a recombinant plasmid of pAd55-dE3-EGFP. The rescued recombinant virus rAdv55-dE3-EGFP is genetically stable and replicates similarly to the wild-type virus in cell culture. The virus rAdv55-dE3-EGFP can be used to quantify neutralizing antibody activity in sera samples, producing results in concordance with the cytopathic effect (CPE)-based microneutralization assay. Using an rAdv55-dE3-EGFP infection of A549 cells, we showed that the assay could be used for antiviral screening. Our findings suggest that the rAdv55-dE3-EGFP-based high-throughput assay provides a reliable tool for rapid neutralization testing and antiviral screening for HAdV-55. Full article

(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV))

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17 pages, 2494 KiB

Open AccessArticle

PTTG1 Enhances Oncolytic Adenovirus 5 Entry into Pancreatic Adenocarcinoma Cells by Increasing CXADR Expression

by Lu Long, Jian Gao and Ruiyang Zhang

Viruses 2023, 15(5), 1153; https://doi.org/10.3390/v15051153 - 11 May 2023

Cited by 2 | Viewed by 1358

Abstract

Pituitary tumor-transforming gene 1 (PTTG1) is overexpressed in various types of tumors and functions as an oncogene; it could also be a potential target in tumor therapy. Meanwhile, the high mortality of pancreatic adenocarcinoma (PAAD) largely depends on the limited effectiveness of therapy. Based on the promising potential of PTTG1 in cancer treatment, we explored the influence of PTTG1 on the treatment of PAAD in this study. The Cancer Genome Atlas Program (TCGA) data showed that higher expression of PTTG1 was associated with higher clinical stages and worse prognosis of pancreatic cancer. In addition, the CCK-8 assay showed that the IC50 of gemcitabine and 5-fluorouracil (5-FU) was increased in BxPC-3-PTTG1^high and MIA PaCa-2-PTTG1^high cells. The TIDE algorithm indicated that the immune checkpoint blockades’ (ICBs) efficiency is poor in the PTTG1 high group. Furthermore, we found that the efficiency of OAd5 was enhanced in BxPC-3-PTTG1^high and MIA PaCa-2-PTTG1^high cells and poor in BxPC-3-PTTG1^low and MIA PaCa-2-PTTG1^low cells. We used the OAd5 expressing GFP for transduction. As a result, the fluorescence intensity was enhanced in BxPC-3-PTTG1^high and MIA PaCa-2-PTTG1^high cells and decreased in BxPC-3-PTTG1^low and MIA PaCa-2-PTTG1^low cells 24 h after OAd5 transduction. The fluorescence intensity indicated that PTTG1 increased OAd5 entry. The flow cytometry assay showed that OAd5 receptor CXADR expression was enhanced by PTTG1. PTTG1 failed to further enhance OAd5 transduction in the case of CXADR knockdown. In summary, PTTG1 enhanced OAd5 transduction into pancreatic cancer cells by increasing CXADR expression on the cell surface. Full article

(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV))

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14 pages, 1362 KiB

Open AccessArticle

Infectivity-Enhanced, Conditionally Replicative Adenovirus for COX-2-Expressing Castration-Resistant Prostate Cancer

by Tatyana Gavrikova, Naohiko Nakamura, Julia Davydova, Emmanuel S. Antonarakis and Masato Yamamoto

Viruses 2023, 15(4), 901; https://doi.org/10.3390/v15040901 - 31 Mar 2023

Cited by 1 | Viewed by 1380

Abstract

Background: The development of conditionally replicative adenoviruses (CRAds) for castration-resistant prostate cancer (CRPC), particularly neuroendocrine prostate cancer (NEPC), has two major obstacles: choice of control element and poor infectivity. We applied fiber-modification-based infectivity enhancement and an androgen-independent promoter (cyclooxynegase-2, COX-2) to overcome these issues. Methods: The properties of the COX-2 promoter and the effect of fiber modification were tested in two CRPC cell lines (Du-145 and PC3). Fiber-modified COX-2 CRAds were tested in vitro for cytocidal effect as well as in vivo for antitumor effect with subcutaneous CRPC xenografts. Results: In both CRPC cell lines, the COX-2 promoter showed high activity, and Ad5/Ad3 fiber modification significantly enhanced adenoviral infectivity. COX-2 CRAds showed a potent cytocidal effect in CRPC cells with remarkable augmentation by fiber modification. In vivo, COX-2 CRAds showed an antitumor effect in Du-145 while only Ad5/Ad3 CRAd showed the strongest antitumor effect in PC3. Conclusion: COX-2 promoter–based, infectivity-enhanced CRAds showed a potent antitumor effect in CRPC/NEPC cells. Full article

(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV))

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18 pages, 5794 KiB

Open AccessArticle

Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment

by Ivan D. Osipov, Valeriia A. Vasikhovskaia, Daria S. Zabelina, Sergei S. Kutseikin, Antonina A. Grazhdantseva, Galina V. Kochneva, Julia Davydova, Sergey V. Netesov and Margarita V. Romanenko

