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Novel Developments and Perspectives in Viral Vector Technology
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Novel Developments and Perspectives in Viral Vector Technology

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 83619

Special Issue Editor

Dr. Stefan Weger

E-Mail Website
Guest Editor
Charité University Medicine Berlin, Campus Benjamin Franklin, Clinic for Neurology with Experimental Neurology, Gene Therapy Group, 12203 Berlin, Germany
Interests: parvoviruses; interaction of viral regulatory proteins with host proteins; viral vectors; gene therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over the past few years, the leading viral platforms for gene therapeutic approaches have been vectors based on adenoviruses and retroviruses, including lentiviruses and adeno-associated viruses (AAV). Whereas clinical successes in the treatment of several monogenic disorders have helped AAV vectors gain popularity as the supposedly ideal therapeutic vector, the death of two children in a recent therapy trial of myotubular myopathy is a tragic reminder that even for this viral vector considered to be very safe, important issues regarding the vector-host interactions still have to be clarified and further vector optimization with regard to transduction efficiency, immunogenicity, pathogenicity and tissue specificity may be required. This also holds true for all other kinds of viral vectors including those already mentioned and many more such as vaccinia virus, poxvirus, and herpes simplex virus (HSV) based vectors to name a few.      

Under this premise this Special Issue of Viruses invites contributions related to all aspects of preclinical viral vector development such as vector design, engineering and targeting as well as novel methods of vector manufacturing, purification, and quality control. Potential applications include gene replacement, gene silencing, gene editing, tumor therapy, and vaccination.

Dr. Stefan Weger
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 submissions that pass pre-check are 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. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • gene therapy
  • viral vectors
  • adenoviral vectors
  • retroviral vectors
  • lentiviral vectors
  • AAV vectors
  • vector production
  • gene silencing
  • gene editing

Published Papers (19 papers)

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Research

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13 pages, 4193 KiB  
Article
Immunostimulatory Profile of Cancer Cell Death by the AdV-Lumc007-Derived Oncolytic Virus ‘GoraVir’ in Cultured Pancreatic Cancer Cells
by Selas T. F. Bots, Sanne L. Landman, Martijn J. W. E. Rabelink, Diana J. M. van den Wollenberg and Rob C. Hoeben
Viruses 2023, 15(2), 283; https://doi.org/10.3390/v15020283 - 19 Jan 2023
Viewed by 1373
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy which shows unparalleled therapeutic resistance. Oncolytic viruses have emerged as a new treatment approach and convey their antitumor activity through lysis of cancer cells. The therapeutic efficacy of oncolytic viruses is largely dependent on [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy which shows unparalleled therapeutic resistance. Oncolytic viruses have emerged as a new treatment approach and convey their antitumor activity through lysis of cancer cells. The therapeutic efficacy of oncolytic viruses is largely dependent on the induction of immunogenic cell death (ICD) and the subsequent antitumor immune responses. However, the concurrent generation of antiviral immune responses may also limit the a virus’ therapeutic window. GoraVir is a new oncolytic adenovirus derived from the Human Adenovirus B (HAdV-B) isolate AdV-lumc007 which was isolated from a gorilla and has demonstrated excellent lytic activity in both in vitro and in vivo models of PDAC. In this study, we characterized the immunostimulatory profile of cancer cell death induced by GoraVir and the concerted cellular antiviral responses in three conventional pancreatic cancer cell lines. While GoraVir was shown to induce late apoptotic/necrotic cell death at earlier time points post infection than the human adenovirus type 5 (HAdV-C5), similar levels of ICD markers were expressed. Moreover, GoraVir was shown to induce ICD not dependent on STING expression and regardless of subsequent antiviral responses. Together, these data demonstrate that GoraVir is an excellent candidate for use in oncolytic virotherapy. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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19 pages, 6439 KiB  
Article
High-Level rAAV Vector Production by rAdV-Mediated Amplification of Small Amounts of Input Vector
by Stefan Weger
Viruses 2023, 15(1), 64; https://doi.org/10.3390/v15010064 - 24 Dec 2022
Cited by 2 | Viewed by 2307
Abstract
The successful application of recombinant adeno-associated virus (rAAV) vectors for long-term transgene expression in clinical studies requires scalable production methods with genetically stable components. Due to their simple production scheme and the high viral titers achievable, first generation recombinant adenoviruses (rAdV) have long [...] Read more.
