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Article ; Online: Defective interfering viruses and their impact on vaccines and viral vectors.

Frensing, Timo

2015 Volume 10, Issue 5, Page(s) 681–689

Abstract: Defective interfering particles (DIPs) have been found for many important viral pathogens and it is believed that most viruses generate DIPs. This article reviews the current knowledge of the generation and amplification of DIPs, which possess deletions ... ...

Abstract	Defective interfering particles (DIPs) have been found for many important viral pathogens and it is believed that most viruses generate DIPs. This article reviews the current knowledge of the generation and amplification of DIPs, which possess deletions in the viral genome but retain the ability to replicate in the presence of a complete helper virus. In addition, mechanisms are discussed by which DIPs interfere with the replication of their helper virus leading to the production of mainly progeny DIPs by coinfected cells. Even though DIPs cannot replicate on their own, they are biologically active and it is well known that they have a huge impact on virus replication, evolution, and pathogenesis. Moreover, defective genomes are potent inducers of the innate immune response. Yet, little attention has been paid to DIPs in recent years and their impact on biotechnological products such as vaccines and viral vectors remains elusive in most cases. With a focus on influenza virus, this review demonstrates that DIPs are important for basic research on viruses and for the production of viral vaccines and vectors. Reducing the generation and/or amplification of DIPs ensures reproducible results as well as high yields and consistent product quality in virus production.
MeSH term(s)	Animals ; Biotechnology/methods ; Genetic Vectors/physiology ; Helper Viruses/physiology ; Humans ; Satellite Viruses/physiology ; Viral Vaccines ; Virus Replication
Chemical Substances	Viral Vaccines
Language	English
Publishing date	2015-05
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	2221885-3
ISSN	1860-7314 ; 1860-6768
ISSN (online)	1860-7314
ISSN	1860-6768
DOI	10.1002/biot.201400429
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Book ; Online ; Thesis: Untersuchungen zur Regulation von Neuregulin-1

Frensing, Timo

2007

Author's details	vorgelegt von Timo Frensing
Language	German
Size	Online-Ressource
Document type	Book ; Online ; Thesis
Thesis / German Habilitation thesis	Univ., Diss--Bielefeld, 2007
Note	Erscheinungsjahr an der Hauptitelstelle: 2006
Database	Former special subject collection: coastal and deep sea fishing

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Article ; Online: A Novel Type of Influenza A Virus-Derived Defective Interfering Particle with Nucleotide Substitutions in Its Genome.

Kupke, Sascha Young / Riedel, Dietmar / Frensing, Timo / Zmora, Pawel / Reichl, Udo

Journal of virology

2019 Volume 93, Issue 4

Abstract: Defective interfering particles (DIPs) replicate at the expense of coinfecting, fully infectious homologous virus. Typically, they contain a highly deleted form of the viral genome. Utilizing single-cell analysis, here we report the discovery of a yet- ... ...

Abstract	Defective interfering particles (DIPs) replicate at the expense of coinfecting, fully infectious homologous virus. Typically, they contain a highly deleted form of the viral genome. Utilizing single-cell analysis, here we report the discovery of a yet-unknown DIP type, derived from influenza A viruses (IAVs), termed OP7 virus. Instead of deletions, the genomic viral RNA (vRNA) of segment 7 (S7) carried 37 point mutations compared to the reference sequence, affecting promoter regions, encoded proteins, and genome packaging signals. Coinfection experiments demonstrated strong interference of OP7 virus with IAV replication, manifested by a dramatic decrease in the infectivity of released virions. Moreover, an overproportional quantity of S7 in relation to other genome segments was observed, both intracellularly and in the released virus population. Concurrently, OP7 virions lacked a large fraction of other vRNA segments, which appears to constitute its defect in virus replication. OP7 virus might serve as a promising candidate for antiviral therapy. Furthermore, this novel form of DIP may also be present in other IAV preparations.
MeSH term(s)	A549 Cells ; Animals ; Antiviral Agents ; Defective Viruses/genetics ; Dogs ; Genome, Viral/genetics ; HEK293 Cells ; Humans ; Influenza A virus/genetics ; Influenza A virus/metabolism ; Madin Darby Canine Kidney Cells ; Nucleotides/genetics ; RNA, Viral/genetics ; Virion/genetics ; Virus Replication/genetics
Chemical Substances	Antiviral Agents ; Nucleotides ; RNA, Viral
Language	English
Publishing date	2019-02-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01786-18
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Article ; Online: Reduction of IL-2 fragmentation during manufacturing of a novel immunocytokine by DoE process optimization.

