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14 pages, 7261 KiB

Open AccessArticle

Internal Ribosome Entry Site Dramatically Reduces Transgene Expression in Hematopoietic Cells in a Position-Dependent Manner

by Qingyun Zheng, Xueyan Zhang, Hua Yang, Jinyan Xie, Yilin Xie, Jinzhong Chen, Chenghui Yu and Chen Zhong

Viruses 2019, 11(10), 920; https://doi.org/10.3390/v11100920 - 08 Oct 2019

Cited by 6 | Viewed by 3304

Abstract

Bicistronic transgene expression mediated by internal ribosome entry site (IRES) elements has been widely used. It co-expresses heterologous transgene products from a message RNA driven by a single promoter. Hematologic gene delivery is a promising treatment for both inherited and acquired diseases. A [...] Read more.

Bicistronic transgene expression mediated by internal ribosome entry site (IRES) elements has been widely used. It co-expresses heterologous transgene products from a message RNA driven by a single promoter. Hematologic gene delivery is a promising treatment for both inherited and acquired diseases. A combined strategy was recently documented for potential genome editing in hematopoietic cells. A transduction efficiency exceeding ~90% can be achieved by capsid-optimized recombinant adeno-associated virus serotype 6 (rAAV6) vectors. In this study, to deliver an encephalomyocarditis virus (EMCV) IRES-containing rAAV6 genome into hematopoietic cells, we observed that EMCV IRES almost completely shut down the transgene expression during the process of mRNA–protein transition. In addition, position-dependent behavior was observed, in which only the EMCV IRES element located between a promoter and the transgenes had an inhibitory effect. Although further studies are warranted to evaluate the involvement of cellular translation machinery, our results propose the use of specific IRES elements or an alternative strategy, such as the 2A system, to achieve bicistronic transgene expression in hematopoietic cells. Full article

(This article belongs to the Special Issue Viruses and Cellular Metabolism)

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Review

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16 pages, 1739 KiB

Open AccessReview

Meal for Two: Human Cytomegalovirus-Induced Activation of Cellular Metabolism

by Irene Rodríguez-Sánchez and Joshua Munger

Viruses 2019, 11(3), 273; https://doi.org/10.3390/v11030273 - 19 Mar 2019

Cited by 28 | Viewed by 4237

Abstract

Viruses are parasites that depend on the host cell’s metabolic resources to provide the energy and molecular building blocks necessary for the production of viral progeny. It has become increasingly clear that viruses extensively modulate the cellular metabolic network to support productive infection. [...] Read more.

Viruses are parasites that depend on the host cell’s metabolic resources to provide the energy and molecular building blocks necessary for the production of viral progeny. It has become increasingly clear that viruses extensively modulate the cellular metabolic network to support productive infection. Here, we review the numerous ways through which human cytomegalovirus (HCMV) modulates cellular metabolism, highlighting known mechanisms of HCMV-mediated metabolic manipulation and identifying key outstanding questions that remain to be addressed. Full article

(This article belongs to the Special Issue Viruses and Cellular Metabolism)

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30 pages, 1864 KiB

Open AccessReview

Metabolomic Insights into Human Arboviral Infections: Dengue, Chikungunya, and Zika Viruses

by Nathaniel M. Byers, Amy C. Fleshman, Rushika Perera and Claudia R. Molins

Viruses 2019, 11(3), 225; https://doi.org/10.3390/v11030225 - 06 Mar 2019

Cited by 34 | Viewed by 6361

Abstract

The global burden of arboviral diseases and the limited success in controlling them calls for innovative methods to understand arbovirus infections. Metabolomics has been applied to detect alterations in host physiology during infection. This approach relies on mass spectrometry or nuclear magnetic resonance [...] Read more.

The global burden of arboviral diseases and the limited success in controlling them calls for innovative methods to understand arbovirus infections. Metabolomics has been applied to detect alterations in host physiology during infection. This approach relies on mass spectrometry or nuclear magnetic resonance spectroscopy to evaluate how perturbations in biological systems alter metabolic pathways, allowing for differentiation of closely related conditions. Because viruses heavily depend on host resources and pathways, they present unique challenges for characterizing metabolic changes. Here, we review the literature on metabolomics of arboviruses and focus on the interpretation of identified molecular features. Metabolomics has revealed biomarkers that differentiate disease states and outcomes, and has shown similarities in metabolic alterations caused by different viruses (e.g., lipid metabolism). Researchers investigating such metabolomic alterations aim to better understand host–virus dynamics, identify diagnostically useful molecular features, discern perturbed pathways for therapeutics, and guide further biochemical research. This review focuses on lessons derived from metabolomics studies on samples from arbovirus-infected humans. Full article

