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Special Issue "Adenovirus: Enduring Toolbox for Basic and Applied Research"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 31 January 2021.

Special Issue Editor

Dr. Ruben Hernandez-Alcoceba
Website
Guest Editor
University of Navarra-CIMA, Pamplona, Spain
Interests: gene therapy; adenovirus; vector production; cancer; monogenic diseases; brain

Special Issue Information

Dear Colleagues,

The Adenoviridae family comprises a wide variety of human and animal viruses sharing genetic and structural characteristics. Their 80–100 nm non-enveloped icosahedral capsids contain core proteins and a ~36 kb double-stranded genome packed with structural and regulatory genes. The study of the adenoviral life cycle and its interactions with the host has revealed fundamental biological processes over several decades, and most likely it will enlighten us for many years to come.

More recently, adenoviruses have become versatile platforms for the development of therapeutic agents. The stability of their genome and the relative simplicity of its manipulation have enabled the development of a wide repertoire of adenovirus-based products with different properties, all of them sharing high transduction efficacy in mammalian cell cultures and in vivo. Their lytic life cycle has been exploited for the development of oncolytic agents, whereas progressive deletions of the viral genomes have resulted in gene therapy vectors with optimal cloning capacity and increased episomal stability. The strong immune responses elicited by adenoviral particles have been a drawback for early generation adenoviral vectors, but they are currently being harnessed to develop vaccines and improve cancer immunotherapies.

The driving force for the continuous refinement of the adenovirus as a toolbox for basic and applied research is attaining a deep understanding of its structure and function. In this Special Issue on the adenovirus, we aim to compile state-of-the art reviews and research articles on basic aspects of the virus’ biology, and the applications of this knowledge for the development of improved therapeutic agents. This includes but is not restricted to viral entry; intracellular trafficking; replication; encapsidation, genome maintenance in infected cells; host interactions; virus persistence; oncolytic adenoviruses; adenoviral vectors, and adenoviral-based vaccines. Currently, gene therapy achievements and limitations are getting attention more than ever before, so we believe this Special Issue is timely and appropriate.

We look forward to receiving your valuable submission, which will undergo a fair and fast review. Please consider this opportunity to contribute to the advancement of this exciting field. For participants of the 14th International Adenovirus Meeting in Spain (https://iam2020.atlantacongress.org/), a 10% discount on Article Processing Charges will be applied.

Dr. Ruben Hernandez-Alcoceba
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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • adenovirus
  • gene therapy
  • oncolytic virus
  • replication
  • encapsidation
  • transduction
  • intracellular trafficking
  • vector production
  • targeting
  • immune response
  • vaccination

Published Papers (7 papers)