Schneider, Alina / Gorr, Ingo H / Larraillet, Vincent / Frensing, Timo / Popp, Oliver

Biotechnology and bioengineering

2019 Volume 116, Issue 10, Page(s) 2503–2513

Abstract: Interleukin-2 (IL-2) is a potent molecule in cancer therapy. Clinical application, however, is limited due to its strong side effects during the treatment. We developed an IL-2 variant (IL-2v) immunocytokine to circumvent the drawbacks of the current IL- ... ...

Abstract	Interleukin-2 (IL-2) is a potent molecule in cancer therapy. Clinical application, however, is limited due to its strong side effects during the treatment. We developed an IL-2 variant (IL-2v) immunocytokine to circumvent the drawbacks of the current IL-2 therapy. During the production of the IL-2v immunocytokine in Chinese hamster ovary (CHO) cells, molecules with fragmented IL-2v and therefore reduced cytokine activity can be observed. To control product fragmentation different production process conditions were investigated. By shifting temperature or pH after the cell growth phase to lower values, fragmented species can be reduced from 10% to 12% to about 4%. However, with the adopted process conditions, the effective titer is decreased concomitantly. Moreover, fermentation length and inoculation cell density are parameters to adjust fragmentation and effective titer. A suitable method for efficient process optimization is the design of experiment approach. With this procedure, novel optimal values for temperature, pH value, harvest day, and inoculation cell densities were proposed and tested subsequently. In comparison to the former process, the improved process reduces fragmentation by 66% while keeping the effective titer comparable. In summary, these findings will help to control fragmentation in CHO production processes of different IL-2v or IL-2 containing therapeutic proteins.
MeSH term(s)	Animals ; CHO Cells ; Cell Culture Techniques ; Cricetulus ; Humans ; Interleukin-2/biosynthesis ; Interleukin-2/genetics ; Protein Stability ; Recombinant Fusion Proteins/biosynthesis ; Recombinant Fusion Proteins/genetics
Chemical Substances	IL2 protein, human ; Interleukin-2 ; Recombinant Fusion Proteins
Language	English
Publishing date	2019-07-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	280318-5
ISSN	1097-0290 ; 0006-3592
ISSN (online)	1097-0290
ISSN	0006-3592
DOI	10.1002/bit.27090
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Book ; Online ; Thesis: Mathematical models of influenza A virus infection

Heldt, Frank Stefan / Frensing, Timo / Reichl, Udo

from intracellular replication to virus growth in cell populations

2015

Author's details	von Frank Stefan Heldt
Language	English
Size	Online-Ressource
Publisher	Universitätsbibl
Publishing place	Magdeburg
Document type	Book ; Online ; Thesis
Thesis / German Habilitation thesis	Univ., Fak. für Verfahrens- und Systemtechnik, Diss.--Magdeburg, 2015
Database	Former special subject collection: coastal and deep sea fishing

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Article ; Online: Model-based analysis of influenza A virus replication in genetically engineered cell lines elucidates the impact of host cell factors on key kinetic parameters of virus growth.

Laske, Tanja / Bachmann, Mandy / Dostert, Melanie / Karlas, Alexander / Wirth, Dagmar / Frensing, Timo / Meyer, Thomas F / Hauser, Hansjörg / Reichl, Udo

PLoS computational biology

2019 Volume 15, Issue 4, Page(s) e1006944

Abstract: The best measure to limit spread of contagious diseases caused by influenza A viruses (IAVs) is annual vaccination. The growing global demand for low-cost vaccines requires the establishment of high-yield production processes. One possible option to ... ...