Viruses 2023, 15(1), 182; https://doi.org/10.3390/v15010182 - 07 Jan 2023

Cited by 2 | Viewed by 2583

Abstract

Human Adenovirus type 6 (HAdV-C6) is a promising candidate for the development of oncolytic vectors as it has low seroprevalence and the intrinsic ability to evade tissue macrophages. However, its further development as a therapeutic agent is hampered by the lack of convenient cloning methods. We have developed a novel technology when a shuttle plasmid carrying the distal genome parts with modified E1A and E3 regions is recombined in vitro with the truncated HAdV-C6 genome. Using this approach, we have constructed a novel Ad6-hT-GM vector controlled by the hTERT promoter and expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) instead of 6.7K and gp19K E3 proteins. We have demonstrated that control by the hTERT promoter may result in delayed viral replication, which nevertheless does not significantly change the cytotoxic ability of recombinant viruses. The insertion of the transgene by displacing the E3-6.7K/gp19K region does not drastically change the expression patterns of E3 genes; however, mild changes in expression from major late promoter were observed. Finally, we have demonstrated that the treatment of human breast cancer xenografts in murine models with Ad6-hT-GM significantly decreased the tumor volume and improved survival time compared to mock-treated mice. Full article

(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV))

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20 pages, 4559 KiB

Open AccessArticle

Seroprevalence of Binding and Neutralizing Antibodies against 39 Human Adenovirus Types in Patients with Neuromuscular Disorders

by Patrick Julian Klann, Xiaoyan Wang, Anna Elfert, Wenli Zhang, Cornelia Köhler, Anne-Katrin Güttsches, Frank Jacobsen, Ute Weyen, Andreas Roos, Eric Ehrke-Schulz, Anja Ehrhardt, Matthias Vorgerd and Wibke Bayer

Viruses 2023, 15(1), 79; https://doi.org/10.3390/v15010079 - 27 Dec 2022

Cited by 3 | Viewed by 1857

Abstract

High pre-existing antibodies against viral vectors reduce their functionality and may lead to adverse complications. To circumvent this problem in future gene therapy approaches, we tested the seroprevalence of a large range of human adenovirus types in patients with neuromuscular disorders (NMDs) to find appropriate viral vector candidates for gene replacement therapy for NMDs. Binding and neutralizing antibodies against 39 human adenovirus types were tested in the sera of 133 patients with NMDs and 76 healthy controls aged 17–92 years. The influence of age, sex, and NMDs on antibody levels was analyzed. The seroprevalence of different adenoviruses in the cohort varied widely. The highest levels of binding antibodies were detected against HAdV-D27, -C1, -D24, -D70, -B14, -C6, -D13, -B34, and -E4, whereas the lowest reactivity was detected against HAdV-F41, -A31, -B11, -D75, -D8, -D65, -D26, -D80, and -D17. The highest neutralizing reactivity was observed against HAdV-B3, -C2, -E4, -C1, -G52, -C5, and -F41, whereas the lowest neutralizing reactivity was observed against HAdV-D74, -B34, -D73, -B37, -D48, -D13, -D75, -D8, -B35, and -B16. We detected no influence of sex and only minor differences between different age groups. Importantly, there were no significant differences between healthy controls and patients with NMDs. Our data show that patients with NMDs have very similar levels of binding and neutralizing antibodies against HAdV compared to healthy individuals, and we identified HAdV-A31, -B16, -B34, -B35, -D8, -D37, -D48, -D73, -D74, -D75, and -D80 as promising candidates for future vector development due to their low binding and neutralizing antibody prevalence. Full article

(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV))

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13 pages, 1689 KiB

Open AccessArticle

Influence of Heparan Sulfate Proteoglycans and Factor X on species D Human Adenovirus Uptake and Transduction

by Katrin Schröer, Montaha Alshawabkeh, Sebastian Schellhorn, Katrin Bronder, Wenli Zhang and Anja Ehrhardt

Viruses 2023, 15(1), 55; https://doi.org/10.3390/v15010055 - 24 Dec 2022

Cited by 1 | Viewed by 1232

Abstract

More than 100 human adenovirus (Ad) types were identified, of which species D comprises the largest group. Heparan sulfate proteoglycans (HSPGs) were shown to function as cell surface receptors for cell binding and uptake of some Ads, but a systematic analysis of species D Ads is lacking. Previous research focused on Ad5 and blood coagulation factor X (FX) complexes, which revealed that Ad5 can transduce cells with low expression levels of its main coxsackievirus-adenovirus receptor in the presence of high HSPG expression levels in a FX dependent manner. Based on our reporter gene-tagged Ad-library, we explored for the first time a broad spectrum of species D Ads to study the role of HSPG on their cellular uptake. This study was performed on three Chinese Hamster Ovary (CHO) cell lines with different forms of HSPG (only proteoglycan (745), non-sulfated HSPG (606) or sulfated HSPG (K1)). The effect of Ad:FX complexes on Ad uptake was explored in the presence of physiological levels of FX in blood (6–10 µg/mL). We found that sulfation of HSPG plays an important role in cellular uptake and transduction of FX-bound Ad5 but neither HSPG nor FX influenced uptake of all tested species D Ads. Because FX has no influence on transduction efficiencies of species D Ads and therefore may not bind to them, these Ads may not be protected from attack by neutralizing IgM antibodies or the complement pathway, which may have implications for species D Ads used as vaccine and gene therapy vectors. Full article

