Journal articles: 'Adenoviru'

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O'Prey, Jim, Simon Wilkinson, and Kevin M. Ryan. "Tumor Antigen LRRC15 Impedes Adenoviral Infection: Implications for Virus-Based Cancer Therapy." Journal of Virology 82, no. 12 (April 2, 2008): 5933–39. http://dx.doi.org/10.1128/jvi.02273-07.

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ABSTRACT Adenoviruses for gene or oncolytic therapy are under development. Notable among these strategies is adenoviral delivery of the tumor suppressor p53. Since all therapeutics have limitations in certain settings, we have undertaken retroviral suppressor screens to identify genes conferring resistance to adenovirus-delivered p53. These studies identified the tumor antigen LRRC15, which is frequently overexpressed in multiple tumor types, as a repressor of cell death due to adenoviral p53. LRRC15, however, does not impede p53 function per se but impedes adenoviral infection. Specifically, LRRC15 causes redistribution of the coxsackievirus-adenovirus receptor away from the cell surface. This effect is manifested in less adenoviral binding to the surfaces of LRRC15-expressing cells. This discovery, therefore, not only is important for understanding adenoviral biology but also has potentially important implications for adenovirus-based anticancer therapeutics.

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Zhu, Jiangao, Xiaopei Huang, and Yiping Yang. "Innate Immune Response to Adenoviral Vectors Is Mediated by both Toll-Like Receptor-Dependent and -Independent Pathways." Journal of Virology 81, no. 7 (January 17, 2007): 3170–80. http://dx.doi.org/10.1128/jvi.02192-06.

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ABSTRACT Recombinant adenoviral vectors have been widely used for gene therapy applications and as vaccine vehicles for treating infectious diseases such as human immunodeficiency virus disease. The innate immune response to adenoviruses represents the most significant hurdle in clinical application of adenoviral vectors for gene therapy, but it is an attractive feature for vaccine development. How adenovirus activates innate immunity remains largely unknown. Here we showed that adenovirus elicited innate immune response through the induction of high levels of type I interferons (IFNs) by both plasmacytoid dendritic cells (pDCs) and non-pDCs such as conventional DCs and macrophages. The innate immune recognition of adenovirus by pDCs was mediated by Toll-like receptor 9 (TLR9) and was dependent on MyD88, whereas that by non-pDCs was TLR independent through cytosolic sensing of adenoviral DNA. Furthermore, type I IFNs were pivotal in innate and adaptive immune responses to adenovirus in vivo, and type I IFN blockade diminished immune responses, resulting in more stable transgene expression and reduction of inflammation. These findings indicate that adenovirus activates innate immunity by its DNA through TLR-dependent and -independent pathways in a cell type-specific fashion, and they highlight a critical role for type I IFNs in innate and adaptive immune responses to adenoviral vectors. Our results that suggest strategies to interfere with type I IFN pathway may improve the outcome of adenovirus-mediated gene therapy, whereas approaches to activate the type I IFN pathway may enhance vaccine potency.

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Nestić, Davor, Ksenija Božinović, Isabela Pehar, Rebecca Wallace, Alan L. Parker, and Dragomira Majhen. "The Revolving Door of Adenovirus Cell Entry: Not All Pathways Are Equal." Pharmaceutics 13, no. 10 (September 29, 2021): 1585. http://dx.doi.org/10.3390/pharmaceutics13101585.

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Adenoviruses represent exceptional candidates for wide-ranging therapeutic applications, from vectors for gene therapy to oncolytics for cancer treatments. The first ever commercial gene therapy medicine was based on a recombinant adenovirus vector, while most recently, adenoviral vectors have proven critical as vaccine platforms in effectively controlling the global coronavirus pandemic. Here, we discuss factors involved in adenovirus cell binding, entry, and trafficking; how they influence efficiency of adenovirus-based vectors; and how they can be manipulated to enhance efficacy of genetically modified adenoviral variants. We focus particularly on endocytosis and how different adenovirus serotypes employ different endocytic pathways to gain cell entry, and thus, have different intracellular trafficking pathways that subsequently trigger different host antiviral responses. In the context of gene therapy, the final goal of the adenovirus vector is to efficiently deliver therapeutic transgenes into the target cell nucleus, thus allowing its functional expression. Aberrant or inefficient endocytosis can impede this goal, therefore, it should be considered when designing and constructing adenovirus-based vectors.

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Harrod, Kevin S., Bruce C. Trapnell, Kazuhisa Otake, Thomas R. Korfhagen, and Jeffrey A. Whitsett. "SP-A enhances viral clearance and inhibits inflammation after pulmonary adenoviral infection." American Journal of Physiology-Lung Cellular and Molecular Physiology 277, no. 3 (September 1, 1999): L580—L588. http://dx.doi.org/10.1152/ajplung.1999.277.3.l580.

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Surfactant protein A (SP-A) is a member of the collectin family of host defense molecules expressed primarily in the epithelial cells of the lung. To determine the role of SP-A in pulmonary adenoviral infection, SP-A-deficient (SP-A −/−) mice were intratracheally infected with a replication-deficient recombinant adenovirus, Av1Luc1. Lung inflammation was markedly increased in SP-A −/− compared with SP-A +/+ mice and was associated with increased hemorrhage and epithelial cell injury. Polymorphonuclear cells in bronchoalveolar lavage fluid (BALF) were increased in SP-A −/− mice after administration of adenovirus. Coadministration of adenovirus and purified human SP-A ameliorated adenoviral-induced lung inflammation in SP-A −/− mice. Concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were increased in BALF of SP-A −/− mice. Likewise, TNF-α, IL-6, macrophage inflammatory protein (MIP)-1α, monocyte chemotactic protein-1, and MIP-2 mRNAs were increased in lung homogenates from SP-A −/− mice 6 and 24 h after viral administration. Clearance of adenoviral DNA from the lung and uptake of fluorescent-labeled adenovirus by alveolar macrophages were decreased in SP-A −/− mice. SP-A enhances viral clearance and inhibits lung inflammation during pulmonary adenoviral infection, providing support for the importance of SP-A in antiviral host defense.

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Jogler, Christian, Dennis Hoffmann, Dirk Theegarten, Thomas Grunwald, Klaus Überla, and Oliver Wildner. "Replication Properties of Human Adenovirus In Vivo and in Cultures of Primary Cells from Different Animal Species." Journal of Virology 80, no. 7 (April 1, 2006): 3549–58. http://dx.doi.org/10.1128/jvi.80.7.3549-3558.2006.

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ABSTRACT Oncolytic adenoviruses have emerged as a promising approach for the treatment of tumors resistant to other treatment modalities. However, preclinical safety studies are hampered by the lack of a permissive nonhuman host. Screening of a panel of primary cell cultures from seven different animal species revealed that porcine cells support productive replication of human adenovirus type 5 (Ad5) nearly as efficiently as human A549 cells, while release of infectious virus by cells from other animal species tested was diminished by several orders of magnitude. Restriction of productive Ad5 replication in rodent and rabbit cells seems to act primarily at a postentry step. Replication efficiency of adenoviral vectors harboring different E1 deletions or mutations in porcine cells was similar to that in A549 cells. Side-by-side comparison of the viral load kinetics in blood of swine and mice injected with Ad5 or a replication-deficient adenoviral vector failed to provide clear evidence for virus replication in mice. In contrast, evidence suggests that adenovirus replication occurs in swine, since adenoviral late gene expression produced a 13.5-fold increase in viral load in an individual swine from day 3 to day 7 and 100-fold increase in viral DNA levels in the Ad5-infected swine compared to the animal receiving a replication-deficient adenovirus. Lung histology of Ad5-infected swine revealed a severe interstitial pneumonia. Although the results in swine are based on a small number of animals and need to be confirmed, our data strongly suggest that infection of swine with human adenovirus or oncolytic adenoviral vectors is a more appropriate animal model to study adenoviral pathogenicity or pharmacodynamic and toxicity profiles of adenoviral vectors than infection of mice.

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Lee, Minhyeok, Seulgi Kim, Oh Jung Kwon, Ji Hye Kim, Inbeom Jeong, Ji Woong Son, Moon Jun Na, Yoo Sang Yoon, Hyun Woong Park, and Sun Jung Kwon. "Treatment of Adenoviral Acute Respiratory Distress Syndrome Using Cidofovir With Extracorporeal Membrane Oxygenation." Journal of Intensive Care Medicine 32, no. 3 (November 30, 2016): 231–38. http://dx.doi.org/10.1177/0885066616681272.

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Adenovirus infections are associated with respiratory (especially upper respiratory) infection and gastrointestinal disease and occur primarily in infants and children. Although rare in adults, severe lower respiratory adenovirus infections including pneumonia are reported in specific populations, such as military recruits and immunocompromised patients. Antiviral treatment is challenging due to limited clinical experience and lack of well-controlled randomized trials. Several previously reported cases of adenoviral pneumonia showed promising efficacy of cidofovir. However, few reports discussed the efficacy of cidofovir in acute respiratory distress syndrome (ARDS). We experienced 3 cases of adenoviral pneumonia associated with ARDS and treated with cidofovir and respiratory support, including extracorporeal membrane oxygenation (ECMO). All 3 patients showed a positive clinical response to cidofovir and survival at 28 days. Cidofovir with early ECMO therapy may be a therapeutic option in adenoviral ARDS. A literature review identified 15 cases of adenovirus pneumonia associated with ARDS.