The successful application of recombinant adeno-associated virus (rAAV) vectors for long-term transgene expression in clinical studies requires scalable production methods with genetically stable components. Due to their simple production scheme and the high viral titers achievable, first generation recombinant adenoviruses (rAdV) have long been taken into consideration as suitable tools for simultaneously providing both the helper functions and the AAV rep and cap genes for rAAV packaging. So far, however, such rAdV-rep/cap vectors have been difficult to generate and often turned out to be genetically unstable. Through ablation of cis and trans inhibitory function in the AAV-2 genome we have succeeded in establishing separate and stable rAdVs for high-level AAV serotype 2 Rep and Cap expression. These allowed rAAV-2 production at high burst sizes by simple coinfection protocols after providing the AAV-ITR flanked transgene vector genome either as rAAV-2 particles at low input concentrations or in form of an additional rAdV. With characteristics such as the ease of producing the required components, the straightforward adaption to other transgenes and the possible extension to further serotypes or capsid variants, especially the rAdV-mediated rAAV amplification system presents a very promising candidate for up-scaling to clinical grade vector preparations. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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12 pages, 2163 KiB  
Article
Performance of Cardiotropic rAAV Vectors Is Dependent on Production Method
by Renuka Rao, Melad Farraha, Grant J. Logan, Sindhu Igoor, Cindy Y. Kok, James J. H. Chong, Ian E. Alexander and Eddy Kizana
Viruses 2022, 14(8), 1623; https://doi.org/10.3390/v14081623 - 26 Jul 2022
Cited by 2 | Viewed by 1697
Abstract
Gene therapy is making significant impact on a modest, yet growing, number of human diseases. Justifiably, the preferred viral vector for clinical use is that based on recombinant adeno-associated virus (rAAV). There is a need to scale up rAAV vector production with the [...] Read more.
Gene therapy is making significant impact on a modest, yet growing, number of human diseases. Justifiably, the preferred viral vector for clinical use is that based on recombinant adeno-associated virus (rAAV). There is a need to scale up rAAV vector production with the transition from pre-clinical models to human application. Standard production methods based on the adherent cell type (HEK293) are limited in scalability and other methods, such as those based on the baculovirus and non-adherent insect cell (Sf9) system, have been pursued as an alternative to increase rAAV production. In this study, we compare these two production methods for cardiotropic rAAVs. Transduction efficiency for both production methods was assessed in primary cardiomyocytes, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), and in mice following systemic delivery. We found that the rAAV produced by the traditional HEK293 method out-performed vector produced using the baculovirus/Sf9 system in vitro and in vivo. This finding provides a potential caveat for vector function when using the baculovirus/Sf9 production system and underscores the need for thorough assessment of vector performance when using diverse rAAV production methods. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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14 pages, 2042 KiB  
Article
Induction of Hepatitis E Virus Anti-ORF3 Antibodies from Systemic Administration of a Muscle-Specific Adeno-Associated Virus (AAV) Vector
by Lars Maurer, Jihad El Andari, Kleopatra Rapti, Laura Spreyer, Eike Steinmann, Dirk Grimm and Viet Loan Dao Thi
Viruses 2022, 14(2), 266; https://doi.org/10.3390/v14020266 - 27 Jan 2022
Cited by 2 | Viewed by 3739
Abstract
The hepatitis E virus (HEV) is a major global health problem, leading to large outbreaks in the developing world and chronic infections in the developed world. HEV is a non-enveloped virus, which circulates in the blood in a quasi-enveloped form. The quasi-envelope protects [...] Read more.
