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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 77626

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Dr. Yasuhiro Takeuchi

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Infection and Immunity, University College London (UCL): Advanced Therapies, National Institute for Biological Standards and Control (NIBSC), Hertfordshire, UK
Interests: Molecular Virology, Gene Therapy, Xenotransplantation, Emerging Infection

Special Issue Information

Dear Colleagues,

Research on lentiviruses has been intensive since the discovery of HIV as the etiological agent of AIDS in 1983 and provided the basis for the development of lentiviral vector (LV) systems. While HIV-1-derived LV are routinely used in a wide range of basic biology research, recent advances leading to their clinical use, e.g. in the commercially approved cell therapies, has been remarkable. Research and development of LVs based on non-human lentivirus species, such as SIV and FIV, has also been substantial and the use of heterologous, non-lentiviral envelopes in LV systems relies on wider virology research. Additionally, clinical translation and development of LV systems to realize improved efficacy and safety requires multi-disciplinary efforts beyond virology to address key issues, such as biologics manufacturing, anti-LV host immune responses and LV-mediated genotoxicity. While LV development benefits from virologic and other research areas, it is noted that LV research can, in turn, provide valuable advanced research tools and insights as well as novel research ideas and questions. This special issue is calling for reviews and original papers in this wide area of research related to lentiviral vectors.

Dr. Yasuhiro Takeuchi
Guest Editor

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Keywords

HIV
Gene Therapy
Gene Vector
Manufacture
Pseudotyping
Safety/Genotoxicity

Published Papers (12 papers)

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Editorial

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2 pages, 165 KiB

Open AccessEditorial

Special Issue “Lentiviral Vectors”

by Yasuhiro Takeuchi

Viruses 2022, 14(7), 1492; https://0-doi-org.brum.beds.ac.uk/10.3390/v14071492 - 08 Jul 2022

Viewed by 1584

Abstract

Lentiviral vectors (LV) have been developed upon knowledge accumulated in the virology field, in particular intensive research on HIV biology since its discovery in 1983 [...] Full article

(This article belongs to the Special Issue Lentiviral Vectors)

Research

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15 pages, 3149 KiB

Open AccessArticle

Retrograde Transgene Expression via Neuron-Specific Lentiviral Vector Depends on Both Species and Input Projections

by Yukiko Otsuka, Hitomi Tsuge, Shiori Uezono, Soshi Tanabe, Maki Fujiwara, Miki Miwa, Shigeki Kato, Katsuki Nakamura, Kazuto Kobayashi, Ken-ichi Inoue and Masahiko Takada

Viruses 2021, 13(7), 1387; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071387 - 16 Jul 2021

Cited by 2 | Viewed by 2552

Abstract

For achieving retrograde gene transfer, we have so far developed two types of lentiviral vectors pseudotyped with fusion envelope glycoprotein, termed HiRet vector and NeuRet vector, consisting of distinct combinations of rabies virus and vesicular stomatitis virus glycoproteins. In the present study, we compared the patterns of retrograde transgene expression for the HiRet vs. NeuRet vectors by testing the cortical input system. These vectors were injected into the motor cortex in rats, marmosets, and macaques, and the distributions of retrograde labels were investigated in the cortex and thalamus. Our histological analysis revealed that the NeuRet vector generally exhibits a higher efficiency of retrograde gene transfer than the HiRet vector, though its capacity of retrograde transgene expression in the macaque brain is unexpectedly low, especially in terms of the intracortical connections, as compared to the rat and marmoset brains. It was also demonstrated that the NeuRet but not the HiRet vector displays sufficiently high neuron specificity and causes no marked inflammatory/immune responses at the vector injection sites in the primate (marmoset and macaque) brains. The present results indicate that the retrograde transgene efficiency of the NeuRet vector varies depending not only on the species but also on the input projections. Full article

(This article belongs to the Special Issue Lentiviral Vectors)