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Reid, Tony, Andrew Kummel, Scott Caroen, Jaimin Shah, Bryan Oronsky, and Christopher Larson. "Abstract P3-07-20: Treatment of 4T1 Breast Cancer with Liposome-Encapsulated AdAPT-001, a TGF-beta Trap Encoded Oncolytic Adenovirus Currently in a Phase 1/2 Anticancer Trial." Cancer Research 83, no. 5_Supplement (March 1, 2023): P3–07–20—P3–07–20. http://dx.doi.org/10.1158/1538-7445.sabcs22-p3-07-20.

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Abstract Adenoviral vectors have been used extensively for gene therapy. However, efficient infection of cells requires expression of the coxsackie-adenoviral receptor (CAR). Many tumor cells lack adequate expression of CAR and, hence, are not good targets for adenoviral based vectors. We have developed a unique nanoparticle (Epi-039) that can be used to efficiently introduce adenoviral vectors into tumor cells that have low or no CAR expression. We used the CAR-negative 4T1 mammary carcinoma model system, which represents a typical triple-negative breast cancer cell line (ER−, PR−, HER2−) and which is refractory to adenoviral infection to demonstrate effective transduction of an encapsulated oncolytic adenovirus. The adenovirus that was used is called AdAPT-001. This armed oncolytic virus, which is currently in a phase I/II clinical trial called BETA PRIME for the treatment of refractory cancers, expresses a TGFb receptor trap to neutralize the immunosuppressive cytokine, TGF beta. Overexpression of TGF-beta positively correlates with metastasis in breast carcinoma and thus confers a poorer prognosis. In this study, the unique Epi-039 nanoparticle carrying AdAPT-001 not only significantly enhanced the transduction efficiency of AdAPT-001 but also protected it from neutralization by natural antibodies in human whole blood. Accordingly, we demonstrate a significant increase (P value= 0.0029) in the expression of green fluorescent protein (GFP) in CAR-negative 4T1 cells infected with the encapsulated AdAPT-001 adenovirus but not the unencapsulated AdAPT-001 adenovirus. Additional in vivo studies using nanoparticle encapsulated adenoviral vectors including AdAPT-001 to treat breast cancer are underway for rapid translation to the clinic. Citation Format: Tony Reid, Andrew Kummel, Scott Caroen, Jaimin Shah, Bryan Oronsky, Christopher Larson. Treatment of 4T1 Breast Cancer with Liposome-Encapsulated AdAPT-001, a TGF-beta Trap Encoded Oncolytic Adenovirus Currently in a Phase 1/2 Anticancer Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-20.

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Bründler, Marie-Anne, Norberto Rodriguez-Baez, Ron Jaffe, Arthur G. Weinberg, and Beverly Barton Rogers. "Adenovirus Ascending Cholangiohepatitis." Pediatric and Developmental Pathology 6, no. 2 (March 2003): 156–59. http://dx.doi.org/10.1007/s10024-002-0063-4.

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Three children, two with liver transplants and one with acquired human immunodeficiency virus (HIV) infection, presented with hepatitis accompanied by elevated gamma glutamyl transpeptidase. Biopsies revealed cholangiohepatitis caused by adenovirus infection. There was a progressive loss of interlobular bile ducts in two of the patients. In one patient, infection of the biliary tree was marked by a necrotizing cholangitis, with adenoviral inclusions noted in the biliary epithelium. In each patient, there was evidence of adenovirus gastrointestinal infection. This is the first report of adenoviral infection of the biliary tree in humans. It is hypothesized that adenovirus cholangiohepatitis occurs as a result of ascending infection from the gastrointestinal tract to the biliary tree.

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Leen, Ann M., Anne Christin, Gary D. Myers, Hao Liu, Conrad R. Cruz, Patrick J. Hanley, Alana A. Kennedy-Nasser, et al. "Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation." Blood 114, no. 19 (November 5, 2009): 4283–92. http://dx.doi.org/10.1182/blood-2009-07-232454.

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Abstract Viral infection or reactivation remains a major cause of morbidity and mortality after allogeneic stem cell transplantation. We now show that infusions of single cytotoxic T lymphocyte (CTL) lines (5 × 106-1.35 × 108 cells/m2) with specificity for 2 commonly detected viruses, Epstein-Barr virus (EBV) and adenovirus, can be safely administered to pediatric transplantation recipients receiving partially human leukocyte antigen–matched and haploidentical stem cell grafts (n = 13), without inducing graft-versus-host disease. The EBV-specific component of the CTLs expanded in vivo and persisted for more than 12 weeks, but the adenovirus-specific component only expanded in vivo in the presence of concomitant adenoviral infection. Nevertheless, adenovirus-specific T cells could be detected for at least 8 weeks in peripheral blood, even in CTL recipients without viral infection, provided the adenovirus-specific component of their circulating lymphocytes was first expanded by exposure to adenoviral antigens ex vivo. After infusion, none of these 13 high-risk recipients developed EBV-associated lymphoproliferative disease, while 2 of the subjects had resolution of their adenoviral disease. Hence, bispecific CTLs containing both EBV- and adenovirus-specific T cells can safely reconstitute an antigen responsive “memory” population of CTLs after human leukocyte antigen–mismatched stem cell transplantation and may provide antiviral activity. This trial was registered at www.clinicaltrials.gov as #NCT00590083.

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Debey, B. M., H. D. Lehmkuhl, C. Chard-Bergstrom, and L. A. Hobbs. "Ovine Adenovirus Serotype 7-associated Mortality in Lambs in the United States." Veterinary Pathology 38, no. 6 (November 2001): 644–48. http://dx.doi.org/10.1354/vp.38-6-644.

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Adenoviral infections were diagnosed in three neonatal lambs that died spontaneously, and no other etiologic agents were identified. Clinical signs were anorexia, weakness, abdominal distention, and sudden death. Microscopic lesions consisted of multifocal necrotizing hepatitis, multifocal subacute interstitial nephritis, and loss of enterocytes from intestinal villi. Adenovirus inclusions were identified by light microscopy in the kidneys only. Adenoviral antigen, however, was identified in the liver, kidney, and intestine of the lambs by immunohistochemical techniques. An ovine adenovirus serotype 7, not previously isolated from sheep in the United States, was characterized from these lambs.

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Asaoka, Katsuyuki, Mitsuhiro Tada, Yutaka Sawamura, Jun Ikeda, and Hiroshi Abe. "Dependence of efficient adenoviral gene delivery in malignant glioma cells on the expression levels of the Coxsackievirus and adenovirus receptor." Journal of Neurosurgery 92, no. 6 (June 2000): 1002–8. http://dx.doi.org/10.3171/jns.2000.92.6.1002.

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Object. Recombinant adenovirus is used as a competent vector in a wide spectrum of cancer gene therapies because of its high efficiency in gene delivery. To study the feasibility of gene therapy in malignant gliomas, the authors examined the antiproliferative effect of the adenovirally transduced wild-type p53 tumor suppressor gene by using 15 different high-grade glioma cell lines.Methods. Although growth suppression in association with a high adenoviral p53 transduction efficiency was seen in five of 15 cell lines, it was not observed in the remaining 10 cell lines. To clarify the underlying mechanism, we examined the expression levels of the Coxsackievirus and adenovirus receptor (CAR), which is the primary receptor for adenovirus, and of the integrins αvβ3 and αvβ5, which promote adenoviral internalization. The expression level of the CAR gene showed a close correlation to adenoviral gene transduction efficiency in the tested cell lines, whereas the expression levels of the integrins did not. The CAR expression was decreased by wild-type p53 transduction in U251MG cells harboring mutant p53 and increased by antisense inhibition of p53 in LN443 cells with endogenous wild-type p53.Conclusions. The results of this study indicate that CAR expression is a critical determinant of transduction efficiencies in adenovirus-based gene therapy for human malignant gliomas.

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Wold, William S. M., Ann E. Tollefson, Baoling Ying, Jacqueline F. Spencer, and Karoly Toth. "Drug development against human adenoviruses and its advancement by Syrian hamster models." FEMS Microbiology Reviews 43, no. 4 (March 27, 2019): 380–88. http://dx.doi.org/10.1093/femsre/fuz008.

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ABSTRACTThe symptoms of human adenovirus infections are generally mild and self-limiting. However, these infections have been gaining importance in recent years because of a growing number of immunocompromised patients. Solid organ and hematopoietic stem cell transplant patients are subjected to severe immunosuppressive regimes and cannot efficaciously eliminate virus infections. In these patients, adenovirus infections can develop into deadly multi-organ disseminated disease. Presently, in the absence of approved therapies, physicians rely on drugs developed for other purposes to treat adenovirus infections. As there is a need for anti-adenoviral therapies, researchers have been developing new agents and repurposing existing ones to treat adenovirus infections. There are several small molecule drugs that are being tested for their efficacy against human adenoviruses; some of these have reached clinical trials, while others are still in the preclinical phase. Besides these compounds, research on immunotherapy against adenoviral infection has made significant progress, promising another modality for treatment. The availability of an animal model confirmed the activity of some drugs already in clinical use while proving that others are inactive. This led to the identification of several lead compounds that await further development. In the present article, we review the current status of anti-adenoviral therapies and their advancement by in vivo studies in the Syrian hamster model.