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Research

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Open AccessArticle
High-Throughput Cloning and Characterization of Emerging Adenovirus Types 70, 73, 74, and 75
Int. J. Mol. Sci. 2020, 21(17), 6370; https://doi.org/10.3390/ijms21176370 - 02 Sep 2020
Abstract
Recently an increasing number of new adenovirus types associated with type-dependent pathogenicity have been identified. However, identification of these clinical isolates represents the very first step to characterize novel pathogens. For deeper analyses, these adenoviruses need to be further characterized in basic virology [...] Read more.
Recently an increasing number of new adenovirus types associated with type-dependent pathogenicity have been identified. However, identification of these clinical isolates represents the very first step to characterize novel pathogens. For deeper analyses, these adenoviruses need to be further characterized in basic virology experiments or they could be applied in translational research. To achieve this goal, it is essential to get genetic access and to enable genetic modification of these novel adenovirus genomes (deletion, insertion, and mutation). Here we demonstrate a high-throughput approach to get genetic access to new adenoviruses via homologous recombination. We first defined the cloning conditions regarding homology arm-length and input adenoviral genome amounts. Then we cloned four naturally occurring adenoviruses (Ad70, Ad73, Ad74, and Ad75) into easy-to-manipulate plasmids and genetically modified them by reporter gene insertion. Three recombinant adenoviruses (Ad70, Ad73, and Ad74) containing a reporter cassette were successfully reconstituted. These novel reporter-labeled adenoviruses were further characterized using the inserted luciferase reporter with respect to receptor usage, presence of anti-adenovirus antibodies, and tropism in vitro. The identified receptor usage, the relatively low prevalence of anti-adenovirus antibodies, and the various cancer cell line transduction pattern are important features of these new pathogens providing essential information for their therapeutic application. Full article
(This article belongs to the Special Issue Adenovirus: Enduring Toolbox for Basic and Applied Research)
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Open AccessArticle
Cell Bank Origin of MDCK Parental Cells Shapes Adaptation to Serum-Free Suspension Culture and Canine Adenoviral Vector Production
Int. J. Mol. Sci. 2020, 21(17), 6111; https://doi.org/10.3390/ijms21176111 - 25 Aug 2020
Abstract
Phenotypic variation in cultured mammalian cell lines is known to be induced by passaging and culture conditions. Yet, the effect these variations have on the production of viral vectors has been overlooked. In this work we evaluated the impact of using Madin–Darby canine [...] Read more.
Phenotypic variation in cultured mammalian cell lines is known to be induced by passaging and culture conditions. Yet, the effect these variations have on the production of viral vectors has been overlooked. In this work we evaluated the impact of using Madin–Darby canine kidney (MDCK) parental cells from American Type Culture Collection (ATCC) or European Collection of Authenticated Cell Cultures (ECACC) cell bank repositories in both adherent and suspension cultures for the production of canine adenoviral vectors type 2 (CAV-2). To further explore the differences between cells, we conducted whole-genome transcriptome analysis. ECACC’s MDCK showed to be a less heterogeneous population, more difficult to adapt to suspension and serum-free culture conditions, but more permissive to CAV-2 replication progression, enabling higher yields. Transcriptome data indicated that this increased permissiveness is due to a general down-regulation of biological networks of innate immunity in ECACC cells, including apoptosis and death receptor signaling, Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling, toll-like receptors signaling and the canonical pathway of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. These results show the impact of MDCK source on the outcome of viral-based production processes further elucidating transcriptome signatures underlying enhanced adenoviral replication. Following functional validation, the genes and networks identified herein can be targeted in future engineering approaches aiming at improving the production of CAV-2 gene therapy vectors. Full article
(This article belongs to the Special Issue Adenovirus: Enduring Toolbox for Basic and Applied Research)
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Open AccessArticle
Arming Oncolytic Adenoviruses: Effect of Insertion Site and Splice Acceptor on Transgene Expression and Viral Fitness
Int. J. Mol. Sci. 2020, 21(14), 5158; https://doi.org/10.3390/ijms21145158 - 21 Jul 2020
Abstract
Oncolytic adenoviruses (OAds) present limited efficacy in clinics. The insertion of therapeutic transgenes into OAds genomes, known as “arming OAds”, has been the main strategy to improve their therapeutic potential. Different approaches were published in the decade of the 2000s, but with few [...] Read more.
Oncolytic adenoviruses (OAds) present limited efficacy in clinics. The insertion of therapeutic transgenes into OAds genomes, known as “arming OAds”, has been the main strategy to improve their therapeutic potential. Different approaches were published in the decade of the 2000s, but with few comparisons. Most armed OAds have complete or partial E3 deletions, leading to a shorter half-life in vivo. We generated E3+ OAds using two insertion sites, After-fiber and After-E4, and two different splice acceptors linked to the major late promoter, either the Ad5 protein IIIa acceptor (IIIaSA) or the Ad40 long fiber acceptor (40SA). The highest transgene levels were obtained with the After-fiber location and 40SA. However, the set of codons of the transgene affected viral fitness, highlighting the relevance of transgene codon usage when arming OAds using the major late promoter. Full article
(This article belongs to the Special Issue Adenovirus: Enduring Toolbox for Basic and Applied Research)
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Review