The hepatitis E virus (HEV) is a major global health problem, leading to large outbreaks in the developing world and chronic infections in the developed world. HEV is a non-enveloped virus, which circulates in the blood in a quasi-enveloped form. The quasi-envelope protects HEV particles from neutralising anti-capsid antibodies in the serum; however, most vaccine approaches are designed to induce an immune response against the HEV capsid. In this study, we explored systemic in vivo administration of a novel synthetic and myotropic Adeno-associated virus vector (AAVMYO3) to express the small HEV phosphoprotein ORF3 (found on quasi-enveloped HEV) in the musculature of mice, resulting in the robust and dose-dependent formation of anti-ORF3 antibodies. Neutralisation assays using the serum of ORF3 AAV-transduced mice showed a modest inhibitory effect on the infection of quasi-enveloped HEV in vivo, comparable to previously characterised anti-ORF3 antibodies used as a control. The novel AAVMYO3 capsid used in this study can serve as a versatile platform for the continued development of vector-based vaccines against HEV and other infectious agents, which could complement traditional vaccines akin to the current positive experience with SARS-CoV-2. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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22 pages, 10123 KiB  
Article
Breaking Entry-and Species Barriers: LentiBOOST® Plus Polybrene Enhances Transduction Efficacy of Dendritic Cells and Monocytes by Adenovirus 5
by Astrid Strack, Andrea Deinzer, Christian Thirion, Silke Schrödel, Jan Dörrie, Tatjana Sauerer, Alexander Steinkasserer and Ilka Knippertz
Viruses 2022, 14(1), 92; https://doi.org/10.3390/v14010092 - 05 Jan 2022
Cited by 5 | Viewed by 2708
Abstract
Due to their ability to trigger strong immune responses, adenoviruses (HAdVs) in general and the serotype5 (HAdV-5) in particular are amongst the most popular viral vectors in research and clinical application. However, efficient transduction using HAdV-5 is predominantly achieved in coxsackie and adenovirus [...] Read more.
Due to their ability to trigger strong immune responses, adenoviruses (HAdVs) in general and the serotype5 (HAdV-5) in particular are amongst the most popular viral vectors in research and clinical application. However, efficient transduction using HAdV-5 is predominantly achieved in coxsackie and adenovirus receptor (CAR)-positive cells. In the present study, we used the transduction enhancer LentiBOOST® comprising the polycationic Polybrene to overcome these limitations. Using LentiBOOST®/Polybrene, we yielded transduction rates higher than 50% in murine bone marrow-derived dendritic cells (BMDCs), while maintaining their cytokine expression profile and their capability to induce T-cell proliferation. In human dendritic cells (DCs), we increased the transduction rate from 22% in immature (i)DCs or 43% in mature (m)DCs to more than 80%, without inducing cytotoxicity. While expression of specific maturation markers was slightly upregulated using LentiBOOST®/Polybrene on iDCs, no effect on mDC phenotype or function was observed. Moreover, we achieved efficient HAdV5 transduction also in human monocytes and were able to subsequently differentiate them into proper iDCs and functional mDCs. In summary, we introduce LentiBOOST® comprising Polybrene as a highly potent adenoviral transduction agent for new in-vitro applications in a set of different immune cells in both mice and humans. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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18 pages, 3200 KiB  
Article
Application Route and Immune Status of the Host Determine Safety and Oncolytic Activity of Oncolytic Coxsackievirus B3 Variant PD-H
by Ahmet Hazini, Babette Dieringer, Karin Klingel, Markian Pryshliak, Anja Geisler, Dennis Kobelt, Ole Daberkow, Jens Kurreck, Sophie van Linthout and Henry Fechner
Viruses 2021, 13(10), 1918; https://doi.org/10.3390/v13101918 - 24 Sep 2021
Cited by 4 | Viewed by 2216
Abstract
The coxsackievirus B3 strain PD-0 has been proposed as a new oncolytic virus for the treatment of colorectal carcinoma. Here, we generated a cDNA clone of PD-0 and analyzed the virus PD-H, newly generated from this cDNA, in xenografted and syngenic models of [...] Read more.
The coxsackievirus B3 strain PD-0 has been proposed as a new oncolytic virus for the treatment of colorectal carcinoma. Here, we generated a cDNA clone of PD-0 and analyzed the virus PD-H, newly generated from this cDNA, in xenografted and syngenic models of colorectal cancer. Replication and cytotoxic assays revealed that PD-H replicated and lysed colorectal carcinoma cell lines in vitro as well as PD-0. Intratumoral injection of PD-H into subcutaneous DLD-1 tumors in nude mice resulted in strong inhibition of tumor growth and significantly prolonged the survival of the animals, but virus-induced systemic infection was observed in one of the six animals. In a syngenic mouse model of subcutaneously growing Colon-26 tumors, intratumoral administration of PD-H led to a significant reduction of tumor growth, the prolongation of animal survival, the prevention of tumor-induced cachexia, and the elevation of CD3+ and dendritic cells in the tumor microenvironment. No virus-induced side effects were observed. After intraperitoneal application, PD-H induced weak pancreatitis and myocarditis in immunocompetent mice. By equipping the virus with target sites of miR-375, which is specifically expressed in the pancreas, organ infections were prevented. Moreover, employment of this virus in a syngenic mouse model of CT-26 peritoneal carcinomatosis resulted in a significant reduction in tumor growth and an increase in animal survival. The results demonstrate that the immune status of the host, the route of virus application, and the engineering of the virus with target sites of suitable microRNAs are crucial for the use of PD-H as an oncolytic virus. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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13 pages, 2755 KiB  
Communication
Targeting the Regulatory Subunit R2Alpha of Protein Kinase A in Human Glioblastoma through shRNA-Expressing Lentiviral Vectors
by Maira Zorzan, Claudia Del Vecchio, Stefania Vogiatzis, Elisa Saccon, Cristina Parolin, Giorgio Palù, Arianna Calistri and Carla Mucignat-Caretta
Viruses 2021, 13(7), 1361; https://doi.org/10.3390/v13071361 - 13 Jul 2021
Cited by 3 | Viewed by 2167
Abstract
Glioblastoma is the most malignant and most common form of brain tumor, still today associated with a poor 14-months median survival from diagnosis. Protein kinase A, particularly its regulatory subunit R2Alpha, presents a typical intracellular distribution in glioblastoma cells compared to the healthy [...] Read more.