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Karimi, Ali, Mohammad-Taghi Moradi, Mohammad Rabiei, and Somayeh Alidadi. "In vitro anti-adenoviral activities of ethanol extract, fractions, and main phenolic compounds of pomegranate (Punica granatum L.) peel." Antiviral Chemistry and Chemotherapy 28 (January 2020): 204020662091657. http://dx.doi.org/10.1177/2040206620916571.

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Background Adenovirus causes a number of diseases in human, and can cause serious infection in severely immunosuppressed individuals. Despite the seriousness of adenovirus infection, there is no definitely approved anti-adenoviral therapy. Many studies have shown that compounds derived from medicinal plants have antiviral activity. Therefore, this study evaluated in vitro anti-adenoviral activity of ethanol extract, fractions, and main phenolic compounds of pomegranate peel. Methods The ethanol extract of pomegranate peel was prepared with maceration method and fractionated by consecutive liquid/liquid partition. The cytotoxic and anti-adenovirus activities of the extract, fractions, and main phenolic compounds (ellagic acid, punicalagin and gallic acid) were evaluated on Hep-2 cell line using MTT assay. Inhibitory effect on adsorption and post-adsorption phases of the virus replication cycle was also evaluated. Results Pomegranate peel extract had a desirable effect against adenovirus with IC50 of 5.77 µg/mL and selectivity index of 49.9. Among the fractions and compounds, the n-butanol fraction and gallic acid had the highest anti-adenoviral activity with IC50 of 2.16 µg/mL and 4.67 µM and selectivity indices of 122.5 and 10.5, respectively. The crude extract, n-butanol fraction and gallic acid inhibited the virus replication in post-adsorption phase ( p < 0.01). Conclusion Pomegranate peel extract, especially its n-butanol fraction, could serve as a new promising anti-adenovirus agent due to high inhibitory effect against adenovirus replication. The effect of the n-butanol fraction may be related to the synergistic effect or other compounds of this fraction. Further understanding of the bioassay guided isolation of natural compounds of this fraction seems essential.

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Chirmule, Narendra, Alemseged Truneh, Sarah Ehlen Haecker, John Tazelaar, Guang-ping Gao, Steven E. Raper, Joseph V. Hughes, and James M. Wilson. "Repeated Administration of Adenoviral Vectors in Lungs of Human CD4 Transgenic Mice Treated with a Nondepleting CD4 Antibody." Journal of Immunology 163, no. 1 (July 1, 1999): 448–55. http://dx.doi.org/10.4049/jimmunol.163.1.448.

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Abstract The central role of CD4+ T cells in regulation of adenovirus vector-mediated immune responses has been documented previously in murine models. We analyzed the effects of a nondepleting mAb to human CD4 (CD4 mAb; Clenoliximab) on immune functions following intratracheal administration of adenoviral vectors in murine CD4-deficient mice (muCD4KO) expressing a human CD4 transgene (HuCD4 mice). Treatment of HuCD4 mice with Clenoliximab inhibited both cell-mediated and humoral immune responses to adenoviral Ags. Chronic treatment of HuCD4 mice with Clenoliximab permitted successful readministration of adenoviral vectors at least four times. The ability to readminister these vectors is associated with marked suppression of neutralizing Ab responses to viral capsid proteins. Clenoliximab also inhibited CTL and prolonged expression of the transgene. T or B cell responses to adenovirus did not emerge after the effects of a short course of Clenoliximab diminished. These data illustrate the potential utility of a nondepleting CD4 Ab in facilitating gene therapy using adenoviral vectors.

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Afrough, Sara, Sophie Rhodes, Thomas Evans, Richard White, and John Benest. "Immunologic Dose-Response to Adenovirus-Vectored Vaccines in Animals and Humans: A Systematic Review of Dose-Response Studies of Replication Incompetent Adenoviral Vaccine Vectors when Given via an Intramuscular or Subcutaneous Route." Vaccines 8, no. 1 (March 17, 2020): 131. http://dx.doi.org/10.3390/vaccines8010131.

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Optimal vaccine dosing is important to ensure the greatest protection and safety. Analysis of dose-response data, from previous studies, may inform future studies to determine the optimal dose. Implementing more quantitative modelling approaches in vaccine dose finding have been recently suggested to accelerate vaccine development. Adenoviral vectored vaccines are in advanced stage of development for a variety of prophylactic and therapeutic indications, however dose-response has not yet been systematically determined. To further inform adenoviral vectored vaccines dose identification, historical dose-response data should be systematically reviewed. A systematic literature review was conducted to collate and describe the available dose-response studies for adenovirus vectored vaccines. Of 2787 papers identified by Medline search strategy, 35 were found to conform to pre-defined criteria. The majority of studies were in mice or humans and studied adenovirus serotype 5. Dose-response data were available for 12 different immunological responses. The majority of papers evaluated three dose levels, only two evaluated more than five dose levels. The most common dosing range was 107–1010 viral particles in mouse studies and 108–1011 viral particles in human studies. Data were available on adenovirus vaccine dose-response, primarily on adenovirus serotype 5 backbones and in mice and humans. These data could be used for quantitative adenoviral vectored vaccine dose optimisation analysis.

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Chirmule, Narendra, Steven E. Raper, Linda Burkly, David Thomas, John Tazelaar, Joseph V. Hughes, and James M. Wilson. "Readministration of Adenovirus Vector in Nonhuman Primate Lungs by Blockade of CD40-CD40 Ligand Interactions." Journal of Virology 74, no. 7 (April 1, 2000): 3345–52. http://dx.doi.org/10.1128/jvi.74.7.3345-3352.2000.

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ABSTRACT The interaction between CD40 on B cells and CD40 ligand (CD40L) on activated T cells is important for B-cell differentiation in T-cell-dependent humoral responses. We have extended our previous murine studies of CD40-CD40L in adenoviral vector-mediated immune responses to rhesus monkeys. Primary immune responses to adenoviral vectors and the ability to readminister vector were studied in rhesus monkeys in the presence or absence of a transient treatment with a humanized anti-CD40 ligand antibody (hu5C8). Adult animals were treated with hu5C8 at the time vector was instilled into the lung. Immunological analyses demonstrated suppression of adenovirus-induced lymphoproliferation and cytokine responses (interleukin-2 [IL-2], gamma interferon, IL-4, and IL-10) in hu5C8-treated animals. Animals treated with hu5C8 secreted adenovirus-specific immunoglobulin M (IgM) levels comparable to control animals, but did not secrete IgA or develop neutralizing antibodies; consequently, the animals could be readministered with adenovirus vector expressing alkaline phosphatase. A second study was designed to examine the long-term effects on immune functions of a short course of hu5C8. Acute hu5C8 treatment resulted in significant and prolonged inhibition of the adenovirus-specific humoral response well beyond the time hu5C8 effects were no longer significant. These studies demonstrate the potential of hu5C8 as an immunomodulatory regimen to enable administration of adenoviral vectors, and they advocate testing this model in humans.

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Kitazono, Masaki, Vemulkonda Koneti Rao, Rob Robey, Takashi Aikou, Susan Bates, Tito Fojo, and Merrill E. Goldsmith. "Histone deacetylase inhibitor FR901228 enhances adenovirus infection of hematopoietic cells." Blood 99, no. 6 (March 15, 2002): 2248–51. http://dx.doi.org/10.1182/blood.v99.6.2248.

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Abstract Adenovirus infection of hematopoietic cells frequently requires high virus concentrations and long incubation times to obtain moderate infection levels because these cells have low levels of Coxsackie and adenovirus receptor (CAR) and αv integrin. The effect of treatment with FR901228 (depsipeptide), a histone deacetylase inhibitor in phase 2 clinical trials, was studied in K562 cells, granulocyte–colony-stimulating factor–mobilized peripheral blood mononuclear cells (PBMCs), and CD34+ peripheral blood stem cells (PBSCs). FR901228 increased CAR and αvintegrin RNA levels and histone H3 acetylation. FR901228 treatment before adenovirus infection was associated with at least a 10-fold increase in transgene expression from a β-galactosidase–expressing adenoviral vector. More than 80% of the PBMCs or CD34+ PBSCs from 7 different donors were β-galactosidase–positive after adenovirus infection with a multiplicity of infection of 10 for 60 minutes. Increased CAR, αv integrin, and acetylated histone H3 levels were observed in PBMCs from a patient treated with FR901228. These studies suggest that FR901228 can increase the efficiency of adenoviral infection in hematopoietic cells.

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Mitsuishi, Michiko, Seiko Masuda, Ichiro Kudo, and Makoto Murakami. "Group V and X secretory phospholipase A2 prevents adenoviral infection in mammalian cells." Biochemical Journal 393, no. 1 (December 12, 2005): 97–106. http://dx.doi.org/10.1042/bj20050781.