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18 pages, 4427 KiB

Open AccessArticle

Integrase-Defective Lentiviral Vector Is an Efficient Vaccine Platform for Cancer Immunotherapy

by Valeria Morante, Martina Borghi, Iole Farina, Zuleika Michelini, Felicia Grasso, Alessandra Gallinaro, Serena Cecchetti, Antonio Di Virgilio, Andrea Canitano, Maria Franca Pirillo, Roberta Bona, Andrea Cara and Donatella Negri

Viruses 2021, 13(2), 355; https://0-doi-org.brum.beds.ac.uk/10.3390/v13020355 - 23 Feb 2021

Cited by 17 | Viewed by 2800

Abstract

Integrase-defective lentiviral vectors (IDLVs) have been used as a safe and efficient delivery system in several immunization protocols in murine and non-human primate preclinical models as well as in recent clinical trials. In this work, we validated in preclinical murine models our vaccine platform based on IDLVs as delivery system for cancer immunotherapy. To evaluate the anti-tumor activity of our vaccine strategy we generated IDLV delivering ovalbumin (OVA) as a non-self-model antigen and TRP2 as a self-tumor associated antigen (TAA) of melanoma. Results demonstrated the ability of IDLVs to eradicate and/or controlling tumor growth after a single immunization in preventive and therapeutic approaches, using lymphoma and melanoma expressing OVA. Importantly, LV-TRP2 but not IDLV-TRP2 was able to break tolerance efficiently and prevent tumor growth of B16F10 melanoma cells. In order to improve the IDLV efficacy, the human homologue of murine TRP2 was used, showing the ability to break tolerance and control the tumor growth. These results validate the use of IDLV for cancer therapy. Full article

(This article belongs to the Special Issue Lentiviral Vectors)

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13 pages, 1839 KiB

Open AccessArticle

Integrase-Defective Lentiviral Vectors for Delivery of Monoclonal Antibodies against Influenza

by Zuleika Michelini, Judith M. Minkoff, Jianjun Yang, Donatella Negri, Andrea Cara, Brendon J. Hanson and Mirella Salvatore

Viruses 2020, 12(12), 1460; https://0-doi-org.brum.beds.ac.uk/10.3390/v12121460 - 17 Dec 2020

Cited by 4 | Viewed by 3011

Abstract

Delivering rapid protection against infectious agents to non-immune populations is a formidable public health challenge. Although passive immunotherapy is a fast and effective method of protection, large-scale production and administration of monoclonal antibodies (mAbs) is expensive and unpractical. Viral vector-mediated delivery of mAbs offers an attractive alternative to their direct injection. Integrase-defective lentiviral vectors (IDLV) are advantageous for this purpose due to the absence of pre-existing anti-vector immunity and the safety features of non-integration and non-replication. We engineered IDLV to produce the humanized mAb VN04-2 (IDLV-VN04-2), which is broadly neutralizing against H5 influenza A virus (IAV), and tested the vectors’ ability to produce antibodies and protect from IAV in vivo. We found that IDLV-transduced cells produced functional VN04-2 mAbs in a time- and dose-dependent fashion. These mAbs specifically bind the hemagglutinin (HA), but not the nucleoprotein (NP) of IAV. VN04-2 mAbs were detected in the serum of mice at different times after intranasal (i.n.) or intramuscular (i.m.) administration of IDLV-VN04-2. Administration of IDLV-VN04-2 by the i.n. route provided rapid protection against lethal IAV challenge, although the protection did not persist at later time points. Our data suggest that administration of mAb-expressing IDLV may represent an effective strategy for rapid protection against infectious diseases. Full article

(This article belongs to the Special Issue Lentiviral Vectors)

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Review

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22 pages, 2962 KiB

Open AccessReview

Lentiviral Vectors for T Cell Engineering: Clinical Applications, Bioprocessing and Future Perspectives

by Roman P. Labbé, Sandrine Vessillier and Qasim A. Rafiq

Viruses 2021, 13(8), 1528; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081528 - 02 Aug 2021