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Open AccessReview
Adenovirus Reveals New Pathway for Cholesterol Egress from the Endolysosomal System
Int. J. Mol. Sci. 2020, 21(16), 5808; https://doi.org/10.3390/ijms21165808 - 13 Aug 2020
Abstract
In addition to providing invaluable insights to the host response to viral infection, adenovirus continues to be an important model system for discovering basic aspects of cell biology. This is especially true for products of early region three (E3), which have provided the [...] Read more.
In addition to providing invaluable insights to the host response to viral infection, adenovirus continues to be an important model system for discovering basic aspects of cell biology. This is especially true for products of early region three (E3), which have provided the foundation for understanding many new mechanisms regulating intracellular trafficking of host cell proteins involved in the host immune response. Cholesterol homeostasis is vital for proper cellular physiology, and disturbances in cholesterol balance are increasingly recognized as important factors in human disease. Despite its central role in numerous aspects of cellular functions, the mechanisms responsible for delivery of dietary cholesterol to the endoplasmic reticulum, where the lipid metabolic and regulatory machinery reside, remain poorly understood. In this review, we describe a novel intracellular pathway for cholesterol trafficking that has been co-opted by an adenovirus E3 gene product. We describe what is known about the molecular regulation of this pathway, how it might benefit viral replication, and its potential involvement in normal cell physiology. Finally, we make a case that adenovirus has co-opted a cellular pathway that may be dysregulated in various human diseases. Full article
(This article belongs to the Special Issue Adenovirus: Enduring Toolbox for Basic and Applied Research)
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Open AccessReview
Cancer Associated Endogenous Retroviruses: Ideal Immune Targets for Adenovirus-Based Immunotherapy
Int. J. Mol. Sci. 2020, 21(14), 4843; https://doi.org/10.3390/ijms21144843 - 08 Jul 2020
Cited by 1
Abstract
Cancer is a major challenge in our societies, according to the World Health Organization (WHO) about 1/6 deaths were cancer related in 2018 and it is considered the second leading cause of death globally. Immunotherapies have changed the paradigm of oncologic treatment for [...] Read more.
Cancer is a major challenge in our societies, according to the World Health Organization (WHO) about 1/6 deaths were cancer related in 2018 and it is considered the second leading cause of death globally. Immunotherapies have changed the paradigm of oncologic treatment for several cancers where the field had fallen short in providing competent therapies. Despite the improvement, broadly acting and highly effective therapies capable of eliminating or preventing human cancers with insufficient mutated antigens are still missing. Adenoviral vector-based vaccines are a successful tool in the treatment of various diseases including cancer; however, their success has been limited. In this review we discuss the potential of adenovirus as therapeutic tools and the current developments to use them against cancer. More specifically, we examine how to use them to target endogenous retroviruses (ERVs). ERVs, comprising 8% of the human genome, have been detected in several cancers, while they remain silent in healthy tissues. Their low immunogenicity together with their immunosuppressive capacity aid cancer to escape immunosurveillance. In that regard, virus-like-vaccine (VLV) technology, combining adenoviral vectors and virus-like-particles (VLPs), can be ideal to target ERVs and elicit B-cell responses, as well as CD8+ and CD4+ T-cells responses. Full article
(This article belongs to the Special Issue Adenovirus: Enduring Toolbox for Basic and Applied Research)
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Open AccessReview
Non-Human Primate-Derived Adenoviruses for Future Use as Oncolytic Agents?
Int. J. Mol. Sci. 2020, 21(14), 4821; https://doi.org/10.3390/ijms21144821 - 08 Jul 2020
Cited by 3
Abstract
Non-human primate (NHP)-derived adenoviruses have formed a valuable alternative for the use of human adenoviruses in vaccine development and gene therapy strategies by virtue of the low seroprevalence of neutralizing immunity in the human population. The more recent use of several human adenoviruses [...] Read more.