Abstract	The best measure to limit spread of contagious diseases caused by influenza A viruses (IAVs) is annual vaccination. The growing global demand for low-cost vaccines requires the establishment of high-yield production processes. One possible option to address this challenge is the engineering of novel vaccine producer cell lines by manipulating gene expression of host cell factors relevant for virus replication. To support detailed characterization of engineered cell lines, we fitted an ordinary differential equation (ODE)-based model of intracellular IAV replication previously established by our group to experimental data obtained from infection studies in human A549 cells. Model predictions indicate that steps of viral RNA synthesis, their regulation and particle assembly and virus budding are promising targets for cell line engineering. The importance of these steps was confirmed in four of five single gene overexpression cell lines (SGOs) that showed small, but reproducible changes in early dynamics of RNA synthesis and virus release. Model-based analysis suggests, however, that overexpression of the selected host cell factors negatively influences specific RNA synthesis rates. Still, virus yield was rescued by an increase in the virus release rate. Based on parameter estimations obtained for SGOs, we predicted that there is a potential benefit associated with overexpressing multiple host cell genes in one cell line, which was validated experimentally. Overall, this model-based study on IAV replication in engineered cell lines provides a step forward in the dynamic and quantitative characterization of IAV-host cell interactions. Furthermore, it suggests targets for gene editing and indicates that overexpression of multiple host cell factors may be beneficial for the design of novel producer cell lines.
MeSH term(s)	A549 Cells ; Active Transport, Cell Nucleus ; Animals ; Computational Biology ; Computer Simulation ; Dogs ; Genetic Engineering ; Genome, Viral ; Host Microbial Interactions/genetics ; Host Microbial Interactions/physiology ; Humans ; Influenza A virus/genetics ; Influenza A virus/physiology ; Influenza Vaccines/biosynthesis ; Kinetics ; Madin Darby Canine Kidney Cells ; Models, Biological ; Virus Replication/genetics ; Virus Replication/physiology
Chemical Substances	Influenza Vaccines
Language	English
Publishing date	2019-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1006944
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Book ; Online ; Thesis: Untersuchungen zur Regulation von Neuregulin-1

Frensing, Timo [Verfasser]

2007

Author's details	vorgelegt von Timo Frensing
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Modeling the intracellular replication of influenza A virus in the presence of defective interfering RNAs.

Laske, Tanja / Heldt, Frank Stefan / Hoffmann, Helene / Frensing, Timo / Reichl, Udo

Virus research

2016 Volume 213, Page(s) 90–99

Abstract: Like many other viral pathogens, influenza A viruses can form defective interfering particles (DIPs). These particles carry a large internal deletion in at least one of their genome segments. Thus, their replication depends on the co-infection of cells ... ...

Abstract	Like many other viral pathogens, influenza A viruses can form defective interfering particles (DIPs). These particles carry a large internal deletion in at least one of their genome segments. Thus, their replication depends on the co-infection of cells by standard viruses (STVs), which supply the viral protein(s) encoded by the defective segment. However, DIPs also interfere with STV replication at the molecular level and, despite considerable research efforts, the mechanism of this interference remains largely elusive. Here, we present a mechanistic mathematical model for the intracellular replication of DIPs. In this model, we account for the common hypothesis that defective interfering RNAs (DI RNAs) possess a replication advantage over full-length (FL) RNAs due to their reduced length. By this means, the model captures experimental data from yield reduction assays and from studies testing different co-infection timings. In addition, our model predicts that one important aspect of interference is the competition for viral proteins, namely the heterotrimeric viral RNA-dependent RNA polymerase (RdRp) and the viral nucleoprotein (NP), which are needed for encapsidation of naked viral RNA. Moreover, we find that there may be an optimum for both the DI RNA synthesis rate and the time point of successive co-infection of a cell by DIPs and STVs. Comparing simulations for the growth of DIPs with a deletion in different genome segments suggests that DI RNAs derived from segments which encode for the polymerase subunits are more competitive than others. Overall, our model, thus, helps to elucidate the interference mechanism of DI RNAs and provides a novel hypothesis why DI RNAs derived from the polymerase-encoding segments are more abundant in DIP preparations.
MeSH term(s)	Defective Viruses/genetics ; Defective Viruses/growth & development ; Influenza A virus/genetics ; Influenza A virus/growth & development ; Models, Theoretical ; RNA, Viral/genetics ; RNA, Viral/metabolism ; Virus Replication
Chemical Substances	RNA, Viral
Language	English
Publishing date	2016-02-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2015.11.016
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Article ; Online: Reprint of "Modeling the intracellular replication of influenza A virus in the presence of defective interfering RNAs.