Cited by 40 | Viewed by 9381

Abstract

Lentiviral vectors have played a critical role in the emergence of gene-modified cell therapies, specifically T cell therapies. Tisagenlecleucel (Kymriah), axicabtagene ciloleucel (Yescarta) and most recently brexucabtagene autoleucel (Tecartus) are examples of T cell therapies which are now commercially available for distribution after successfully obtaining EMA and FDA approval for the treatment of blood cancers. All three therapies rely on retroviral vectors to transduce the therapeutic chimeric antigen receptor (CAR) into T lymphocytes. Although these innovations represent promising new therapeutic avenues, major obstacles remain in making them readily available tools for medical care. This article reviews the biological principles as well as the bioprocessing of lentiviral (LV) vectors and adoptive T cell therapy. Clinical and engineering successes, shortcomings and future opportunities are also discussed. The development of Good Manufacturing Practice (GMP)-compliant instruments, technologies and protocols will play an essential role in the development of LV-engineered T cell therapies. Full article

(This article belongs to the Special Issue Lentiviral Vectors)

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46 pages, 1004 KiB

Open AccessReview

Lentiviral Vector Bioprocessing

by Christopher Perry and Andrea C. M. E. Rayat

Viruses 2021, 13(2), 268; https://0-doi-org.brum.beds.ac.uk/10.3390/v13020268 - 09 Feb 2021

Cited by 65 | Viewed by 16102

Abstract

Lentiviral vectors (LVs) are potent tools for the delivery of genes of interest into mammalian cells and are now commonly utilised within the growing field of cell and gene therapy for the treatment of monogenic diseases and adoptive therapies such as chimeric antigen T-cell (CAR-T) therapy. This is a comprehensive review of the individual bioprocess operations employed in LV production. We highlight the role of envelope proteins in vector design as well as their impact on the bioprocessing of lentiviral vectors. An overview of the current state of these operations provides opportunities for bioprocess discovery and improvement with emphasis on the considerations for optimal and scalable processing of LV during development and clinical production. Upstream culture for LV generation is described with comparisons on the different transfection methods and various bioreactors for suspension and adherent producer cell cultivation. The purification of LV is examined, evaluating different sequences of downstream process operations for both small- and large-scale production requirements. For scalable operations, a key focus is the development in chromatographic purification in addition to an in-depth examination of the application of tangential flow filtration. A summary of vector quantification and characterisation assays is also presented. Finally, the assessment of the whole bioprocess for LV production is discussed to benefit from the broader understanding of potential interactions of the different process options. This review is aimed to assist in the achievement of high quality, high concentration lentiviral vectors from robust and scalable processes. Full article

(This article belongs to the Special Issue Lentiviral Vectors)

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18 pages, 713 KiB

Open AccessReview

More Than Just Gene Therapy Vectors: Lentiviral Vector Pseudotypes for Serological Investigation

by Kamilla Toon, Emma M. Bentley and Giada Mattiuzzo

Viruses 2021, 13(2), 217; https://0-doi-org.brum.beds.ac.uk/10.3390/v13020217 - 31 Jan 2021

Cited by 11 | Viewed by 4886

Abstract

Serological assays detecting neutralising antibodies are important for determining the immune responses following infection or vaccination and are also often considered a correlate of protection. The target of neutralising antibodies is usually located in the Envelope protein on the viral surface, which mediates cell entry. As such, presentation of the Envelope protein on a lentiviral particle represents a convenient alternative to handling of a potentially high containment virus or for those viruses with no established cell culture system. The flexibility, relative safety and, in most cases, ease of production of lentiviral pseudotypes, have led to their use in serological assays for many applications such as the evaluation of candidate vaccines, screening and characterization of anti-viral therapeutics, and sero-surveillance. Above all, the speed of production of the lentiviral pseudotypes, once the envelope sequence is published, makes them important tools in the response to viral outbreaks, as shown during the COVID-19 pandemic in 2020. In this review, we provide an overview of the landscape of the serological applications of pseudotyped lentiviral vectors, with a brief discussion on their production and batch quality analysis. Finally, we evaluate their role as surrogates for the real virus and possible alternatives. Full article