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sPLA2 (secretory phospholipase A2) enzymes have been implicated in various biological events, yet their precise physiological functions remain largely unresolved. In the present study we show that group V and X sPLA2s, which are two potent plasma membrane-acting sPLA2s, are capable of preventing host cells from being infected with an adenovirus. Bronchial epithelial cells and lung fibroblasts pre-expressing group V and X sPLA2s showed marked resistance to adenovirus-mediated gene delivery in a manner dependent on their catalytic activity. Although adenovirus particles were insensitive to recombinant group V and X sPLA2s, direct addition of these enzymes to 293A cells suppressed both number and size of adenovirus plaque formation. Group V and X sPLA2s retarded the entry of adenovirus into endosomes. Moreover, adenoviral infection was suppressed by LPC (lysophosphatidylcholine), a membrane-hydrolytic product of these sPLA2s. Thus hydrolysis of the plasma membrane by these sPLA2s may eventually lead to the protection of host cells from adenovirus entry. Given that group V and X sPLA2s are expressed in human airway epithelium and macrophages and that the expression of endogenous group V sPLA2 is upregulated by virus-related stimuli in these cells, our present results raise the possibility that group V and X sPLA2s may play a role in innate immunity against adenoviral infection in the respiratory tract.

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Barcia, Carlos, Christian Gerdes, Wei-Dong Xiong, Clare E. Thomas, Chunyan Liu, Kurt M. Kroeger, Maria G. Castro, and Pedro R. Lowenstein. "Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells." Neuron Glia Biology 2, no. 4 (November 2006): 309–22. http://dx.doi.org/10.1017/s1740925x07000579.

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AbstractFirst-generation adenovirus can be engineered with powerful promoters to drive expression of therapeutic transgenes. Numerous clinical trials for glioblastoma multiforme using first generation adenoviral vectors have either been performed or are ongoing, including an ongoing, Phase III, multicenter trial in Europe and Israel (Ark Therapeutics, Inc.). Although in the absence of anti-adenovirus immune responses expression in the brain lasts 6–18 months, systemic infection with adenovirus induces immune responses that inhibit dramatically therapeutic transgene expression from first generation adenoviral vectors, thus, potentially compromising therapeutic efficacy. Here, we show evidence of an immunization threshold for the dose that generates an immune response strong enough to eliminate transgene expression from the CNS. For the systemic immunization to eliminate transgene expression from the brain, ≥1×107 infectious units (iu) of adenovirus need to be used as immunogen. Furthermore, this immune response eliminates >90% of transgene expression from 1×107–1×103 iu of vector injected into the striatum 60 days earlier. Importantly, elimination of transgene expression is independent of the nature of the promoter that drives transgene expression and is accompanied by brain infiltration of CD8+ T cells and macrophages. In conclusion, once the threshold for systemic immunization (i.e. 1×107 iu) is crossed, the immune response eliminates transgene expression by >90% even from brains that receive as little as 1000 iu of adenoviral vectors, independently of the type of promoter that drives expression.

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Christian, Vikram J., Raiya Sarwar, Joseph C. Resch, Sarah Lim, Arif Somani, Catherine Larson-Nath, Shane McAllister, et al. "Use of Cidofovir for Safe Transplantation in a Toddler with Acute Liver Failure and Adenovirus Viremia." Case Reports in Transplantation 2022 (November 9, 2022): 1–5. http://dx.doi.org/10.1155/2022/9426175.

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Background. Since October 2021, there have been more than 500 cases of severe hepatitis of unknown origin in children reported worldwide, including 180 cases in the U.S. The most frequently detected potential pathogen to date has been adenovirus, typically serotype 41. Adenovirus is known to cause a self-limited infection in the immunocompetent host. However, in immunosuppressed individuals, severe or disseminated infections may occur. Method. We present the case of a two-year-old female who presented with cholestatic hepatitis and acute liver failure (ALF). Work up for etiologies of ALF was significant for adenovirus viremia, but liver biopsy was consistently negative for the virus. The risk for severe adenoviral infection in the setting of anticipated immunosuppression prompted us to initiate cidofovir to decrease viral load prior to undergoing liver transplantation. Result. Our patient received a successful liver transplant, cleared the viremia after 5 doses of cidofovir, and continues to maintain allograft function without signs of infection at the time of this report, 5 months posttransplant. Conclusion. Recent reports of pediatric hepatitis cases may be associated with adenoviral infection although the exact relationship is unclear. There is the possibility of the ongoing SARS-CoV-2 environment, or other immunologic modifying factors. All patients presenting with hepatitis or acute liver failure should be screened for adenovirus and reported to state health departments. Cidofovir may be used to decrease viral load prior to liver transplantation, to decrease risk of severe adenoviral infection.

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Kelley, Cynthia. "A Fatal Case of Neonatal Adenovirus Infection." Neonatal Network 29, no. 5 (September 2010): 297–305. http://dx.doi.org/10.1891/0730-0832.29.5.297.

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Adenovirus can produce severe disease and even death in the immunocompromised neonate. Symptoms of adenovirus infection are similar to those seen with bacterial infections in neonates, making early recognition and diagnosis difficult. Consideration of adenovirus as a causative agent is important to early diagnosis. Currently available culture techniques, particularly the shell vial culture technique, make more rapid identification of adenovirus infection possible. Early identification and treatment are necessary to improve patient outcomes and prevent the spread of infection to other neonates. Available agents for the treatment of adenovirus have had mixed results, yet their use is preferable to nontreatment of critical patients. This article presents the case of a preterm infant who became fatally ill from disseminated adenoviral infection.

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Benkő, Mária, Péter Élő, Krisztina Ursu, Winfried Ahne, Scott E. LaPatra, Darelle Thomson, and Balázs Harrach. "First Molecular Evidence for the Existence of Distinct Fish and Snake Adenoviruses." Journal of Virology 76, no. 19 (October 1, 2002): 10056–59. http://dx.doi.org/10.1128/jvi.76.19.10056-10059.2002.

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ABSTRACT From adenovirus-like viruses originating from a fish and a snake species, a conserved part of the adenoviral DNA polymerase gene was PCR amplified, cloned and sequenced. Phylogenetic analysis showed that the snake adenovirus is closely related to the members of the proposed genus Atadenovirus, whereas the fish isolate seems to represent a separate cluster, likely a new genus.

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Ikegami, Machiko, Kevin S. Harrod, Jeffrey A. Whitsett, and Alan H. Jobe. "CCSP deficiency does not alter surfactant homeostasis during adenoviral infection." American Journal of Physiology-Lung Cellular and Molecular Physiology 277, no. 5 (November 1, 1999): L983—L987. http://dx.doi.org/10.1152/ajplung.1999.277.5.l983.

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Clara cell secretory protein (CCSP) deficiency in mice is associated with increased susceptibility to pulmonary inflammation after hyperoxia or viral infection. Because adenoviral exposure perturbs pulmonary surfactant homeostasis in vivo, we hypothesized that CCSP deficiency would influence surfactant metabolism after pulmonary infection. Alveolar and total lung saturated phosphatidylcholine pool sizes were similar in CCSP-deficient [CCSP(−/−)] and wild-type [CCSP(+/+)] mice before and 7 days after intratracheal administration of adenovirus. Radiolabeled choline and palmitate incorporation into saturated phosphatidylcholine was similar, and there was no alteration by previous infection 7 days before the incorporation measurements. Furthermore, CCSP deficiency did not influence clearance of [14C]dipalmitoylphosphatidylcholine and 125I-labeled recombinant surfactant protein C. Increased persistence of alveolar capillary leak was observed in CCSP(−/−) mice after adenoviral infection. Surfactant lipid homeostasis was not influenced by CCSP before or after administration of adenovirus to the lung. Persistence of alveolar capillary leak in CCSP(−/−) mice after adenovirus provides further evidence for the role of CCSP in the regulation of pulmonary inflammation.

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Leen, Ann M., Anne Christin, Mariam Khalil, Heidi Weiss, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, Cliona M. Rooney, and Catherine M. Bollard. "Identification of Hexon-Specific CD4 and CD8 T-Cell Epitopes for Vaccine and Immunotherapy." Journal of Virology 82, no. 1 (October 17, 2007): 546–54. http://dx.doi.org/10.1128/jvi.01689-07.

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ABSTRACT Adenoviral infections in the immunocompromised host are associated with significant morbidity and mortality. Although the adoptive transfer of adenovirus-specific T cells may prevent and treat such infections, the T-cell immune response to the multiplicity of adenovirus serotypes and subspecies that infect humans has not been well characterized, impeding the development of such approaches. We have, therefore, analyzed the specificities of T-cell responses to the viral capsid hexon antigen, since this structure is highly conserved in human pathogens. We screened 25 human cytotoxic T-cell lines with adenovirus specificity to extensively characterize their responses to adenoviral hexon and to identify a panel of novel CD4+ and CD8+ T-cell epitopes. Using a peptide library spanning the entire sequence of the hexon protein, we confirmed the responsiveness of these cytotoxic T-cell lines to seven peptides described previously and also identified 33 new CD4- or CD8-restricted hexon epitopes. Importantly, the majority of these epitopes were shared among different adenovirus subspecies, suggesting that T cells with such specificities could recognize and be protective against multiple serotypes, simplifying the task of effective adoptive transfer or vaccine-based immunotherapy for treating infection by this virus.