Glioblastoma is the most malignant and most common form of brain tumor, still today associated with a poor 14-months median survival from diagnosis. Protein kinase A, particularly its regulatory subunit R2Alpha, presents a typical intracellular distribution in glioblastoma cells compared to the healthy brain parenchyma and this peculiarity might be exploited in a therapeutic setting. In the present study, a third-generation lentiviral system for delivery of shRNA targeting the regulatory subunit R2Alpha of protein kinase A was developed. Generated lentiviral vectors are able to induce an efficient and stable downregulation of R2Alpha in different cellular models, including non-stem and stem-like glioblastoma cells. In addition, our data suggest a potential correlation between silencing of the regulatory subunit of protein kinase A and reduced viability of tumor cells, apparently due to a reduction in replication rate. Thus, our findings support the role of protein kinase A as a promising target for novel anti-glioma therapies. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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16 pages, 3941 KiB  
Article
Modular Lentiviral Vectors for Highly Efficient Transgene Expression in Resting Immune Cells
by Christina Fichter, Anupriya Aggarwal, Andrew Kam Ho Wong, Samantha McAllery, Vennila Mathivanan, Bailey Hao, Hugh MacRae, Melissa J. Churchill, Paul R. Gorry, Michael Roche, Lachlan R. Gray and Stuart Turville
Viruses 2021, 13(6), 1170; https://doi.org/10.3390/v13061170 - 18 Jun 2021
Cited by 5 | Viewed by 4825
Abstract
Gene/cell therapies are promising strategies for the many presently incurable diseases. A key step in this process is the efficient delivery of genes and gene-editing enzymes to many cell types that may be resistant to lentiviral vector transduction. Herein we describe tuning of [...] Read more.
Gene/cell therapies are promising strategies for the many presently incurable diseases. A key step in this process is the efficient delivery of genes and gene-editing enzymes to many cell types that may be resistant to lentiviral vector transduction. Herein we describe tuning of a lentiviral gene therapy platform to focus on genetic modifications of resting CD4+ T cells. The motivation for this was to find solutions for HIV gene therapy efforts. Through selection of the optimal viral envelope and further modification to its expression, lentiviral fusogenic delivery into resting CD4+ T cells exceeded 80%, yet Sterile Alpha Motif and HD domain 1 (SAMHD1) dependent and independent intracellular restriction factors within resting T cells then dominate delivery and integration of lentiviral cargo. Overcoming SAMHD1-imposed restrictions, only observed up to 6-fold increase in transduction, with maximal gene delivery and expression of 35%. To test if the biologically limiting steps of lentiviral delivery are reverse transcription and integration, we re-engineered lentiviral vectors to simply express biologically active mRNA to direct transgene expression in the cytoplasm. In this setting, we observed gene expression in up to 65% of resting CD4+ T cells using unconcentrated MS2 lentivirus-like particles (MS2-LVLPs). Taken together, our findings support a gene therapy platform that could be readily used in resting T cell gene editing. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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19 pages, 12682 KiB  
Article
Experimental Evaluation of an Interferometric Light Microscopy Particle Counter for Titering and Characterization of Virus Preparations
by Vesa Turkki, Elisa Alppila, Seppo Ylä-Herttuala and Hanna P. Lesch
Viruses 2021, 13(5), 939; https://doi.org/10.3390/v13050939 - 19 May 2021
Cited by 10 | Viewed by 5394
Abstract
Virus particle concentration is a critical piece of information for virology, viral vaccines and gene therapy research. We tested a novel nanoparticle counting device, “Videodrop”, for its efficacy in titering and characterization of virus particles. The Videodrop nanoparticle counter is based on interferometric [...] Read more.
