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Adenovirus: Enduring Toolbox for Basic and Applied Research

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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: closed (30 September 2021) | Viewed by 64863

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Dr. Ruben Hernandez-Alcoceba

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Gene Therapy Program, Center for Applied Medical Research (CIMA), University of Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pío XII 55, 31008 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

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Keywords

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

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Published Papers (13 papers)

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Research

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22 pages, 7669 KiB

Open AccessArticle

Human Adenovirus Type 5 Infection Leads to Nuclear Envelope Destabilization and Membrane Permeability Independently of Adenovirus Death Protein

by Søren Pfitzner, Jens B. Bosse, Helga Hofmann-Sieber, Felix Flomm, Rudolph Reimer, Thomas Dobner, Kay Grünewald and Linda E. Franken

Int. J. Mol. Sci. 2021, 22(23), 13034; https://doi.org/10.3390/ijms222313034 - 2 Dec 2021

Cited by 3 | Viewed by 2904

Abstract

The human adenovirus type 5 (HAdV5) infects epithelial cells of the upper and lower respiratory tract. The virus causes lysis of infected cells and thus enables spread of progeny virions to neighboring cells for the next round of infection. The mechanism of adenovirus virion egress across the nuclear barrier is not known. The human adenovirus death protein (ADP) facilitates the release of virions from infected cells and has been hypothesized to cause membrane damage. Here, we set out to answer whether ADP does indeed increase nuclear membrane damage. We analyzed the nuclear envelope morphology using a combination of fluorescence and state-of-the-art electron microscopy techniques, including serial block-face scanning electron microscopy and electron cryo-tomography of focused ion beam-milled cells. We report multiple destabilization phenotypes of the nuclear envelope in HAdV5 infection. These include reduction of lamin A/C at the nuclear envelope, large-scale membrane invaginations, alterations in double membrane separation distance and small-scale membrane protrusions. Additionally, we measured increased nuclear membrane permeability and detected nuclear envelope lesions under cryoconditions. Unexpectedly, and in contrast to previous hypotheses, ADP did not have an effect on lamin A/C reduction or nuclear permeability. Full article

(This article belongs to the Special Issue Adenovirus: Enduring Toolbox for Basic and Applied Research)

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15 pages, 3026 KiB

Open AccessArticle

Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

by Maria Buñuales, Maria Cristina Ballesteros-Briones, Manuela Gonzalez-Aparicio, Sandra Hervas-Stubbs, Eva Martisova, Uxua Mancheño, Ana Ricobaraza, Sara Lumbreras, Cristian Smerdou and Ruben Hernandez-Alcoceba

Int. J. Mol. Sci. 2021, 22(8), 4176; https://doi.org/10.3390/ijms22084176 - 17 Apr 2021

Cited by 6 | Viewed by 2928

Abstract

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer. Full article

(This article belongs to the Special Issue Adenovirus: Enduring Toolbox for Basic and Applied Research)

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18 pages, 7425 KiB

Open AccessArticle

Adenovirus Terminal Protein Contains a Bipartite Nuclear Localisation Signal Essential for Its Import into the Nucleus

by Hareth A. Al-Wassiti, David R. Thomas, Kylie M. Wagstaff, Stewart A. Fabb, David A. Jans, Angus P. Johnston and Colin W. Pouton

Int. J. Mol. Sci. 2021, 22(7), 3310; https://doi.org/10.3390/ijms22073310 - 24 Mar 2021

Cited by 5 | Viewed by 3369

Abstract

Adenoviruses contain dsDNA covalently linked to a terminal protein (TP) at the 5′end. TP plays a pivotal role in replication and long-lasting infectivity. TP has been reported to contain a nuclear localisation signal (NLS) that facilitates its import into the nucleus. We studied the potential NLS motifs within TP using molecular and cellular biology techniques to identify the motifs needed for optimum nuclear import. We used confocal imaging microscopy to monitor the localisation and nuclear association of GFP fusion proteins. We identified two nuclear localisation signals, PV(R)6VP and MRRRR, that are essential for fully efficient TP nuclear entry in transfected cells. To study TP–host interactions further, we expressed TP in Escherichia coli (E. coli). Nuclear uptake of purified protein was determined in digitonin-permeabilised cells. The data confirmed that nuclear uptake of TP requires active transport using energy and shuttling factors. This mechanism of nuclear transport was confirmed when expressed TP was microinjected into living cells. Finally, we uncovered the nature of TP binding to host nuclear shuttling proteins, revealing selective binding to Imp β, and a complex of Imp α/β but not Imp α alone. TP translocation to the nucleus could be inhibited using selective inhibitors of importins. Our results show that the bipartite NLS is required for fully efficient TP entry into the nucleus and suggest that this translocation can be carried out by binding to Imp β or Imp α/β. This work forms the biochemical foundation for future work determining the involvement of TP in nuclear delivery of adenovirus DNA. Full article