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Twomey, David F., Sylvia S. Grierson, Francesca Martelli, Robert J. Higgins, and Martin Jeffrey. "Enteritis in an alpaca (Vicugna pacos) associated with a potentially novel adenovirus." Journal of Veterinary Diagnostic Investigation 24, no. 5 (July 11, 2012): 1000–1003. http://dx.doi.org/10.1177/1040638712452109.

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Adenovirus-associated enteritis was diagnosed by histopathology of small intestine in a 2-year-old alpaca ( Vicugna pacos). Electron microscopy confirmed intracytoplasmic and intranuclear adenoviral particles within enterocytes. Nucleic acid was extracted from paraffin-embedded tissue sections, and a pan-adenovirus nested polymerase chain reaction (PCR) assay was employed to target a partial sequence of the polymerase gene. The PCR product (321 bp) was cloned and sequenced. Comparison of the nucleotide sequence against the National Center for Biotechnology Information (NCBI) nucleotide database demonstrated 68% identity with the isolates Canine adenovirus 1 and Bovine adenovirus 3. Comparison of the predicted amino acid sequence against the NCBI database demonstrated 75% identity with Bovine adenovirus 3. Phylogenetic analysis supported the relatively close relationship of this isolate to Bovine adenovirus 3, but the alpaca isolate was sufficiently distant to be considered a potentially novel adenovirus for this species.

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Mezentseva, A. V., E. V. Skorobogatova, A. E. Burya, K. I. Kirgizov, V. V. Konstantinova, E. B. Machneva, and E. A. Pristanskova. "Clinical case of curing a generalized adenovirus infection on the background of graft versus host reaction in a child after bone marrow transplantation from a haploidentical donor." Russian Journal of Pediatric Hematology and Oncology 6, no. 1 (February 12, 2019): 61–66. http://dx.doi.org/10.21682/2311-1267-2019-6-1-61-66.

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Adenovirus infection is one of the causes of transplant-associated mortality after allogeneic hematopoietic stem cell transplantation. Fulminant liver failure with adenovirus infection is a diagnostic and therapeutic problem due to its aggressive clinical course and extremely poor prognosis, while modern methods of treating adenovirus infection are based on the use of virostatic drugs and virus-specific lymphocytes and are associated with severe side effects. The article presents a rare clinical case of elimination of disseminated adenoviral infection with fulminantly developing liver failure in a patient after allogeneic bone marrow transplantation from a haploidentical donor.

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Richardson, Ciarán, Paul Brennan, Martin Powell, Stuart Prince, Yun-Hsiang Chen, O. Brad Spiller, and Martin Rowe. "Susceptibility of B lymphocytes to adenovirus type 5 infection is dependent upon both coxsackie–adenovirus receptor and αvβ5 integrin expression." Journal of General Virology 86, no. 6 (June 1, 2005): 1669–79. http://dx.doi.org/10.1099/vir.0.80806-0.

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Human lymphocytes are resistant to genetic modification, particularly from recombinant adenoviruses, thus hampering the analysis of gene function using adenoviral vectors. This study engineered an Epstein–Barr virus-transformed B-lymphoblastoid cell line permissive to adenovirus infection and elucidated key roles for both the coxsackie–adenovirus receptor and αvβ5 integrin in mediating entry of adenoviruses into these cells. The work identified a strategy for engineering B cells to become susceptible to adenovirus infection and showed that such a strategy could be useful for the introduction of genes to alter lymphoblastoid-cell gene expression.

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Sundaramurthy, Raja, Rahul Dhodapkar, Subashini Kaliaperumal, and Belgode Narasimha Harish. "Investigational approach to adenoviral conjunctivitis: comparison of three diagnostic tests using a Bayesian latent class model." Journal of Infection in Developing Countries 12, no. 01 (January 31, 2018): 043–51. http://dx.doi.org/10.3855/jidc.9439.

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Introduction: Highly contagious adenoviral conjunctivitis represents 15-70% of all conjunctivitis worldwide. Human adenovirus (hAdV) serotypes 3,4,7,8,19 and 37 contributes to 89% of all adenoviral conjunctivitis. Accurate and rapid diagnosis of adenoviral infections at serotype level could prevent misdiagnosis, spread of disease, unnecessary antibiotic use and increased treatment costs. Methodology: Sixty-two suspected viral conjunctivitis cases were recruited from November2013-January2015. Swabs collected from inferior palpebral conjunctiva and processed for viral culture (Hep2 cell line), immunofluorescence assay (IFA) and polymerase chain reaction (PCR) (targeting hexon gene). Serotype 3,4,7,8,19 and 37 identification was carried out with an optimized multiplex-PCR (based on hypervariable region of hexon gene) and confirmed by sequence analysis. Bayesian Latent Class Model (LCM) analysis was used to compare sensitivity and specificity of three tests. Results: Adenovirus was detected in 54.8% (34/62) of cases by combination of all three methods. Culture was positive in 23/34 cases (67.6%). PCR and IFA detected adenovirus in 24 (70.5%) and 21 (61.7%) cases respectively. LCM analysis revealed, sensitivity and specificity of PCR, Culture and IFA was 77.8% and 92.4%; 72.2% and 90.8%; 67.6% and 92.9% respectively. Serotyping by multiplex-PCR showed, two cases each were hAdV3 and hAdV4, 18 hAdV8 and two remained unidentified. Results of Multiplex-PCR and sequence analysis showed 100% concordance Conclusion: LCM analysis revealed, PCR is the most appropriate method for identification. Multiplex-PCR is a simple and rapid method (serotypes identification within two days); owing its short turnaround time and accuracy, it can be used as a diagnostic tool for surveillance of adenoviral keratoconjunctivitis.

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Lee, Benjamin H., Rahul Kushwah, Paul Bertics, and Jim Hu. "ATP plays a role as a danger signal that activates macrophages during adenoviral infection (133.38)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 133.38. http://dx.doi.org/10.4049/jimmunol.182.supp.133.38.

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Abstract We have previously shown that adenovirus infection of epithelial cells and macrophages co-culture resulted in synergistic induction of pro-inflammatory mediators such as cytokines, nitric oxide (NO), and reactive oxygen species (ROS) and caused cytotoxic responses. Here, we investigated whether ATP plays a role during the inflammatory response against adenovirus using the co-culture system. We found that pre-treatment of the co-culture with oxidized-ATP inhibited induction of NO and ROS and reduced cytotoxicity during adenoviral infection. Furthermore, we demonstrated that ATP signalling through P2X7 receptor is required in generation of NO and ROS using P2X7 deficient macrophage cell line. These results indicate that ATP plays a role as a danger signal to regulate macrophage activation during inflammatory response against adenoviral infection.

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B, Tadesse. "Review on Adeno Virus; As a Vaccine Vehicle." Open Access Journal of Veterinary Science & Research 2, no. 3 (2017): 1–12. http://dx.doi.org/10.23880/oajvsr-16000138.

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Adenoviruses have moved to the forefront of vaccinology and are showing substantial prom ise as vehicles for antigen delivery for a number of vaccines currently being developed. Most studies to date have focused on human serotype adenoviruses, particularly human adenovirus type 5. Human serotype adenovirus vaccine vectors are particularly usef ul for development of veterinary vaccines as neutralizing antibodies to the vector will not usually be present in the vaccinates. Most vectors currently used as vaccine carriers are deleted in E1 gene. The original E1 deleted adenoviral vectors were constr ucted by homologous recombination. Replication incompetent vectors contain an antigen expression cassette substituted for the deleted E1A – E1B region. These replication incompitant adenoviruses can not replicate because of the deletion of the essential vir al E1 gene region containing two genes. Replication competent adenoviral vectors encode all of the remaining adenoviral antigens in addition to the transgene product, i.e., the vaccine antigen. The potential for adenoviruses to elicit powerful B cell and T cell responses in the mammalian host are the main reason for the use of these vectors in vaccine development. For effective veterinary use, extensive research on adenoviral vaccine vectors should be undertaken.

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Bayer, Wibke, Matthias Tenbusch, Ruth Lietz, Lena Johrden, Simone Schimmer, Klaus Überla, Ulf Dittmer, and Oliver Wildner. "Vaccination with an Adenoviral Vector That Encodes and Displays a Retroviral Antigen Induces Improved Neutralizing Antibody and CD4+ T-Cell Responses and Confers Enhanced Protection." Journal of Virology 84, no. 4 (December 9, 2009): 1967–76. http://dx.doi.org/10.1128/jvi.01840-09.