(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV))

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11 pages, 2590 KiB

Open AccessArticle

A Novel Piggyback Strategy for mRNA Delivery Exploiting Adenovirus Entry Biology

by Myungeun Lee, Paul J. Rice-Boucher, Logan Thrasher Collins, Ernst Wagner, Lorenzo Aulisa, Jeffrey Hughes and David T. Curiel

Viruses 2022, 14(10), 2169; https://doi.org/10.3390/v14102169 - 30 Sep 2022

Cited by 1 | Viewed by 2466

Abstract

Molecular therapies exploiting mRNA vectors embody enormous potential, as evidenced by the utility of this technology for the context of the COVID-19 pandemic. Nonetheless, broad implementation of these promising strategies has been restricted by the limited repertoires of delivery vehicles capable of mRNA transport. On this basis, we explored a strategy based on exploiting the well characterized entry biology of adenovirus. To this end, we studied an adenovirus-polylysine (AdpL) that embodied “piggyback” transport of the mRNA on the capsid exterior of adenovirus. We hypothesized that the efficient steps of Ad binding, receptor-mediated entry, and capsid-mediated endosome escape could provide an effective pathway for transport of mRNA to the cellular cytosol for transgene expression. Our studies confirmed that AdpL could mediate effective gene transfer of mRNA vectors in vitro and in vivo. Facets of this method may offer key utilities to actualize the promise of mRNA-based therapeutics. Full article

(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV))

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Review

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30 pages, 1277 KiB

Open AccessReview

An Old Acquaintance: Could Adenoviruses Be Our Next Pandemic Threat?

by Gustavo Saint-Pierre Contreras, Daniel Conei Valencia, Luis Lizama, Daniela Vargas Zuñiga, Luis Fidel Avendaño Carvajal and Sandra Ampuero Llanos

Viruses 2023, 15(2), 330; https://doi.org/10.3390/v15020330 - 24 Jan 2023

Cited by 8 | Viewed by 2826

Abstract

Human adenoviruses (HAdV) are one of the most important pathogens detected in acute respiratory diseases in pediatrics and immunocompromised patients. In 1953, Wallace Rowe described it for the first time in oropharyngeal lymphatic tissue. To date, more than 110 types of HAdV have been described, with different cellular tropisms. They can cause respiratory and gastrointestinal symptoms, even urinary tract inflammation, although most infections are asymptomatic. However, there is a population at risk that can develop serious and even lethal conditions. These viruses have a double-stranded DNA genome, 25–48 kbp, 90 nm in diameter, without a mantle, are stable in the environment, and resistant to fat-soluble detergents. Currently the diagnosis is made with lateral flow immunochromatography or molecular biology through a polymerase chain reaction. This review aimed to highlight the HAdV variability and the pandemic potential that a HAdV3 and 7 recombinant could have considering the aggressive outbreaks produced in health facilities. Herein, we described the characteristics of HAdV, from the infection to treatment, vaccine development, and the evaluation of the social determinants of health associated with HAdV, suggesting the necessary measures for future sanitary control to prevent disasters such as the SARS-CoV-2 pandemic, with an emphasis on the use of recombinant AdV vaccines to control other potential pandemics. Full article

(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV))

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16 pages, 1396 KiB

Open AccessReview

Human Adenovirus Gene Expression and Replication Is Regulated through Dynamic Changes in Nucleoprotein Structure throughout Infection

by Morgan R. Jennings and Robin J. Parks

Viruses 2023, 15(1), 161; https://doi.org/10.3390/v15010161 - 05 Jan 2023

Cited by 6 | Viewed by 4717

Abstract

Human adenovirus (HAdV) is extremely common and can rapidly spread in confined populations such as daycare centers, hospitals, and retirement homes. Although HAdV usually causes only minor illness in otherwise healthy patients, HAdV can cause significant morbidity and mortality in certain populations, such as the very young, very old, or immunocompromised individuals. During infection, the viral DNA undergoes dramatic changes in nucleoprotein structure that promote the rapid expression of viral genes, replication of the DNA, and generation of thousands of new infectious virions—each process requiring a distinct complement of virus and host-encoded proteins. In this review, we summarize our current understanding of the nucleoprotein structure of HAdV DNA during the various phases of infection, the cellular proteins implicated in mediating these changes, and the role of epigenetics in HAdV gene expression and replication. Full article

(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV))

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