(This article belongs to the Special Issue Viruses and Cellular Metabolism)

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17 pages, 592 KiB

Open AccessReview

Influenza Virus Infections and Cellular Kinases

by Robert Meineke, Guus F. Rimmelzwaan and Husni Elbahesh

Viruses 2019, 11(2), 171; https://doi.org/10.3390/v11020171 - 20 Feb 2019

Cited by 74 | Viewed by 10242

Abstract

Influenza A viruses (IAVs) are a major cause of respiratory illness and are responsible for yearly epidemics associated with more than 500,000 annual deaths globally. Novel IAVs may cause pandemic outbreaks and zoonotic infections with, for example, highly pathogenic avian influenza virus (HPAIV) [...] Read more.

Influenza A viruses (IAVs) are a major cause of respiratory illness and are responsible for yearly epidemics associated with more than 500,000 annual deaths globally. Novel IAVs may cause pandemic outbreaks and zoonotic infections with, for example, highly pathogenic avian influenza virus (HPAIV) of the H5N1 and H7N9 subtypes, which pose a threat to public health. Treatment options are limited and emergence of strains resistant to antiviral drugs jeopardize this even further. Like all viruses, IAVs depend on host factors for every step of the virus replication cycle. Host kinases link multiple signaling pathways in respond to a myriad of stimuli, including viral infections. Their regulation of multiple response networks has justified actively targeting cellular kinases for anti-cancer therapies and immune modulators for decades. There is a growing volume of research highlighting the significant role of cellular kinases in regulating IAV infections. Their functional role is illustrated by the required phosphorylation of several IAV proteins necessary for replication and/or evasion/suppression of the innate immune response. Identified in the majority of host factor screens, functional studies further support the important role of kinases and their potential as host restriction factors. PKC, ERK, PI3K and FAK, to name a few, are kinases that regulate viral entry and replication. Additionally, kinases such as IKK, JNK and p38 MAPK are essential in mediating viral sensor signaling cascades that regulate expression of antiviral chemokines and cytokines. The feasibility of targeting kinases is steadily moving from bench to clinic and already-approved cancer drugs could potentially be repurposed for treatments of severe IAV infections. In this review, we will focus on the contribution of cellular kinases to IAV infections and their value as potential therapeutic targets. Full article

(This article belongs to the Special Issue Viruses and Cellular Metabolism)

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21 pages, 3645 KiB

Open AccessReview

Metabolic Reprogramming of the Host Cell by Human Adenovirus Infection

by Martin A. Prusinkiewicz and Joe S. Mymryk

Viruses 2019, 11(2), 141; https://doi.org/10.3390/v11020141 - 08 Feb 2019

Cited by 59 | Viewed by 9327

Abstract

Viruses are obligate intracellular parasites that alter many cellular processes to create an environment optimal for viral replication. Reprogramming of cellular metabolism is an important, yet underappreciated feature of many viral infections, as this ensures that the energy and substrates required for viral [...] Read more.

Viruses are obligate intracellular parasites that alter many cellular processes to create an environment optimal for viral replication. Reprogramming of cellular metabolism is an important, yet underappreciated feature of many viral infections, as this ensures that the energy and substrates required for viral replication are available in abundance. Human adenovirus (HAdV), which is the focus of this review, is a small DNA tumor virus that reprograms cellular metabolism in a variety of ways. It is well known that HAdV infection increases glucose uptake and fermentation to lactate in a manner resembling the Warburg effect observed in many cancer cells. However, HAdV infection induces many other metabolic changes. In this review, we integrate the findings from a variety of proteomic and transcriptomic studies to understand the subtleties of metabolite and metabolic pathway control during HAdV infection. We review how the E4ORF1 protein of HAdV enacts some of these changes and summarize evidence for reprogramming of cellular metabolism by the viral E1A protein. Therapies targeting altered metabolism are emerging as cancer treatments, and similar targeting of aberrant components of virally reprogrammed metabolism could have clinical antiviral applications. Full article

(This article belongs to the Special Issue Viruses and Cellular Metabolism)

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19 pages, 443 KiB

Open AccessReview

Chewing the Fat: The Conserved Ability of DNA Viruses to Hijack Cellular Lipid Metabolism

by Philip T. Lange, Michael Lagunoff and Vera L. Tarakanova

Viruses 2019, 11(2), 119; https://doi.org/10.3390/v11020119 - 29 Jan 2019

Cited by 29 | Viewed by 5841

Abstract

Viruses manipulate numerous host factors and cellular pathways to facilitate the replication of viral genomes and the production of infectious progeny. One way in which viruses interact with cells is through the utilization and exploitation of the host lipid metabolism. While it is [...] Read more.