(This article belongs to the Special Issue Lentiviral Vectors)

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18 pages, 1376 KiB

Open AccessReview

Toward Tightly Tuned Gene Expression Following Lentiviral Vector Transduction

by Audrey Page, Floriane Fusil and François-Loïc Cosset

Viruses 2020, 12(12), 1427; https://0-doi-org.brum.beds.ac.uk/10.3390/v12121427 - 11 Dec 2020

Cited by 6 | Viewed by 5204

Abstract

Lentiviral vectors are versatile tools for gene delivery purposes. While in the earlier versions of retroviral vectors, transgene expression was controlled by the long terminal repeats (LTRs), the latter generations of vectors, including those derived from lentiviruses, incorporate internal constitutive or regulated promoters in order to regulate transgene expression. This allows to temporally and/or quantitatively control transgene expression, which is required for many applications such as for clinical applications, when transgene expression is required in specific tissues and at a specific timing. Here we review the main systems that have been developed for transgene regulated expression following lentiviral gene transfer. First, the induction of gene expression can be triggered either by external or by internal cues. Indeed, these regulated vector systems may harbor promoters inducible by exogenous stimuli, such as small molecules (e.g., antibiotics) or temperature variations, offering the possibility to tune rapidly transgene expression in case of adverse events. Second, expression can be indirectly adjusted by playing on inserted sequence copies, for instance by gene excision. Finally, synthetic networks can be developed to sense specific endogenous signals and trigger defined responses after information processing. Regulatable lentiviral vectors (LV)-mediated transgene expression systems have been widely used in basic research to uncover gene functions or to temporally reprogram cells. Clinical applications are also under development to induce therapeutic molecule secretion or to implement safety switches. Such regulatable approaches are currently focusing much attention and will benefit from the development of other technologies in order to launch autonomously controlled systems. Full article

(This article belongs to the Special Issue Lentiviral Vectors)

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23 pages, 2694 KiB

Open AccessReview

Pseudotyping Lentiviral Vectors: When the Clothes Make the Virus

by Alexis Duvergé and Matteo Negroni

Viruses 2020, 12(11), 1311; https://0-doi-org.brum.beds.ac.uk/10.3390/v12111311 - 16 Nov 2020

Cited by 20 | Viewed by 5252

Abstract

Delivering transgenes to human cells through transduction with viral vectors constitutes one of the most encouraging approaches in gene therapy. Lentivirus-derived vectors are among the most promising vectors for these approaches. When the genetic modification of the cell must be performed in vivo, efficient specific transduction of the cell targets of the therapy in the absence of off-targeting constitutes the Holy Grail of gene therapy. For viral therapy, this is largely determined by the characteristics of the surface proteins carried by the vector. In this regard, an important property of lentiviral vectors is the possibility of being pseudotyped by envelopes of other viruses, widening the panel of proteins with which they can be armed. Here, we discuss how this is achieved at the molecular level and what the properties and the potentialities of the different envelope proteins that can be used for pseudotyping these vectors are. Full article

(This article belongs to the Special Issue Lentiviral Vectors)

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21 pages, 1764 KiB

Open AccessReview

Gene Therapy Applications of Non-Human Lentiviral Vectors

by Altar M. Munis

Viruses 2020, 12(10), 1106; https://0-doi-org.brum.beds.ac.uk/10.3390/v12101106 - 29 Sep 2020