Laske, Tanja / Heldt, Frank Stefan / Hoffmann, Helene / Frensing, Timo / Reichl, Udo

Virus research

2016 Volume 218, Page(s) 86–95

Abstract	Like many other viral pathogens, influenza A viruses can form defective interfering particles (DIPs). These particles carry a large internal deletion in at least one of their genome segments. Thus, their replication depends on the co-infection of cells by standard viruses (STVs), which supply the viral protein(s) encoded by the defective segment. However, DIPs also interfere with STV replication at the molecular level and, despite considerable research efforts, the mechanism of this interference remains largely elusive. Here, we present a mechanistic mathematical model for the intracellular replication of DIPs. In this model, we account for the common hypothesis that defective interfering RNAs (DI RNAs) possess a replication advantage over full-length (FL) RNAs due to their reduced length. By this means, the model captures experimental data from yield reduction assays and from studies testing different co-infection timings. In addition, our model predicts that one important aspect of interference is the competition for viral proteins, namely the heterotrimeric viral RNA-dependent RNA polymerase (RdRp) and the viral nucleoprotein (NP), which are needed for encapsidation of naked viral RNA. Moreover, we find that there may be an optimum for both the DI RNA synthesis rate and the time point of successive co-infection of a cell by DIPs and STVs. Comparing simulations for the growth of DIPs with a deletion in different genome segments suggests that DI RNAs derived from segments which encode for the polymerase subunits are more competitive than others. Overall, our model, thus, helps to elucidate the interference mechanism of DI RNAs and provides a novel hypothesis why DI RNAs derived from the polymerase-encoding segments are more abundant in DIP preparations.
Language	English
Publishing date	2016-06-15
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2016.05.009
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Article ; Online: Impact of defective interfering particles on virus replication and antiviral host response in cell culture-based influenza vaccine production.

Frensing, Timo / Pflugmacher, Antje / Bachmann, Mandy / Peschel, Britta / Reichl, Udo

Applied microbiology and biotechnology

2014 Volume 98, Issue 21, Page(s) 8999–9008

Abstract: During the replication of influenza viruses, defective interfering particles (DIPs) can be generated. These are noninfectious deletion mutants that require coinfection with a wild-type virus but interfere with its helper virus replication. Consequently, ... ...

Abstract	During the replication of influenza viruses, defective interfering particles (DIPs) can be generated. These are noninfectious deletion mutants that require coinfection with a wild-type virus but interfere with its helper virus replication. Consequently, coinfected cells mainly produce DIPs. Little is known about how such noninfectious virus particles affect the virus yield of cell culture-based influenza vaccine production. We compared infections of Madin-Darby canine kidney cells with two seed virus preparations of the influenza virus strain A/Puerto Rico/8/34 that contain different amounts of DIPs. A combination of conventional RT-PCR, RT-qPCR, and flow cytometry revealed that DI genomes indeed strongly accumulate in coinfected cells and impede the viral RNA synthesis. Additionally, cells infected at the higher DIP concentration showed a stronger antiviral response characterized by increased interferon-β expression and apoptosis induction. Furthermore, in the presence of DIPs, a significant fraction of cells did not show any productive accumulation of viral proteins at all. Together, these effects of DIPs significantly reduce the virus yield. Therefore, the accumulation of DIPs should be avoided during influenza vaccine production which can be achieved by quality controls of working seed viruses based on conventional RT-PCR. The strategy for the depletion of DIPs presented here can help to make cell culture-based vaccine production more reliable and robust.
MeSH term(s)	Animals ; Antiviral Agents/metabolism ; Apoptosis ; Defective Viruses/physiology ; Dogs ; Flow Cytometry ; Host-Pathogen Interactions ; Influenza A virus/growth & development ; Influenza A virus/immunology ; Influenza A virus/physiology ; Influenza Vaccines/isolation & purification ; Interferons/metabolism ; Madin Darby Canine Kidney Cells ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Viral Load ; Virus Replication
Chemical Substances	Antiviral Agents ; Influenza Vaccines ; Interferons (9008-11-1)
Language	English
Publishing date	2014-11
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	392453-1
ISSN	1432-0614 ; 0171-1741 ; 0175-7598
ISSN (online)	1432-0614
ISSN	0171-1741 ; 0175-7598
DOI	10.1007/s00253-014-5933-y
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