Virus particle concentration is a critical piece of information for virology, viral vaccines and gene therapy research. We tested a novel nanoparticle counting device, “Videodrop”, for its efficacy in titering and characterization of virus particles. The Videodrop nanoparticle counter is based on interferometric light microscopy (ILM). The method allows the detection of particles under the diffraction limit capabilities of conventional light microscopy. We analyzed lenti-, adeno-, and baculovirus samples in different concentrations and compared the readings against traditional titering and characterization methods. The tested Videodrop particle counter is especially useful when measuring high-concentration purified virus preparations. Certain non-purified sample types or small viruses may be impossible to characterize or may require the use of standard curve or background subtraction methods, which increases the duration of the analysis. Together, our testing shows that Videodrop is a reasonable option for virus particle counting in situations where a moderate number of samples need to be analyzed quickly. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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13 pages, 4381 KiB  
Communication
Bombyx mori Pupae Efficiently Produce Recombinant AAV2/HBoV1 Vectors with a Bombyx mori Nuclear Polyhedrosis Virus Expression System
by Qian Yu, Pengfei Chang, Xiaoxuan Liu, Peng Lü, Qi Tang, Zhongjian Guo, Jianming Qiu, Keping Chen and Qin Yao
Viruses 2021, 13(4), 704; https://doi.org/10.3390/v13040704 - 18 Apr 2021
Cited by 3 | Viewed by 2357
Abstract
Recombinant adeno-associated virus (AAV) vectors have broad application prospects in the field of gene therapy. The establishment of low-cost and large-scale manufacturing is now the general agenda for industry. The baculovirus-insect cell/larva expression system has great potential for these applications due to its [...] Read more.
Recombinant adeno-associated virus (AAV) vectors have broad application prospects in the field of gene therapy. The establishment of low-cost and large-scale manufacturing is now the general agenda for industry. The baculovirus-insect cell/larva expression system has great potential for these applications due to its scalability and predictable biosafety. To establish a more efficient production system, Bombyx mori pupae were used as a new platform and infected with recombinant Bombyx mori nuclear polyhedrosis virus (BmNPV). The production of a chimeric recombinant adeno-associated virus (rAAV) serotype 2/human bocavirus type-1 (HBoV1) vector was used to evaluate the efficiency of this new baculovirus expression vector (BEV)–insect expression system. For this purpose, we constructed two recombinant BmNPVs, which were named rBmNPV/AAV2Rep-HBoV1Cap and rBmNPV/AAV2ITR-eGFP. The yields of rAAV2/HBoV1 derived from the rBmNPV/AAV2Rep-HBoV1Cap and rBmNPV/AAV2ITR-eGFP co-infected BmN cells exceeded 2 × 104 vector genomes (VG) per cell. The rBmNPV/AAV2Rep-HBoV1Cap and rBmNPV/AAV2ITR-eGFP can express stably for at least five passages. Significantly, rAAV2/HBoV1 could be efficiently generated from BmNPV-infected silkworm larvae and pupae at average yields of 2.52 × 1012 VG/larva and 4.6 × 1012 VG/pupa, respectively. However, the vectors produced from the larvae and pupae had a high percentage of empty particles, which suggests that further optimization is required for this platform in the future. Our work shows that silkworm pupae, as an efficient bioreactor, have great potential for application in the production of gene therapy vectors. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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14 pages, 3491 KiB  
Article
Species D Adenoviruses as Oncolytic Viral Vectors
by Brianna L. Bullard, Brigette N. Corder and Eric A. Weaver
Viruses 2020, 12(12), 1399; https://doi.org/10.3390/v12121399 - 06 Dec 2020
Cited by 4 | Viewed by 2799
Abstract
Oncolytic adenoviruses (Ad) have shown promising results in the therapeutic treatment of cancer. Ad type 5 (Ad5) is the most extensively utilized Ad type. However, several limitations exist to using Ad5 as an oncolytic virus, including high levels of anti-Ad5 neutralizing antibodies in [...] Read more.
