Special Issue "Adenovirus Cell and Immune Interactions"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: 31 December 2021.

Special Issue Editor

Prof. Glen R. Nemerow
E-Mail Website
Guest Editor
Scripps Research Institute, Department of Microbiology and Immunology, San Diego, USA
Interests: virus-host receptor interactions;adenovirus structural biology;adenovirus-innate immune interactions

Special Issue Information

Ever since their discovery in the early 1950s, human adenoviruses (HAdVs), the cause of respiratory diseases of young children, have been the subject of intense basic research as well as efforts to engineer HAdV vectors to ameliorate human diseases. Although much information has been gleaned over the past 67 years from laboratory and clinical investigations, we still have an incomplete picture of the critical associations of HAdV with host cells and specific components of the immune system. An ability to uncover additional information will likely influence the future success (or failure) for exploiting HAdV vectors for gene and vaccine therapies.

Each chapter in this series will highlight the efforts and progress made to acquire basic knowledge of adenovirus host interactions and will indicate particular areas that remain to be uncovered. Topics in this new series include key steps in HAdV–host cell interactions as well as structure-based investigations of virus and virus capsid protein associations with cell receptors and innate immune molecules. These topics will culminate with discussions on examples of HAdV vector design and how these approaches are influenced by the accumulation of knowledge of host–vector interactions.

Prof. Glen R. Nemerow
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • adenovirus
  • gene therapy
  • vaccine
  • immune system
  • respiratory disease

Published Papers (9 papers)