(This article belongs to the Special Issue Adenovirus: Enduring Toolbox for Basic and Applied Research)

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15 pages, 2818 KiB

Open AccessArticle

High-Throughput Cloning and Characterization of Emerging Adenovirus Types 70, 73, 74, and 75

by Wenli Zhang, Kemal Mese, Sebastian Schellhorn, Nora Bahlmann, Nicolas Mach, Oskar Bunz, Akshay Dhingra, Elias Hage, Marie-Edith Lafon, Harald Wodrich, Albert Heim and Anja Ehrhardt

Int. J. Mol. Sci. 2020, 21(17), 6370; https://doi.org/10.3390/ijms21176370 - 2 Sep 2020

Cited by 13 | Viewed by 2951

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 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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27 pages, 11195 KiB

Open AccessArticle

Cell Bank Origin of MDCK Parental Cells Shapes Adaptation to Serum-Free Suspension Culture and Canine Adenoviral Vector Production

by Ana Filipa Rodrigues, Paulo Fernandes, Tanja Laske, Rute Castro, Paula Marques Alves, Yvonne Genzel and Ana Sofia Coroadinha

Int. J. Mol. Sci. 2020, 21(17), 6111; https://doi.org/10.3390/ijms21176111 - 25 Aug 2020

Cited by 6 | Viewed by 5343

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 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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15 pages, 3580 KiB

Open AccessArticle

Arming Oncolytic Adenoviruses: Effect of Insertion Site and Splice Acceptor on Transgene Expression and Viral Fitness

by Martí Farrera-Sal, Jana de Sostoa, Estela Nuñez-Manchón, Rafael Moreno, Cristina Fillat, Miriam Bazan-Peregrino and Ramon Alemany

Int. J. Mol. Sci. 2020, 21(14), 5158; https://doi.org/10.3390/ijms21145158 - 21 Jul 2020

Cited by 5 | Viewed by 2954

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 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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16 pages, 4600 KiB

Open AccessReview

Adenovirus Structure: What Is New?

by José Gallardo, Marta Pérez-Illana, Natalia Martín-González and Carmen San Martín

Int. J. Mol. Sci. 2021, 22(10), 5240; https://doi.org/10.3390/ijms22105240 - 15 May 2021

Cited by 63 | Viewed by 10399

Abstract

Adenoviruses are large (~950 Å) and complex non-enveloped, dsDNA icosahedral viruses. They have a pseudo-T = 25 triangulation number with at least 12 different proteins composing the virion. These include the major and minor capsid proteins, core proteins, maturation protease, terminal protein, and packaging machinery. Although adenoviruses have been studied for more than 60 years, deciphering their architecture has presented a challenge for structural biology techniques. An outstanding event was the first near-atomic resolution structure of human adenovirus type 5 (HAdV-C5), solved by cryo-electron microscopy (cryo-EM) in 2010. Discovery of new adenovirus types, together with methodological advances in structural biology techniques, in particular cryo-EM, has lately produced a considerable amount of new, high-resolution data on the organization of adenoviruses belonging to different species. In spite of these advances, the organization of the non-icosahedral core is still a great unknown. Nevertheless, alternative techniques such as atomic force microscopy (AFM) are providing interesting glimpses on the role of the core proteins in genome condensation and virion stability. Here we summarize the current knowledge on adenovirus structure, with an emphasis on high-resolution structures obtained since 2010. Full article

(This article belongs to the Special Issue Adenovirus: Enduring Toolbox for Basic and Applied Research)