Non-human primate (NHP)-derived adenoviruses have formed a valuable alternative for the use of human adenoviruses in vaccine development and gene therapy strategies by virtue of the low seroprevalence of neutralizing immunity in the human population. The more recent use of several human adenoviruses as oncolytic agents has exhibited excellent safety profiles and firm evidence of clinical efficacy. This proffers the question whether NHP-derived adenoviruses could also be employed for viral oncolysis in human patients. While vaccine vectors are conventionally made as replication-defective vectors, in oncolytic applications replication-competent viruses are used. The data on NHP-derived adenoviral vectors obtained from vaccination studies can only partially support the suitability of NHP-derived adenoviruses for use in oncolytic virus therapy. In addition, the use of NHP-derived adenoviruses in humans might be received warily given the recent zoonotic infections with influenza viruses and coronaviruses. In this review, we discuss the similarities and differences between human- and NHP-derived adenoviruses in view of their use as oncolytic agents. These include their genome organization, receptor use, replication and cell lysis, modulation of the host’s immune responses, as well as their pathogenicity in humans. Together, the data should facilitate a rational and data-supported decision on the suitability of NHP-derived adenoviruses for prospective use in oncolytic virus therapy. Full article
(This article belongs to the Special Issue Adenovirus: Enduring Toolbox for Basic and Applied Research)
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Open AccessReview
High-Capacity Adenoviral Vectors: Expanding the Scope of Gene Therapy
Int. J. Mol. Sci. 2020, 21(10), 3643; https://doi.org/10.3390/ijms21103643 - 21 May 2020
Cited by 5
Abstract
The adaptation of adenoviruses as gene delivery tools has resulted in the development of high-capacity adenoviral vectors (HC-AdVs), also known, helper-dependent or “gutless”. Compared with earlier generations (E1/E3-deleted vectors), HC-AdVs retain relevant features such as genetic stability, remarkable efficacy of in vivo transduction, [...] Read more.
The adaptation of adenoviruses as gene delivery tools has resulted in the development of high-capacity adenoviral vectors (HC-AdVs), also known, helper-dependent or “gutless”. Compared with earlier generations (E1/E3-deleted vectors), HC-AdVs retain relevant features such as genetic stability, remarkable efficacy of in vivo transduction, and production at high titers. More importantly, the lack of viral coding sequences in the genomes of HC-AdVs extends the cloning capacity up to 37 Kb, and allows long-term episomal persistence of transgenes in non-dividing cells. These properties open a wide repertoire of therapeutic opportunities in the fields of gene supplementation and gene correction, which have been explored at the preclinical level over the past two decades. During this time, production methods have been optimized to obtain the yield, purity, and reliability required for clinical implementation. Better understanding of inflammatory responses and the implementation of methods to control them have increased the safety of these vectors. We will review the most significant achievements that are turning an interesting research tool into a sound vector platform, which could contribute to overcome current limitations in the gene therapy field. Full article
(This article belongs to the Special Issue Adenovirus: Enduring Toolbox for Basic and Applied Research)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Review
Title: High-Capacity Adenoviral vectors: expanding the scope of gene therapy
Authors: Ruben Hernandez Alcoceba, etc.

Review
Title: Non-human primate adenoviruses and their potential for use as oncolytic agents
Authors: Selas T.F. Bots, Vera Kemp, Martine L.M. Lamfers, Gabri Van der Pluijm and Rob C. Hoeben

Review
Title: Fowl adenovirus: pathogenesis and control
Authors: Shijun Zheng, etc.

Title: Adenovirus reveals new pathway for cholesterol egress from the endolysosomal system
Authors: Cathy Carlin, etc.

Review
Title: Cancer Associated Endogenous Retroviruses: Ideal Immune targets for adenovirus based immunotherapy
Authors: Amaia Vergara Bermejo, Peter Johannes Holst, etc.

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