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Research

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Article
IgG-Complexed Adenoviruses Induce Human Plasmacytoid Dendritic Cell Activation and Apoptosis
Viruses 2021, 13(9), 1699; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091699 - 27 Aug 2021
Viewed by 409
Abstract
Following repeat exposure to many human adenoviruses (HAdVs), most adults harbour long-lived B- and T-cell responses. Combined, this response typically protects us for years from re-infection by the same HAdV type. In spite of these immune responses, some HAdV types are associated with [...] Read more.
Following repeat exposure to many human adenoviruses (HAdVs), most adults harbour long-lived B- and T-cell responses. Combined, this response typically protects us for years from re-infection by the same HAdV type. In spite of these immune responses, some HAdV types are associated with persistent infections that constitute a life-threatening risk when an individual’s T-cell response is compromised. By contrast, patients with B-cell deficiencies do not appear to be at a greater risk of HAdV disease. This dichotomy begs the question of the secondary role of anti-HAdV antibodies during host defence. In this study, we explored IgG-complexed (IC)-HAdV5 and primary human plasmacytoid dendritic cell (pDC) interactions. We found that IC-HAdV5 are efficiently internalized in pDCs, stimulate their activation through TLR9 signalling, and cause apoptosis. These data may help reconcile the enigma of robust immune response to HAdVs, while concurrently allowing persistence. Full article
(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)
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Article
In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications
Viruses 2021, 13(8), 1483; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081483 - 28 Jul 2021
Viewed by 940
Abstract
The human adenovirus phylogenetic tree is split across seven species (A–G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of pre-existing immunity detected across screened populations. However, many aspects of the basic virology of species D—such as their [...] Read more.
The human adenovirus phylogenetic tree is split across seven species (A–G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of pre-existing immunity detected across screened populations. However, many aspects of the basic virology of species D—such as their cellular tropism, receptor usage, and in vivo biodistribution profile—remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49)—a relatively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry, but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting, whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells, and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen, whilst avoiding liver interactions, such as intravascular vaccine applications. Full article
(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)
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Communication
Intracellular Sequestration of the NKG2D Ligand MIC B by Species F Adenovirus
Viruses 2021, 13(7), 1289; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071289 - 01 Jul 2021
Viewed by 754
Abstract
The enteric human adenoviruses of species F (HAdVs-F), which comprise HAdV-F40 and HAdV-F41, are significant pathogens that cause acute gastroenteritis in children worldwide. The early transcription unit 3 (E3) of HAdVs-F is markedly different from that of all other HAdV species. To date, [...] Read more.
The enteric human adenoviruses of species F (HAdVs-F), which comprise HAdV-F40 and HAdV-F41, are significant pathogens that cause acute gastroenteritis in children worldwide. The early transcription unit 3 (E3) of HAdVs-F is markedly different from that of all other HAdV species. To date, the E3 proteins unique to HAdVs-F have not been characterized and the mechanism by which HAdVs-F evade immune defenses in the gastrointestinal (GI) tract is poorly understood. Here, we show that HAdV-F41 infection of human intestinal HCT116 cells upregulated the expression of MHC class I-related chain A (MIC A) and MIC B relative to uninfected cells. Our results also showed that, for MIC B, this response did not however result in a significant increase of MIC B on the cell surface. Instead, MIC B was largely sequestered intracellularly. Thus, although HAdV-F41 infection of HCT116 cells upregulated MIC B expression, the ligand remained inside infected cells. A similar observation could not be made for MIC A in these cells. Our preliminary findings represent a novel function of HAdVs-F that may enable these viruses to evade immune surveillance by natural killer (NK) cells in the infected gut, thereby paving the way for the future investigation of their unique E3 proteins. Full article
(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)
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Communication
Differential Regulation of Cellular FAM111B by Human Adenovirus C Type 5 E1 Oncogenes
Viruses 2021, 13(6), 1015; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061015 - 28 May 2021
Viewed by 1094
Abstract
The adenovirus type 5 (HAdV-C5) E1 transcription unit encodes regulatory proteins that are essential for viral replication and transformation. Among these, E1A and E1B-55K act as key multifunctional HAdV-C5 proteins involved in various steps of the viral replication cycle and in virus-induced cell [...] Read more.
The adenovirus type 5 (HAdV-C5) E1 transcription unit encodes regulatory proteins that are essential for viral replication and transformation. Among these, E1A and E1B-55K act as key multifunctional HAdV-C5 proteins involved in various steps of the viral replication cycle and in virus-induced cell transformation. In this context, HAdV-C5-mediated dysregulations of cellular factors such as the tumor suppressors p53 and pRB have been intensively investigated. However, cellular components of downstream events that could affect infection and viral transformation are widely unknown. We recently observed that cellular FAM111B is highly regulated in an E1A-dependent fashion. Intriguingly, previous reports suggest that FAM111B might play roles in tumorigenesis, but its exact functions are not known to date. Here, we set out to investigate the role of FAM111B in HAdV-C5 infections. We found that (i) FAM111B levels are upregulated early and downregulated late during infection, that (ii) FAM111B expression is differentially regulated, that (iii) FAM111B expression levels depend on the presence of E1B-55K and E4orf6 and that (iv) a FAM111B knockdown increases HAdV-C5 replication. Our data indicate that FAM111B acts as an anti-adenoviral host factor that is involved in host cell defense mechanisms in productive HAdV-C5 infection. Moreover, these findings suggest that FAM111B might play an important role in the host antiviral immune response that is counteracted by HAdV-C5 E1B-55K and E4orf6 oncoproteins. Full article
(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)
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Article
Heparan Sulfate Is a Cellular Receptor for Enteric Human Adenoviruses
Viruses 2021, 13(2), 298; https://0-doi-org.brum.beds.ac.uk/10.3390/v13020298 - 14 Feb 2021
Viewed by 840
Abstract
Human adenovirus (HAdV)-F40 and -F41 are leading causes of diarrhea and diarrhea-associated mortality in children under the age of five, but the mechanisms by which they infect host cells are poorly understood. HAdVs initiate infection through interactions between the knob domain of the [...] Read more.
Human adenovirus (HAdV)-F40 and -F41 are leading causes of diarrhea and diarrhea-associated mortality in children under the age of five, but the mechanisms by which they infect host cells are poorly understood. HAdVs initiate infection through interactions between the knob domain of the fiber capsid protein and host cell receptors. Unlike most other HAdVs, HAdV-F40 and -F41 possess two different fiber proteins—a long fiber and a short fiber. Whereas the long fiber binds to the Coxsackievirus and adenovirus receptor (CAR), no binding partners have been identified for the short fiber. In this study, we identified heparan sulfate (HS) as an interaction partner for the short fiber of enteric HAdVs. We demonstrate that exposure to acidic pH, which mimics the environment of the stomach, inactivates the interaction of enteric adenovirus with CAR. However, the short fiber:HS interaction is resistant to and even enhanced by acidic pH, which allows attachment to host cells. Our results suggest a switch in receptor usage of enteric HAdVs after exposure to acidic pH and add to the understanding of the function of the short fibers. These results may also be useful for antiviral drug development and the utilization of enteric HAdVs for clinical applications such as vaccine development. Full article
(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)
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Article
Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus
Viruses 2021, 13(1), 111; https://0-doi-org.brum.beds.ac.uk/10.3390/v13010111 - 15 Jan 2021
Viewed by 663
Abstract
Adenovirus (AdV) infection elicits a strong immune response with the production of neutralizing antibodies and opsonization by complement and coagulation factors. One anti-hexon neutralizing antibody, called 9C12, is known to activate the complement cascade, resulting in the deposition of complement component C4b on [...] Read more.
Adenovirus (AdV) infection elicits a strong immune response with the production of neutralizing antibodies and opsonization by complement and coagulation factors. One anti-hexon neutralizing antibody, called 9C12, is known to activate the complement cascade, resulting in the deposition of complement component C4b on the capsid, and the neutralization of the virus. The mechanism of AdV neutralization by C4b is independent of downstream complement proteins and involves the blockage of the release of protein VI, which is required for viral escape from the endosome. To investigate the structural basis underlying how C4b blocks the uncoating of AdV, we built a model for the complex of human adenovirus type-5 (HAdV5) with 9C12, together with complement components C1 and C4b. This model positions C4b near the Arg-Gly-Asp (RGD) loops of the penton base. There are multiple amino acids in the RGD loop that might serve as covalent binding sites for the reactive thioester of C4b. Molecular dynamics simulations with a multimeric penton base and C4b indicated that stabilizing interactions may form between C4b and multiple RGD loops. We propose that C4b deposition on one RGD loop leads to the entanglement of C4b with additional RGD loops on the same penton base multimer and that this entanglement blocks AdV uncoating. Full article
(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)
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Review