Oncolytic adenoviruses (Ad) have shown promising results in the therapeutic treatment of cancer. Ad type 5 (Ad5) is the most extensively utilized Ad type. However, several limitations exist to using Ad5 as an oncolytic virus, including high levels of anti-Ad5 neutralizing antibodies in the population, binding of the Ad5 hexon to blood coagulation factor X leading to liver sequestration and toxicity, and reduced expression of the primary receptor CAR on many tumors. Here, we use in vitro methods to explore the oncolytic potential of four alternative Ad types (Ad26, 28, 45, and 48) belonging to the species D Ad subgroup and developed replication-competent species D Ads expressing the human sodium iodide symporter protein (hNIS) for combination radiovirotherapy. We evaluated the species D Ad vectors transduction, replication, cytotoxicity, and gene expression in six different cancer cell lines. Species D Ads showed the greatest transduction and cytotoxic killing in the SKBR3 breast cancer cells, followed by 293, A549, and HepG2 cells, however the cytotoxicity was less than the wild type Ad5 virus. In contrast, species D Ads showed limited transduction and cytotoxicity in the Hela and SKOV3 cancer cell lines. These species D Ad vectors also successfully expressed the hNIS gene during infection leading to increased iodide uptake in multiple cancer cell lines. These results, the low seroprevalence of anti-species D antibodies, and the lack of binding to blood coagulation FX, support further exploration of species D Ads as alternative oncolytic adenoviruses against multiple types of cancer. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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Review

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24 pages, 1646 KiB  
Review
Baculovirus Display of Peptides and Proteins for Medical Applications
by Aaron Pavel Rodríguez-Hernández, Daniel Martínez-Flores, Adolfo Cruz-Reséndiz, Teresa Padilla-Flores, Rodrigo González-Flores, Kenia Estrada, Alicia Sampieri, Aldo Román Camacho-Zarco and Luis Vaca
Viruses 2023, 15(2), 411; https://doi.org/10.3390/v15020411 - 01 Feb 2023
Cited by 2 | Viewed by 2500
Abstract
Baculoviridae is a large family of arthropod-infective viruses. Recombinant baculoviruses have many applications, the best known is as a system for large scale protein production in combination with insect cell cultures. More recently recombinant baculoviruses have been utilized for the display of proteins [...] Read more.
Baculoviridae is a large family of arthropod-infective viruses. Recombinant baculoviruses have many applications, the best known is as a system for large scale protein production in combination with insect cell cultures. More recently recombinant baculoviruses have been utilized for the display of proteins of interest with applications in medicine. In the present review we analyze the different strategies for the display of proteins and peptides on the surface of recombinant baculoviruses and provide some examples of the different proteins displayed. We analyze briefly the commercially available systems for recombinant baculovirus production and display and discuss the future of this emerging and powerful technology. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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15 pages, 1404 KiB  
Review
Adenovirus Biology, Recombinant Adenovirus, and Adenovirus Usage in Gene Therapy
by Maki Watanabe, Yuya Nishikawaji, Hirotaka Kawakami and Ken-ichiro Kosai
Viruses 2021, 13(12), 2502; https://doi.org/10.3390/v13122502 - 14 Dec 2021
Cited by 45 | Viewed by 8018
Abstract
Gene therapy is currently in the public spotlight. Several gene therapy products, including oncolytic virus (OV), which predominantly replicates in and kills cancer cells, and COVID-19 vaccines have recently been commercialized. Recombinant adenoviruses, including replication-defective adenoviral vector and conditionally replicating adenovirus (CRA; oncolytic [...] Read more.
Gene therapy is currently in the public spotlight. Several gene therapy products, including oncolytic virus (OV), which predominantly replicates in and kills cancer cells, and COVID-19 vaccines have recently been commercialized. Recombinant adenoviruses, including replication-defective adenoviral vector and conditionally replicating adenovirus (CRA; oncolytic adenovirus), have been extensively studied and used in clinical trials for cancer and vaccines. Here, we review the biology of wild-type adenoviruses, the methodological principle for constructing recombinant adenoviruses, therapeutic applications of recombinant adenoviruses, and new technologies in pluripotent stem cell (PSC)-based regenerative medicine. Moreover, this article describes the technology platform for efficient construction of diverse “CRAs that can specifically target tumors with multiple factors” (m-CRAs). This technology allows for modification of four parts in the adenoviral E1 region and the subsequent insertion of a therapeutic gene and promoter to enhance cancer-specific viral replication (i.e., safety) as well as therapeutic effects. The screening study using the m-CRA technology successfully identified survivin-responsive m-CRA (Surv.m-CRA) as among the best m-CRAs, and clinical trials of Surv.m-CRA are underway for patients with cancer. This article also describes new recombinant adenovirus-based technologies for solving issues in PSC-based regenerative medicine. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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14 pages, 705 KiB  
Review
Designing Lentiviral Vectors for Gene Therapy of Genetic Diseases
by Valentina Poletti and Fulvio Mavilio
Viruses 2021, 13(8), 1526; https://doi.org/10.3390/v13081526 - 02 Aug 2021
Cited by 23 | Viewed by 5704
Abstract
Lentiviral vectors are the most frequently used tool to stably transfer and express genes in the context of gene therapy for monogenic diseases. The vast majority of clinical applications involves an ex vivo modality whereby lentiviral vectors are used to transduce autologous somatic [...] Read more.