Viruses manipulate numerous host factors and cellular pathways to facilitate the replication of viral genomes and the production of infectious progeny. One way in which viruses interact with cells is through the utilization and exploitation of the host lipid metabolism. While it is likely that most—if not all—viruses require lipids or intermediates of lipid synthesis to replicate, many viruses also actively induce lipid metabolic pathways to sustain a favorable replication environment. From the formation of membranous replication compartments, to the generation of ATP or protein modifications, viruses exhibit differing requirements for host lipids. Thus, while the exploitation of lipid metabolism is a common replication strategy, diverse viruses employ a plethora of mechanisms to co-opt these critical cellular pathways. Here, we review recent literature regarding the exploitation of host lipids and lipid metabolism specifically by DNA viruses. Importantly, furthering the understanding of the viral requirements for host lipids may offer new targets for antiviral therapeutics and provide opportunities to repurpose the numerous FDA-approved compounds targeting lipid metabolic pathways as antiviral agents. Full article

(This article belongs to the Special Issue Viruses and Cellular Metabolism)

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18 pages, 1257 KiB

Open AccessReview

Role of Host Cell Secretory Machinery in Zika Virus Life Cycle

by Garrett Sager, Samuel Gabaglio, Elizabeth Sztul and George A. Belov

Viruses 2018, 10(10), 559; https://doi.org/10.3390/v10100559 - 15 Oct 2018

Cited by 54 | Viewed by 8607

Abstract

The high human cost of Zika virus infections and the rapid establishment of virus circulation in novel areas, including the United States, present an urgent need for countermeasures against this emerging threat. The development of an effective vaccine against Zika virus may be [...] Read more.

The high human cost of Zika virus infections and the rapid establishment of virus circulation in novel areas, including the United States, present an urgent need for countermeasures against this emerging threat. The development of an effective vaccine against Zika virus may be problematic because of the cross reactivity of the antibodies with other flaviviruses leading to antibody-dependent enhancement of infection. Moreover, rapidly replicating positive strand RNA viruses, including Zika virus, generate large spectrum of mutant genomes (quasi species) every replication round, allowing rapid selection of variants resistant to drugs targeting virus-specific proteins. On the other hand, viruses are ultimate cellular parasites and rely on the host metabolism for every step of their life cycle, thus presenting an opportunity to manipulate host processes as an alternative approach to suppress virus replication and spread. Zika and other flaviviruses critically depend on the cellular secretory pathway, which transfers proteins and membranes from the ER through the Golgi to the plasma membrane, for virion assembly, maturation and release. In this review, we summarize the current knowledge of interactions of Zika and similar arthropod-borne flaviviruses with the cellular secretory machinery with a special emphasis on virus-specific changes of the secretory pathway. Identification of the regulatory networks and effector proteins required to accommodate the trafficking of virions, which represent a highly unusual cargo for the secretory pathway, may open an attractive and virtually untapped reservoir of alternative targets for the development of superior anti-viral drugs. Full article

(This article belongs to the Special Issue Viruses and Cellular Metabolism)

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13 pages, 4832 KiB

Open AccessReview

A Systems Approach to Study Immuno- and Neuro-Modulatory Properties of Antiviral Agents

by Eva Zusinaite, Aleksandr Ianevski, Diana Niukkanen, Minna M. Poranen, Magnar Bjørås, Jan Egil Afset, Tanel Tenson, Vidya Velagapudi, Andres Merits and Denis E. Kainov

Viruses 2018, 10(8), 423; https://doi.org/10.3390/v10080423 - 12 Aug 2018

Cited by 7 | Viewed by 4995

Abstract

There are dozens of approved, investigational and experimental antiviral agents. Many of these agents cause serious side effects, which can only be revealed after drug administration. Identification of the side effects prior to drug administration is challenging. Here we describe an ex vivo [...] Read more.

There are dozens of approved, investigational and experimental antiviral agents. Many of these agents cause serious side effects, which can only be revealed after drug administration. Identification of the side effects prior to drug administration is challenging. Here we describe an ex vivo approach for studying immuno- and neuro-modulatory properties of antiviral agents, which may be associated with potential side effects of these therapeutics. The current approach combines drug toxicity/efficacy tests and transcriptomics, which is followed by mRNA, cytokine and metabolite profiling. We demonstrated the utility of this approach with several examples of antiviral agents. We also showed that the approach can utilize different immune stimuli and cell types. It can also include other omics techniques, such as genomics and epigenomics, to allow identification of individual markers associated with adverse reactions to antivirals with immuno- and neuro-modulatory properties. Full article

(This article belongs to the Special Issue Viruses and Cellular Metabolism)

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