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ABSTRACT We present a new type of adenoviral vector that both encodes and displays a vaccine antigen on the capsid, thus combining in itself gene-based and protein vaccination; this vector resulted in an improved vaccination outcome in the Friend virus (FV) model. For presentation of the envelope protein gp70 of Friend murine leukemia virus on the adenoviral capsid, gp70 was fused to the adenovirus capsid protein IX. When compared to vaccination with conventional FV Env- and Gag-encoding adenoviral vectors, vaccination with the adenoviral vector that encodes and displays pIX-gp70 combined with an FV Gag-encoding vector resulted in significantly improved protection against systemic FV challenge infection, with highly controlled viral loads in plasma and spleen. This improved protection correlated with improved neutralizing antibody titers and stronger CD4+ T-cell responses. Using a vector that displays gp70 without encoding it, we found that while the antigen display on the capsid alone was sufficient to induce high levels of binding antibodies, in vivo expression was necessary for the induction of neutralizing antibodies. This new type of adenovirus-based vaccine could be a valuable tool for vaccination.

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Farkas, Judit, M. C. Horzinek, H. F. Egberink, H. Vennema, Mária Benkő, and B. Lakatos. "DETECTION OF ADENOVIRUS HEXON SEQUENCE IN A CAT BY POLYMERASE CHAIN REACTION (SHORT COMMUNICATION)." Acta Veterinaria Hungarica 47, no. 4 (November 1, 1999): 493–97. http://dx.doi.org/10.1556/avet.47.1999.4.9.

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Adenoviral nucleic acid was detected by polymerase chain reaction (PCR) in pharyngeal and rectal swab samples of a cat seropositive for adenovirus and suffering from transient hepatic failure. The samples were taken at a one-year interval, and both faecal samples as well as the second pharyngeal sample were positive in PCR performed with general adenovirus primers. The size of the amplified products corresponded to that of the positive control. The identity of the amplicons was also confirmed by DNA sequencing. The 301 bp long hexon gene fragment was very similar to but distinguishable from the corresponding hexon sequence of human adenovirus type 2. This result suggests the possibility of persistent carrier status and shedding of adenovirus in cats.

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Roy, Soumitra, Yan Zhi, Gary P. Kobinger, Joanita Figueredo, Roberto Calcedo, James R. Miller, Heinz Feldmann, and James M. Wilson. "Generation of an adenoviral vaccine vector based on simian adenovirus 21." Journal of General Virology 87, no. 9 (September 1, 2006): 2477–85. http://dx.doi.org/10.1099/vir.0.81989-0.

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Adenoviral vectors can be used to generate potent humoral and cellular immune responses to transgene products. Use of adenoviral vectors based on non-human isolates may allow for their utilization in populations harbouring neutralizing antibodies to common human serotypes. A vector chimera was constructed using simian adenovirus 22 (a serotype belonging to the species Human adenovirus E) and simian adenovirus 21 (a serotype belonging to the species Human adenovirus B) expressing the Ebola (Zaire) virus glycoprotein (Ad C5/C1-ZGP). This chimeric adenovirus vector was used as a model to test its efficacy as a genetic vaccine and comparisons were made to a vector based on the commonly used human adenovirus C serotype 5 (Adhu5-ZGP). Ebola glycoprotein-specific T- and B-cell responses were measured in B10BR mice vaccinated with either Adhu5-ZGP or Ad C5/C1-ZGP vectors. Both vectors resulted in Ebola glycoprotein-specific gamma interferon-expressing T cells, although the Ad C5/C1-ZGP vector appeared to induce lower frequencies with kinetics slower than those elicited by the Adhu5-ZGP vector. The total immunoglobulin G response to Ebola glycoprotein was similar in sera from mice vaccinated with either vector. Two rhesus macaques vaccinated with the Ad C5/C1-ZGP vector were found to mount T-cell and antibody responses to the Ebola glycoprotein. It was found that a single administration of the chimeric Ad C5/C1-ZGP vector protected mice against a lethal challenge with a mouse-adapted strain of the Ebola (Zaire) virus.

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Tsoukas, Raphael L., Wolfram Volkwein, Jian Gao, Maren Schiwon, Nora Bahlmann, Thomas Dittmar, Claudia Hagedorn, et al. "A Human In Vitro Model to Study Adenoviral Receptors and Virus Cell Interactions." Cells 11, no. 5 (March 1, 2022): 841. http://dx.doi.org/10.3390/cells11050841.

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To develop adenoviral cell- or tissue-specific gene delivery, understanding of the infection mechanisms of adenoviruses is crucial. Several adenoviral attachment proteins such as CD46, CAR and sialic acid have been identified and studied. However, most receptor studies were performed on non-human cells. Combining our reporter gene-tagged adenovirus library with an in vitro human gene knockout model, we performed a systematic analysis of receptor usage comparing different adenoviruses side-by-side. The CRISPR/Cas9 system was used to knockout CD46 and CAR in the human lung epithelial carcinoma cell line A549. Knockout cells were infected with 22 luciferase-expressing adenoviruses derived from adenovirus species B, C, D and E. HAdV-B16, -B21 and -B50 from species B1 as well as HAdV-B34 and -B35 were found to be CD46-dependent. HAdV-C5 and HAdV-E4 from species E were found to be CAR-dependent. Regarding cell entry of HAdV-B3 and -B14 and all species D viruses, both CAR and CD46 play a role, and here, other receptors or attachment structures may also be important since transductions were reduced but not completely inhibited. The established human knockout cell model enables the identification of the most applicable adenovirus types for gene therapy and to further understand adenovirus infection biology.

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Deng, Weiwen, Troy A. Giambernardi, Rick V. Hay, Daniel W. Pietryga, and Aly S. Abdel-Mageed. "Adenovirus-Mediated Gene Transfer to Mesenchymal Stem Cells: Comparison of the Cytomegalovirus- and Rous Sarcoma Virus-Promoter." Blood 110, no. 11 (November 16, 2007): 5145. http://dx.doi.org/10.1182/blood.v110.11.5145.5145.

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Abstract We have compared the efficacy and toxicity of the cytomegalovirus (CMV) promoter and the Rous sarcoma virus (RSV) promoter for expressing genes for adenovirus-mediated gene transfer to mesenchymal stem cells (MSCs). Mouse MSCs (mMSCs) were isolated from the femurs and tibias of 6-week old, female BALB/c mice and ex vivo expanded in MEM-alpha containing 20% fetal bovine serum, 100 u/ml penicillin, 100 μg/ml streptomycin, 250 ng/ml amphotericin B, and 2 mM L-glutamine. To transduce mMSCs with adenovirus, the cells were plated at a density of 10,000 cells/cm2 in 6-well plates and cultured overnight. The cells were counted and then exposed to fresh culture medium containing adenovirus at 0 to 2,000 multiplicities of infection (MOI) for 48 h. Two adenoviral vectors with CMV promoter (Adv/CMV) and two adenoviral vectors with RSV promoter (Adv/RSV) were used in this study. Transduction efficiency and cell survival were then determined. The Adv/CMVs, i.e. AdvCMVlacZ and AdvCMVIL-10, were more potent in terms of transduction efficiency and transgene expression than their corresponding Adv/RSVs, i.e. AdvRSVlacZ and AdvRSVIL-10. However, both vectors exhibit a dose-dependent relationship between the adenoviral vector MOI and the percentage of transgene-expressing cells. Furthermore, no toxicity was observed in Adv/CMV or Adv/RSV transduced mMSCs.

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Serrano, Ryan M., Robert K. Darragh, and John J. Parent. "Successful treatment of disseminated adenovirus infection with cidofovir and intravenous immunoglobulin in an infant following heart transplant." Cardiology in the Young 28, no. 6 (April 25, 2018): 888–89. http://dx.doi.org/10.1017/s1047951118000379.

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AbstractFor most patients, adenoviruses cause few acute health concerns and are often self-limiting. Patients who are immunocompromised or immunosuppressed, however, are at risk for disseminated adenovirus and suffer high morbidity and mortality, without well-defined treatment options. We report the case of a 9-month-old boy who was successfully treated for disseminated adenovirus infection with intravenous immunoglobulin and cidofovir 3 months post heart transplant, tailored to serum adenoviral load and clinical response. We emphasise the importance of early identification, monitoring, and a potentially novel treatment in the paediatric cardiac transplant population with disseminated adenovirus infection.

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Nicke, Barbara, Min-Jen Tseng, Marycarol Fenrich, and Craig D. Logsdon. "Adenovirus-mediated gene transfer of RasN17 inhibits specific CCK actions on pancreatic acinar cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 276, no. 2 (February 1, 1999): G499—G506. http://dx.doi.org/10.1152/ajpgi.1999.276.2.g499.

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CCK stimulates pleiotrophic responses in pancreatic acinar cells; however, the intracellular signaling pathways involved are not well understood. To evaluate the role of the ras gene product in CCK actions, a strategy involving in vitro adenoviral-mediated gene delivery of a dominant-negative mutant Ras (RasN17) was utilized. Isolated acini were infected with various titers of either a control adenovirus or an adenoviral construct expressing RasN17 for 24 h before being treated with CCK. Titer-dependent expression of RasN17 in the acini was confirmed by Western blotting. Infection with control adenovirus [106–109plaque-forming units/mg acinar protein (multiplicity of infection of ∼1–1,000)] had no effect on CCK stimulation of acinar cell amylase release, extracellular-regulated kinase (ERK) or c-Jun kinase (JNK) kinases, or DNA synthesis. In contrast, infection with adenovirus bearing ras N17 increased basal amylase release, inhibited CCK-mediated JNK activation, had no effect on CCK activation of ERK, and inhibited DNA synthesis. These data demonstrate important roles for Ras in specific actions of CCK on pancreatic acinar function.