Lentiviral vectors are the most frequently used tool to stably transfer and express genes in the context of gene therapy for monogenic diseases. The vast majority of clinical applications involves an ex vivo modality whereby lentiviral vectors are used to transduce autologous somatic cells, obtained from patients and re-delivered to patients after transduction. Examples are hematopoietic stem cells used in gene therapy for hematological or neurometabolic diseases or T cells for immunotherapy of cancer. We review the design and use of lentiviral vectors in gene therapy of monogenic diseases, with a focus on controlling gene expression by transcriptional or post-transcriptional mechanisms in the context of vectors that have already entered a clinical development phase. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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18 pages, 629 KiB  
Review
Nonhuman Adenoviral Vector-Based Platforms and Their Utility in Designing Next Generation of Vaccines for Infectious Diseases
by Marwa Alhashimi, Ahmed Elkashif, Ekramy E. Sayedahmed and Suresh K. Mittal
Viruses 2021, 13(8), 1493; https://doi.org/10.3390/v13081493 - 29 Jul 2021
Cited by 9 | Viewed by 3638
Abstract
Several human adenoviral (Ad) vectors have been developed for vaccine delivery owing to their numerous advantages, including the feasibility of different vector designs, the robustness of elicited immune responses, safety, and scalability. To expand the repertoire of Ad vectors for receptor usage and [...] Read more.
Several human adenoviral (Ad) vectors have been developed for vaccine delivery owing to their numerous advantages, including the feasibility of different vector designs, the robustness of elicited immune responses, safety, and scalability. To expand the repertoire of Ad vectors for receptor usage and circumvention of Ad vector immunity, the use of less prevalent human Ad types or nonhuman Ads were explored for vector design. Notably, many nonhuman Ad vectors have shown great promise in preclinical and clinical studies as vectors for vaccine delivery. This review describes the key features of several nonhuman Ad vector platforms and their implications in developing effective vaccines against infectious diseases. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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25 pages, 5531 KiB  
Review
Adeno-Associated Virus (AAV) Gene Delivery: Dissecting Molecular Interactions upon Cell Entry
by Edward E. Large, Mark A. Silveria, Grant M. Zane, Onellah Weerakoon and Michael S. Chapman
Viruses 2021, 13(7), 1336; https://doi.org/10.3390/v13071336 - 10 Jul 2021
Cited by 25 | Viewed by 9341
Abstract
Human gene therapy has advanced from twentieth-century conception to twenty-first-century reality. The recombinant Adeno-Associated Virus (rAAV) is a major gene therapy vector. Research continues to improve rAAV safety and efficacy using a variety of AAV capsid modification strategies. Significant factors influencing rAAV transduction [...] Read more.
Human gene therapy has advanced from twentieth-century conception to twenty-first-century reality. The recombinant Adeno-Associated Virus (rAAV) is a major gene therapy vector. Research continues to improve rAAV safety and efficacy using a variety of AAV capsid modification strategies. Significant factors influencing rAAV transduction efficiency include neutralizing antibodies, attachment factor interactions and receptor binding. Advances in understanding the molecular interactions during rAAV cell entry combined with improved capsid modulation strategies will help guide the design and engineering of safer and more efficient rAAV gene therapy vectors. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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17 pages, 2163 KiB  
Review
Lentiviral Vectors for Delivery of Gene-Editing Systems Based on CRISPR/Cas: Current State and Perspectives
by Wendy Dong and Boris Kantor
Viruses 2021, 13(7), 1288; https://doi.org/10.3390/v13071288 - 01 Jul 2021
Cited by 41 | Viewed by 11391
Abstract
CRISPR/Cas technology has revolutionized the fields of the genome- and epigenome-editing by supplying unparalleled control over genomic sequences and expression. Lentiviral vector (LV) systems are one of the main delivery vehicles for the CRISPR/Cas systems due to (i) its ability to [...] Read more.