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15 pages, 592 KiB

Open AccessReview

Oncolytic Adenoviruses for Cancer Therapy

by Lorella Tripodi, Maria Vitale, Vincenzo Cerullo and Lucio Pastore

Int. J. Mol. Sci. 2021, 22(5), 2517; https://doi.org/10.3390/ijms22052517 - 3 Mar 2021

Cited by 21 | Viewed by 3435

Abstract

Many immuno-therapeutic strategies are currently being developed to fight cancer. In this scenario, oncolytic adenoviruses (Onc.Ads) have an interesting role for their peculiar tumor selectivity, safety, and transgene-delivery capability. The major strength of the Onc.Ads is the extraordinary immunogenicity that leads to a strong T-cell response, which, together with the possibility of the delivery of a therapeutic transgene, could be more effective than current strategies. In this review, we travel in the adenovirus (Ads) and Onc.Ads world, focusing on a variety of strategies that can enhance Onc.Ads antitumoral efficacy, passing through tumor microenvironment modulation. Onc.Ads-based therapeutic strategies constitute additional weapons in the fight against cancer and appear to potentiate conventional and immune checkpoint inhibitors (ICIs)-based therapies leading to a promising scenario. Full article

(This article belongs to the Special Issue Adenovirus: Enduring Toolbox for Basic and Applied Research)

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11 pages, 286 KiB

Open AccessReview

Capsid and Genome Modification Strategies to Reduce the Immunogenicity of Adenoviral Vectors

by Florian Kreppel and Claudia Hagedorn

Int. J. Mol. Sci. 2021, 22(5), 2417; https://doi.org/10.3390/ijms22052417 - 28 Feb 2021

Cited by 19 | Viewed by 4505

Abstract

Adenovirus-based gene transfer vectors are the most frequently used vector type in gene therapy clinical trials to date, and they play an important role as genetic vaccine candidates during the ongoing SARS-CoV-2 pandemic. Immediately upon delivery, adenovirus-based vectors exhibit multiple complex vector-host interactions and induce innate and adaptive immune responses. This can severely limit their safety and efficacy, particularly after delivery through the blood stream. In this review article we summarize two strategies to modulate Ad vector-induced immune responses: extensive genomic and chemical capsid modifications. Both strategies have shown beneficial effects in a number of preclinical studies while potential synergistic effects warrant further investigations. Full article

(This article belongs to the Special Issue Adenovirus: Enduring Toolbox for Basic and Applied Research)

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16 pages, 1923 KiB

Open AccessReview

Adenovirus Reveals New Pathway for Cholesterol Egress from the Endolysosomal System

by Cathleen Carlin and Danny Manor

Int. J. Mol. Sci. 2020, 21(16), 5808; https://doi.org/10.3390/ijms21165808 - 13 Aug 2020

Cited by 4 | Viewed by 3047

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 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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21 pages, 2659 KiB

Open AccessReview

Cancer Associated Endogenous Retroviruses: Ideal Immune Targets for Adenovirus-Based Immunotherapy

by Amaia Vergara Bermejo, Emeline Ragonnaud, Joana Daradoumis and Peter Holst

Int. J. Mol. Sci. 2020, 21(14), 4843; https://doi.org/10.3390/ijms21144843 - 8 Jul 2020

Cited by 22 | Viewed by 8296

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 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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20 pages, 2787 KiB

Open AccessReview

Non-Human Primate-Derived Adenoviruses for Future Use as Oncolytic Agents?

by Selas T.F. Bots and Rob C. Hoeben

Int. J. Mol. Sci. 2020, 21(14), 4821; https://doi.org/10.3390/ijms21144821 - 8 Jul 2020

Cited by 20 | Viewed by 4962

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 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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33 pages, 971 KiB

Open AccessReview

High-Capacity Adenoviral Vectors: Expanding the Scope of Gene Therapy

by Ana Ricobaraza, Manuela Gonzalez-Aparicio, Lucia Mora-Jimenez, Sara Lumbreras and Ruben Hernandez-Alcoceba

Int. J. Mol. Sci. 2020, 21(10), 3643; https://doi.org/10.3390/ijms21103643 - 21 May 2020

Cited by 92 | Viewed by 8521

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, 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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