Cited by 26 | Viewed by 5533

Abstract

Recent commercialization of lentiviral vector (LV)-based cell therapies and successful reports of clinical studies have demonstrated the untapped potential of LVs to treat diseases and benefit patients. LVs hold notable and inherent advantages over other gene transfer agents based on their ability to transduce non-dividing cells, permanently transform target cell genome, and allow stable, long-term transgene expression. LV systems based on non-human lentiviruses are attractive alternatives to conventional HIV-1-based LVs due to their lack of pathogenicity in humans. This article reviews non-human lentiviruses and highlights their unique characteristics regarding virology and molecular biology. The LV systems developed based on these lentiviruses, as well as their successes and shortcomings, are also discussed. As the field of gene therapy is advancing rapidly, the use of LVs uncovers further challenges and possibilities. Advances in virology and an improved understanding of lentiviral biology will aid in the creation of recombinant viral vector variants suitable for translational applications from a variety of lentiviruses. Full article

(This article belongs to the Special Issue Lentiviral Vectors)

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14 pages, 499 KiB

Open AccessReview

The Old and the New: Prospects for Non-Integrating Lentiviral Vector Technology

by Luis Apolonia

Viruses 2020, 12(10), 1103; https://0-doi-org.brum.beds.ac.uk/10.3390/v12101103 - 29 Sep 2020

Cited by 28 | Viewed by 5044

Abstract

Lentiviral vectors have been developed and used in multiple gene and cell therapy applications. One of their main advantages over other vectors is the ability to integrate the genetic material into the genome of the host. However, this can also be a disadvantage as it may lead to insertional mutagenesis. To address this, non-integrating lentiviral vectors (NILVs) were developed. To generate NILVs, it is possible to introduce mutations in the viral enzyme integrase and/or mutations on the viral DNA recognised by integrase (the attachment sites). NILVs are able to stably express transgenes from episomal DNA in non-dividing cells or transiently if the target cells divide. It has been shown that these vectors are able to transduce multiple cell types and tissues. These characteristics make NILVs ideal vectors to use in vaccination and immunotherapies, among other applications. They also open future prospects for NILVs as tools for the delivery of CRISPR/Cas9 components, a recent revolutionary technology now widely used for gene editing and repair. Full article

(This article belongs to the Special Issue Lentiviral Vectors)

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22 pages, 1825 KiB

Open AccessReview

Lentiviral Vector Pseudotypes: Precious Tools to Improve Gene Modification of Hematopoietic Cells for Research and Gene Therapy

by Alejandra Gutierrez-Guerrero, François-Loïc Cosset and Els Verhoeyen

Viruses 2020, 12(9), 1016; https://0-doi-org.brum.beds.ac.uk/10.3390/v12091016 - 11 Sep 2020

Cited by 39 | Viewed by 13513

Abstract

Viruses have been repurposed into tools for gene delivery by transforming them into viral vectors. The most frequently used vectors are lentiviral vectors (LVs), derived from the human immune deficiency virus allowing efficient gene transfer in mammalian cells. They represent one of the safest and most efficient treatments for monogenic diseases affecting the hematopoietic system. LVs are modified with different viral envelopes (pseudotyping) to alter and improve their tropism for different primary cell types. The vesicular stomatitis virus glycoprotein (VSV-G) is commonly used for pseudotyping as it enhances gene transfer into multiple hematopoietic cell types. However, VSV-G pseudotyped LVs are not able to confer efficient transduction in quiescent blood cells, such as hematopoietic stem cells (HSC), B and T cells. To solve this problem, VSV-G can be exchanged for other heterologous viral envelopes glycoproteins, such as those from the Measles virus, Baboon endogenous retrovirus, Cocal virus, Nipah virus or Sendai virus. Here, we provide an overview of how these LV pseudotypes improved transduction efficiency of HSC, B, T and natural killer (NK) cells, underlined by multiple in vitro and in vivo studies demonstrating how pseudotyped LVs deliver therapeutic genes or gene editing tools to treat different genetic diseases and efficiently generate CAR T cells for cancer treatment. Full article

(This article belongs to the Special Issue Lentiviral Vectors)

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