CRISPR/Cas technology has revolutionized the fields of the genome- and epigenome-editing by supplying unparalleled control over genomic sequences and expression. Lentiviral vector (LV) systems are one of the main delivery vehicles for the CRISPR/Cas systems due to (i) its ability to carry bulky and complex transgenes and (ii) sustain robust and long-term expression in a broad range of dividing and non-dividing cells in vitro and in vivo. It is thus reasonable that substantial effort has been allocated towards the development of the improved and optimized LV systems for effective and accurate gene-to-cell transfer of CRISPR/Cas tools. The main effort on that end has been put towards the improvement and optimization of the vector’s expression, development of integrase-deficient lentiviral vector (IDLV), aiming to minimize the risk of oncogenicity, toxicity, and pathogenicity, and enhancing manufacturing protocols for clinical applications required large-scale production. In this review, we will devote attention to (i) the basic biology of lentiviruses, and (ii) recent advances in the development of safer and more efficient CRISPR/Cas vector systems towards their use in preclinical and clinical applications. In addition, we will discuss in detail the recent progress in the repurposing of CRISPR/Cas systems related to base-editing and prime-editing applications. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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10 pages, 1013 KiB  
Review
On the Relationship of Viral Particles and Extracellular Vesicles: Implications for Viral Vector Technology
by Christoph Metzner and Marianne Zaruba
Viruses 2021, 13(7), 1238; https://doi.org/10.3390/v13071238 - 26 Jun 2021
Cited by 6 | Viewed by 2527
Abstract
Gene therapy vectors derived from different viral species have become a fixture in biomedicine, both for direct therapeutic intervention and as tools to facilitate cell-based therapies, such as chimeric antigen receptor-based immunotherapies. On the contrary, extracellular vesicles have only recently gained a massive [...] Read more.
Gene therapy vectors derived from different viral species have become a fixture in biomedicine, both for direct therapeutic intervention and as tools to facilitate cell-based therapies, such as chimeric antigen receptor-based immunotherapies. On the contrary, extracellular vesicles have only recently gained a massive increase in interest and, concomitantly, knowledge in the field has drastically risen. Viral infections and extracellular vesicle biology overlap in many ways, both with pro- and antiviral outcomes. In this review, we take a closer look at these interactions for the most prominent groups of viral vectors (Adenoviral, Adeno-associated and Retro/Lentiviral vectors) and the possible implications of these overlaps for viral vector technology and its biomedical applications. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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22 pages, 6503 KiB  
Review
Coxsackievirus B3—Its Potential as an Oncolytic Virus
by Anja Geisler, Ahmet Hazini, Lisanne Heimann, Jens Kurreck and Henry Fechner
Viruses 2021, 13(5), 718; https://doi.org/10.3390/v13050718 - 21 Apr 2021
Cited by 17 | Viewed by 6026
Abstract
Oncolytic virotherapy represents one of the most advanced strategies to treat otherwise untreatable types of cancer. Despite encouraging developments in recent years, the limited fraction of patients responding to therapy has demonstrated the need to search for new suitable viruses. Coxsackievirus B3 (CVB3) [...] Read more.
Oncolytic virotherapy represents one of the most advanced strategies to treat otherwise untreatable types of cancer. Despite encouraging developments in recent years, the limited fraction of patients responding to therapy has demonstrated the need to search for new suitable viruses. Coxsackievirus B3 (CVB3) is a promising novel candidate with particularly valuable features. Its entry receptor, the coxsackievirus and adenovirus receptor (CAR), and heparan sulfate, which is used for cellular entry by some CVB3 variants, are highly expressed on various cancer types. Consequently, CVB3 has broad anti-tumor activity, as shown in various xenograft and syngeneic mouse tumor models. In addition to direct tumor cell killing the virus induces a strong immune response against the tumor, which contributes to a substantial increase in the efficiency of the treatment. The toxicity of oncolytic CVB3 in healthy tissues is variable and depends on the virus strain. It can be abrogated by genetic engineering the virus with target sites of microRNAs. In this review, we present an overview of the current status of the development of CVB3 as an oncolytic virus and outline which steps still need to be accomplished to develop CVB3 as a therapeutic agent for clinical use in cancer treatment. Full article
(This article belongs to the Special Issue Novel Developments and Perspectives in Viral Vector Technology)
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