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Review
Genetic and Chemical Capsid Modifications of Adenovirus Vectors to Modulate Vector–Host Interactions
Viruses 2021, 13(7), 1300; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071300 - 02 Jul 2021
Viewed by 855
Abstract
Adenovirus-based vectors are playing an important role as efficacious genetic vaccines to fight the current COVID-19 pandemic. Furthermore, they have an enormous potential as oncolytic vectors for virotherapy and as vectors for classic gene therapy. However, numerous vector–host interactions on a cellular and [...] Read more.
Adenovirus-based vectors are playing an important role as efficacious genetic vaccines to fight the current COVID-19 pandemic. Furthermore, they have an enormous potential as oncolytic vectors for virotherapy and as vectors for classic gene therapy. However, numerous vector–host interactions on a cellular and noncellular level, including specific components of the immune system, must be modulated in order to generate safe and efficacious vectors for virotherapy or classic gene therapy. Importantly, the current widespread use of Ad vectors as vaccines against COVID-19 will induce antivector immunity in many humans. This requires the development of strategies and techniques to enable Ad-based vectors to evade pre-existing immunity. In this review article, we discuss the current status of genetic and chemical capsid modifications as means to modulate the vector–host interactions of Ad-based vectors. Full article
(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)
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Review
Understanding Post Entry Sorting of Adenovirus Capsids; A Chance to Change Vaccine Vector Properties
Viruses 2021, 13(7), 1221; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071221 - 24 Jun 2021
Viewed by 738
Abstract
Adenovirus vector-based genetic vaccines have emerged as a powerful strategy against the SARS-CoV-2 health crisis. This success is not unexpected because adenoviruses combine many desirable features of a genetic vaccine. They are highly immunogenic and have a low and well characterized pathogenic profile [...] Read more.
Adenovirus vector-based genetic vaccines have emerged as a powerful strategy against the SARS-CoV-2 health crisis. This success is not unexpected because adenoviruses combine many desirable features of a genetic vaccine. They are highly immunogenic and have a low and well characterized pathogenic profile paired with technological approachability. Ongoing efforts to improve adenovirus-vaccine vectors include the use of rare serotypes and non-human adenoviruses. In this review, we focus on the viral capsid and how the choice of genotypes influences the uptake and subsequent subcellular sorting. We describe how understanding capsid properties, such as stability during the entry process, can change the fate of the entering particles and how this translates into differences in immunity outcomes. We discuss in detail how mutating the membrane lytic capsid protein VI affects species C viruses’ post-entry sorting and briefly discuss if such approaches could have a wider implication in vaccine and/or vector development. Full article
(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)
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Other

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Case Report
DIC-Like Syndrome Following Administration of ChAdOx1 nCov-19 Vaccination
Viruses 2021, 13(6), 1046; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061046 - 01 Jun 2021
Viewed by 1143
Abstract
In recent weeks, adverse reactions have been reported after administration of Oxford–AstraZeneca chimpanzee adenovirus vectored vaccine ChAdOx1 nCoV-19 (AZD1222), in particular thrombus formation, which has led several European Countries to discontinue administration of this vaccine. On March 8, 2021, the European Medicines Agency [...] Read more.
In recent weeks, adverse reactions have been reported after administration of Oxford–AstraZeneca chimpanzee adenovirus vectored vaccine ChAdOx1 nCoV-19 (AZD1222), in particular thrombus formation, which has led several European Countries to discontinue administration of this vaccine. On March 8, 2021, the European Medicines Agency Safety Committee did not confirm this probable association. We report the case of a patient who developed disseminated intravascular coagulation after the first dose of Oxford-Astra Zeneca vaccine, which resolved in a few days with the administration of dexamethasone and enoxaparin. This work demonstrates the safety of the Oxford-Astra Zeneca vaccine and that any development of side effects can be easily managed with a prompt diagnosis and in a short time with a few commonly used drugs. Full article
(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)
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