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Crenshaw, Brennetta J., Leandra B. Jones, Courtnee’ R. Bell, Sanjay Kumar, and Qiana L. Matthews. "Perspective on Adenoviruses: Epidemiology, Pathogenicity, and Gene Therapy." Biomedicines 7, no. 3 (August 19, 2019): 61. http://dx.doi.org/10.3390/biomedicines7030061.

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Human adenoviruses are large (150 MDa) doubled-stranded DNA viruses that cause respiratory infections. These viruses are particularly pathogenic in healthy and immune-compromised individuals, and currently, no adenovirus vaccine is available for the general public. The purpose of this review is to describe (i) the epidemiology and pathogenicity of human adenoviruses, (ii) the biological role of adenovirus vectors in gene therapy applications, and (iii) the potential role of exosomes in adenoviral infections.

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Lakatos, Béla, Ákos Hornyák, Zoltán Demeter, Petra Forgách, Frances Kennedy, and Miklós Rusvai. "Detection of a putative novel adenovirus by PCR amplification, sequencing and phylogenetic characterisation of two gene fragments from formalin-fixed paraffin-embedded tissues of a cat diagnosed with disseminated adenovirus disease." Acta Veterinaria Hungarica 65, no. 4 (December 2017): 574–84. http://dx.doi.org/10.1556/004.2017.056.

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Adenoviral nucleic acid was detected by polymerase chain reaction (PCR) in formalin-fixed paraffin-embedded tissue samples of a cat that had suffered from disseminated adenovirus infection. The identity of the amplified products from the hexon and DNA-dependent DNA polymerase genes was confirmed by DNA sequencing. The sequences were clearly distinguishable from corresponding hexon and polymerase sequences of other mastadenoviruses, including human adenoviruses. These results suggest the possible existence of a distinct feline adenovirus.

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Affeldt, John, Neha Gadaria-Rathod, Karen B. Fernandez, and Penny A. Asbell. "Ganciclovir in the Treatment of Ophthalmic Viral Infections – Case Reports." US Ophthalmic Review 05, no. 02 (2012): 100. http://dx.doi.org/10.17925/usor.2012.05.02.100.

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Adenovirus is likely the most common cause of eye infections but remains a challenge for ophthalmologists to diagnose as well as treat. While ganciclovir gel is approved for the topical treatment of eye infections arising due to herpes simplex virus, it is not licensed for use against adenoviral conjunctivitis. This antiviral agent selectively targets infected cells and disrupts viral DNA replication. A small study and previous anecdotal reports had illustrated the potential of ganciclovir in improving symptoms and transmissibility of adenoviral eye infections. The present article describes a series of case studies where ganciclovir was used off label in the management of the morbidity caused by adenovirus. The observations are promising and suggest that ganciclovir can be used successfully in this patient population. However, large-scale randomised trials are needed to confirm these findings.

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Schröer, Katrin, Fatima Arakrak, Annika Bremke, Anja Ehrhardt, and Wenli Zhang. "HEHR: Homing Endonuclease-Mediated Homologous Recombination for Efficient Adenovirus Genome Engineering." Genes 13, no. 11 (November 16, 2022): 2129. http://dx.doi.org/10.3390/genes13112129.

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Adenoviruses are non-enveloped linear double-stranded DNA viruses with over 100 types in humans. Adenovirus vectors have gained tremendous attention as gene delivery vehicles, as vaccine vectors and as oncolytic viruses. Although various methods have been used to generate adenoviral vectors, the vector-producing process remains technically challenging regarding efficacious genome modification. Based on our previously reported adenoviral genome modification streamline via linear–circular homologous recombination, we further develop an HEHR (combining Homing Endonucleases and Homologous Recombination) method to engineer adenoviral genomes more efficiently. I-PpoI, a rare endonuclease encoded by a group I intron, was introduced into the previously described ccdB counter-selection marker. We found that the I-PpoI pre-treatment of counter-selection containing parental plasmid increased the homologous recombination efficiency up to 100%. The flanking of the counter-selection marker with either single or double I-PpoI sites showed enhanced efficacy. In addition, we constructed a third counter-selection marker flanked by an alternative restriction enzyme: AbsI, which could be applied in case the I-PpoI site already existed in the transgene cassette that was previously inserted in the adenovirus genome. Together, HEHR can be applied for seamless sequence replacements, deletions and insertions. The advantages of HEHR in seamless mutagenesis will facilitate rational design of adenoviral vectors for diverse purposes.

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Kim, Yun-Sun, Seung-Hee Han, Yeon-Jeong Kim, Hyun-Jeong Ko, Hae-Jung Park, Alexander V. Pereboev, Huan H. Nguyen, and Chang-Yuil Kang. "Increase of antigen expression and activation of APCs by targeting adenovirus to CD40 significantly enhanced therapeutic effect of antigen presenting cell-based anti-tumor vaccine (41.18)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 41.18. http://dx.doi.org/10.4049/jimmunol.182.supp.41.18.

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Abstract The efficacy of antigen presenting cell (APC)-based vaccines generated in vitro by genetic transduction critically depends on the expression level of target antigen and the activation status of APCs. Although APCs such as DCs and B cells transduced by recombinant adenovirus (AdV) readily induced antigen specific immune responses, they are relative resistant to adenoviral transduction due to the lack of coxsackievirus-adenovirus receptor (CAR), which mediates adenovirus entry. In this study, we used recombinant adapter molecule, CFm40L, which consists of CAR genetically fused to CD40 ligand via a trimerization motif, to target Her-2/neu or HPV16 E6/E7-encoding AdV to DCs and B cells that express CD40. Such transduced DCs and B cells enhanced substantially immunity against Her-2/neu or HPV16 E6/E7-expressing tumor resulted in significant inhibition of tumor growth. Especially, the anti-tumor effect of B cell-based vaccines transduced with CD40-targeted adenoviral vector is comparable to that of DC-based vaccines, indicating the feasibility of B cell-based vaccine for anti-cancer therapy. Our results suggest that targeting AdV to APC via CD40 using CFm40L offers a novel approach in anti-tumor therapy

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Turner, Roberta L., Peter Groitl, Thomas Dobner, and David A. Ornelles. "Adenovirus Replaces Mitotic Checkpoint Controls." Journal of Virology 89, no. 9 (February 18, 2015): 5083–96. http://dx.doi.org/10.1128/jvi.00213-15.

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ABSTRACTInfection with adenovirus triggers the cellular DNA damage response, elements of which include cell death and cell cycle arrest. Early adenoviral proteins, including the E1B-55K and E4orf3 proteins, inhibit signaling in response to DNA damage. A fraction of cells infected with an adenovirus mutant unable to express the E1B-55K and E4orf3 genes appeared to arrest in a mitotic-like state. Cells infected early in G1of the cell cycle were predisposed to arrest in this state at late times of infection. This arrested state, which displays hallmarks of mitotic catastrophe, was prevented by expression of either the E1B-55K or the E4orf3 genes. However, E1B-55K mutant virus-infected cells became trapped in a mitotic-like state in the presence of the microtubule poison colcemid, suggesting that the two viral proteins restrict entry into mitosis or facilitate exit from mitosis in order to prevent infected cells from arresting in mitosis. The E1B-55K protein appeared to prevent inappropriate entry into mitosis through its interaction with the cellular tumor suppressor protein p53. The E4orf3 protein facilitated exit from mitosis by possibly mislocalizing and functionally inactivating cyclin B1. When expressed in noninfected cells, E4orf3 overcame the mitotic arrest caused by the degradation-resistant R42A cyclin B1 variant.IMPORTANCECells that are infected with adenovirus type 5 early in G1of the cell cycle are predisposed to arrest in a mitotic-like state in a p53-dependent manner. The adenoviral E1B-55K protein prevents entry into mitosis. This newly described activity for the E1B-55K protein appears to depend on the interaction between the E1B-55K protein and the tumor suppressor p53. The adenoviral E4orf3 protein facilitates exit from mitosis, possibly by altering the intracellular distribution of cyclin B1. By preventing entry into mitosis and by promoting exit from mitosis, these adenoviral proteins act to prevent the infected cell from arresting in a mitotic-like state.

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Mantwill, Klaus, Florian Gerhard Klein, Dongbiao Wang, Sruthi Vasantamadhava Hindupur, Maximilian Ehrenfeld, Per Sonne Holm, and Roman Nawroth. "Concepts in Oncolytic Adenovirus Therapy." International Journal of Molecular Sciences 22, no. 19 (September 29, 2021): 10522. http://dx.doi.org/10.3390/ijms221910522.

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Oncolytic adenovirus therapy is gaining importance as a novel treatment option for the management of various cancers. Different concepts of modification within the adenovirus vector have been identified that define the mode of action against and the interaction with the tumour. Adenoviral vectors allow for genetic manipulations that restrict tumour specificity and also the expression of specific transgenes in order to support the anti-tumour effect. Additionally, replication of the virus and reinfection of neighbouring tumour cells amplify the therapeutic effect. Another important aspect in oncolytic adenovirus therapy is the virus induced cell death which is a process that activates the immune system against the tumour. This review describes which elements in adenovirus vectors have been identified for modification not only to utilize oncolytic adenovirus vectors into conditionally replicating adenoviruses (CRAds) that allow replication specifically in tumour cells but also to confer specific characteristics to these viruses. These advances in development resulted in clinical trials that are summarized based on the conceptual design.

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Perkins, Laura E. Leigh, Raymond P. Campagnoli, Barry G. Harmon, Christopher R. Gregory, W. L. Steffens, Ken Latimer, Susan Clubb, and Maria Crane. "Detection and Confirmation of Reptilian Adenovirus Infection by in Situ Hybridization." Journal of Veterinary Diagnostic Investigation 13, no. 4 (July 2001): 365–68. http://dx.doi.org/10.1177/104063870101300418.

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Adenovirus infections are documented in at least 12 different species of reptiles. In contrast to their mammalian and avian counterparts reptilian adenoviruses are not well characterized as to their pathogenic potential and their ability to cause primary disease. In the diagnostic setting, fresh tissues are often not available for virus isolation, and the confirmation of reptilian adenovirus infections is dependent largely upon electron microscopy for the identification of intranuclear viral inclusions associated with histopathologic changes. The diagnosis of adenovirus infection in 2 different species of snake was confirmed by the application of DNA in situ hybridization. Using an aviadenovirus specific oligoprobe, adenoviral DNA was observed in the nuclei of hepatocytes, Kupffer cells, endothelial cells, and enterocytes. Electron microscopy of the liver confirmed the presence of intranuclear viral particles morphologically consistent with an adenovirus. DNA in situ hybridization on formalin-fixed tissues can serve as a suitable alternative to electron microscopy in the diagnosis of reptilian adenovirus infections. Both affected snakes had other concurrent diseases, suggesting that the adenovirus may not have been the primary pathogen.

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Hensen, Lobke C. M., Rob C. Hoeben, and Selas T. F. Bots. "Adenovirus Receptor Expression in Cancer and Its Multifaceted Role in Oncolytic Adenovirus Therapy." International Journal of Molecular Sciences 21, no. 18 (September 17, 2020): 6828. http://dx.doi.org/10.3390/ijms21186828.

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Oncolytic adenovirus therapy is believed to be a promising way to treat cancer patients. To be able to target tumor cells with an oncolytic adenovirus, expression of the adenovirus receptor on the tumor cell is essential. Different adenovirus types bind to different receptors on the cell, of which the expression can vary between tumor types. Pre-existing neutralizing immunity to human adenovirus species C type 5 (HAdV-C5) has hampered its therapeutic efficacy in clinical trials, hence several adenoviral vectors from different species are currently being developed as a means to evade pre-existing immunity. Therefore, knowledge on the expression of appropriate adenovirus receptors on tumor cells is important. This could aid in determining which tumor types would benefit most from treatment with a certain oncolytic adenovirus type. This review provides an overview of the known receptors for human adenoviruses and how their expression on tumor cells might be differentially regulated compared to healthy tissue, before and after standardized anticancer treatments. Mechanisms behind the up- or downregulation of adenovirus receptor expression are discussed, which could be used to find new targets for combination therapy to enhance the efficacy of oncolytic adenovirus therapy. Additionally, the utility of the adenovirus receptors in oncolytic virotherapy is examined, including their role in viral spread, which might even surpass their function as primary entry receptors. Finally, future directions are offered regarding the selection of adenovirus types to be used in oncolytic adenovirus therapy in the fight against cancer.

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Pollack, Alisa, and Rick Varma. "Adenovirus-associated paraphimosis." International Journal of STD & AIDS 30, no. 8 (May 9, 2019): 825–27. http://dx.doi.org/10.1177/0956462419842448.

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We present the first reported case of paraphimosis associated with concurrent adenoviral urethritis and conjunctivitis in a heterosexual man. This case reinforces the need to consider adenovirus in the differential diagnosis of non-gonococcal urethritis and describes a potentially serious complication.

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Othman, Maha, Andrea Labelle, Ian Mazzetti, Hisham S. Elbatarny, and David Lillicrap. "Adenovirus-induced thrombocytopenia: the role of von Willebrand factor and P-selectin in mediating accelerated platelet clearance." Blood 109, no. 7 (December 5, 2006): 2832–39. http://dx.doi.org/10.1182/blood-2006-06-032524.

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AbstractThrombocytopenia has been consistently reported following the administration of adenoviral gene transfer vectors. The mechanism underlying this phenomenon is currently unknown. In this study, we have assessed the influence of von Willebrand Factor (VWF) and P-selectin on the clearance of platelets following adenovirus administration. In mice, thrombocytopenia occurs between 5 and 24 hours after adenovirus delivery. The virus activates platelets and induces platelet-leukocyte aggregate formation. There is an associated increase in platelet and leukocyte-derived microparticles. Adenovirus-induced endothelial cell activation was shown by VCAM-1 expression on virus-treated, cultured endothelial cells and by the release of ultra-large molecular weight multimers of VWF within 1 to 2 hours of virus administration with an accompanying elevation of endothelial microparticles. In contrast, VWF knockout (KO) mice did not show significant thrombocytopenia after adenovirus administration. We have also shown that adenovirus interferes with adhesion of platelets to a fibronectin-coated surface and flow cytometry revealed the presence of the Coxsackie adenovirus receptor on the platelet surface. We conclude that VWF and P-selectin are critically involved in a complex platelet-leukocyte-endothelial interplay, resulting in platelet activation and accelerated platelet clearance following adenovirus administration.

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Lin, Cheng-Wei. "Colchicine May Interfere With the Efficacy of the Adenoviral Vector–Based Vaccine for COVID-19." Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders 15 (January 2022): 117954412210810. http://dx.doi.org/10.1177/11795441221081061.

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Under the ongoing COVID-19 pandemic, vaccines have become the crucial players to reduce the spread of the infection. Among them, the ChAdOx1 nCoV-19 vaccine is an adenoviral vector vaccine with an overall efficacy of 70.4% in protection. The engineered adenovirus contains the SARS-CoV-2 spike protein gene and pushes its DNA into the vaccinated cell’s nucleus and subsequently, the spike protein can be made. During vaccination, the genome transition of adenovirus is influenced by the architecture and dynamics of the microtubule. Colchicine can alter microtubule dynamics by suppressing microtubule dynamics at lower concentrations and inducing depolymerization of microtubules at higher concentrations. Accordingly, the delivery of the genome to the vaccinated cell’s nucleus by the adenoviral vector could be hindered under the presence of colchicine. Nevertheless, colchicine is a common medication for gout therapy worldwide, and though not recommended by guidelines, colchicine has even been taken into consideration as a possible therapeutic option for COVID-19 infection. Given the above reasons and the worldwide use of colchicine, the impact of colchicine on the efficacy of the COVID-19 vaccine via adenoviral vector should be viewed cautiously.

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Xiang, Zhiquan, Guangping Gao, Arturo Reyes-Sandoval, Christopher J. Cohen, Yan Li, Jeffrey M. Bergelson, James M. Wilson, and Hildegund C. J. Ertl. "Novel, Chimpanzee Serotype 68-Based Adenoviral Vaccine Carrier for Induction of Antibodies to a Transgene Product." Journal of Virology 76, no. 6 (March 15, 2002): 2667–75. http://dx.doi.org/10.1128/jvi.76.6.2667-2675.2002.

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ABSTRACT An E1-deletion-containing adenoviral recombinant based on the chimpanzee serotype 68 (AdC68) was developed to express the rabies virus glycoprotein. Mice immunized with this construct (AdC68rab.gp) developed antibodies to rabies virus and remained resistant to challenge with an otherwise lethal dose of rabies virus. In naïve mice immunized intranasally, the rabies virus-specific antibody responses elicited by AdC68rab.gp were comparable with regard to both titers and isotype profiles to those induced by an adenoviral recombinant based on human serotype 5 (Adhu5) expressing the same transgene product. In contrast, subcutaneous immunization with the AdC68rab.gp vaccine resulted in markedly lower antibody responses to the rabies virus glycoprotein than the corresponding Adhu5 vaccine. Antibodies from AdC68rab.gp-immunized mice were strongly biased towards the immunoglobulin G2a isotype. The antibody response to the rabies virus glycoprotein presented by Adhu5rab.gp was severely compromised in animals preexposed to the homologous adenovirus. In contrast, the rabies virus-specific antibody response to the AdC68rab.gp vaccine was at most marginally affected by preexisting immunity to common human adenovirus serotypes, such as 2, 4, 5, 7, and 12. This novel vaccine carrier thus offers a distinct advantage over adenoviral vaccines based on common human serotypes.

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Journal articles on the topic 'Adenoviru'

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