The Immunogenicity in Mice of HCV Core Delivered as DNA Is Modulated by Its Capacity to Induce Oxidative Stress and Oxidative Stress Response

Jansons, Juris; Sominskaya, Irina; Петракова, Н. В.; Starodubova, Elizaveta; Smirnova, Olga A.; Алексеева, Е. И.; Brüvere, Rüta; Eliseeva, Olesja; Skrastiņa, Dace; Kashuba, Elena; Mihailova, Marija; Kochetkov, Sergey N.; Ivanov, Alexander; Isaguliants, Maria

doi:10.3390/cells8030208

Cited by 5 publications

(9 citation statements)

References 121 publications

(172 reference statements)

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“…HCV core has several domains that interfere with viability of expressing cells, their metabolism, induction of innate immune response ( Figure 1 A). Specifically, we have earlier shown that C-terminal domain of HCV core interferes with HCV core immunogenicity [ 36 ]. We reasoned that the removal of C-terminus, the immunogenicity of the truncated variant can be further enhanced by increasing its expression level.…”

Section: Resultsmentioning

confidence: 99%

“…The endpoint immune response was assessed by flow cytometry assessing the percentage of CD4+ and CD8+ T cells responding to DNA immunogens by production of IFN-γ, IL-2 and TNF-α after stimulation with synthetic peptides derived from each of the immunogens. For this, we have selected a panel of peptides derived from HCV core and TERT shown to represent their immunodominant epitopes recognized in mice [ 35 , 36 ]. Peptides were used alone or in pools ( Supplementary Table S1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Plasmid directing expression of the full-length HCV core using the genomic sequence of HCV 1b isolate 274933RU (GeneBank accession #AF176573) based on eukaryotic expression vector pVax1 was described by us previously (pVaxCore191v; [ 36 ]). The sequence encoding HCV core aa 1-191 codon optimized for expression in mammalian cells, carrying flanking endonuclease restriction sites Hind III and Xho I, was synthesized by Epoch Life Science Inc. (Missouri City, TX, USA), cloned into SmaI-digested pBluescript II SK(-) and further recloned into pVax1 generating pVaxCore191opt.…”

Section: Methodsmentioning

confidence: 99%

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Reciprocal Inhibition of Immunogenic Performance in Mice of Two Potent DNA Immunogens Targeting HCV-Related Liver Cancer

et al. 2021

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Chronic HCV infection and associated liver cancer impose a heavy burden on the healthcare system. Direct acting antivirals eliminate HCV, unless it is drug resistant, and partially reverse liver disease, but they cannot cure HCV-related cancer. A possible remedy could be a multi-component immunotherapeutic vaccine targeting both HCV-infected and malignant cells, but also those not infected with HCV. To meet this need we developed a two-component DNA vaccine based on the highly conserved core protein of HCV to target HCV-infected cells, and a renowned tumor-associated antigen telomerase reverse transcriptase (TERT) based on the rat TERT, to target malignant cells. Their synthetic genes were expression-optimized, and HCV core was truncated after aa 152 (Core152opt) to delete the domain interfering with immunogenicity. Core152opt and TERT DNA were highly immunogenic in BALB/c mice, inducing IFN-γ/IL-2/TNF-α response of CD4+ and CD8+ T cells. Additionally, DNA-immunization with TERT enhanced cellular immune response against luciferase encoded by a co-delivered plasmid (Luc DNA). However, DNA-immunization with Core152opt and TERT mix resulted in abrogation of immune response against both components. A loss of bioluminescence signal after co-delivery of TERT and Luc DNA into mice indicated that TERT affects the in vivo expression of luciferase directed by the immediate early cytomegalovirus and interferon-β promoters. Panel of mutant TERT variants was created and tested for their expression effects. TERT with deleted N-terminal nucleoli localization signal and mutations abrogating telomerase activity still suppressed the IFN-β driven Luc expression, while the inactivated reverse transcriptase domain of TERT and its analogue, enzymatically active HIV-1 reverse transcriptase, exerted only weak suppressive effects, implying that suppression relied on the presence of the full-length/nearly full-length TERT, but not its enzymatic activity. The effect(s) could be due to interference of the ectopically expressed xenogeneic rat TERT with biogenesis of mRNA, ribosomes and protein translation in murine cells, affecting the expression of immunogens. HCV core can aggravate this effect, leading to early apoptosis of co-expressing cells, preventing the induction of immune response.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Reciprocal Inhibition of Immunogenic Performance in Mice of Two Potent DNA Immunogens Targeting HCV-Related Liver Cancer

et al. 2021

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“…The induction of oxidative stress by HCV has been summarized recently in excellent reviews [26–28, 110]. Most of the HCV proteins are involved in the induction of oxidative stress, including the core, E1, E2, NS3, NS4B, and NS5A [111–121]. It is worth noting that the HCV core protein serves as a key regulator causing calcium perturbations and ROS production, and multiple mechanisms are exploited by the HCV core to induce oxidative stress.…”

Section: Oxidative Stress and Viral Infectionsmentioning

confidence: 99%

Flaviviridae Viruses and Oxidative Stress: Implications for Viral Pathogenesis

Zhang

Liang

2019

Oxidative Medicine and Cellular Longevity

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Oxidative stress is induced once the balance of generation and neutralization of reactive oxygen species (ROS) is broken in the cell, and it plays crucial roles in a variety of natural and diseased processes. Infections of Flaviviridae viruses trigger oxidative stress, which affects both the cellular metabolism and the life cycle of the viruses. Oxidative stress associated with specific viral proteins, experimental culture systems, and patient infections, as well as its correlations with the viral pathogenesis attracts much research attention. In this review, we primarily focus on hepatitis C virus (HCV), dengue virus (DENV), Zika virus (ZIKV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and tick-borne encephalitis virus (TBEV) as representatives of Flaviviridae viruses and we summarize the mechanisms involved in the relevance of oxidative stress for virus-associated pathogenesis. We discuss the current understanding of the pathogenic mechanisms of oxidative stress induced by Flaviviridae viruses and highlight the relevance of autophagy and DNA damage in the life cycle of viruses. Understanding the crosstalk between viral infection and oxidative stress-induced molecular events may offer new avenues for antiviral therapeutics.

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“…Other studies also highlighted reduced total antioxidant activity [ 36 ], decreased reduced glutathione/oxidized glutathione (GSH/GSSG) ratio [ 37 ] in lung epithelial fluid and decreased GSH content in blood during HIV infection [ 33–35 ]. The majority of the Hepatitis C virus (HCV) proteins (E1, E2, NS3, NS4B, NS5A) induce oxidative stress in hepatocytes, hepatic stellate cells and peripheral blood mononuclear cells (PBMC) [ 38–42 ]. Localization of HCV core proteinsin ER and mitochondria affects Ca 2 + efflux from ER to mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Noncoding RNAs: modulators and modulatable players during infection-induced stress response

Chattopadhyay¹,

Vasudevan²,

Pandey³

2021

Briefings in Functional Genomics

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The human genome has an almost equal distribution of unique and transposable genetic elements. Although at the transcriptome level, a relatively higher contribution from transposable elements derived RNA has been reported. This is further highlighted with evidence from pervasive transcription. Of the total RNA, noncoding RNAs (ncRNAs) are significant contributors to the transcriptome pool with sizeable fraction from repetitive elements of the human genome, inclusive of Long Interspersed Nuclear Elements (LINEs) and Short Interspersed Nuclear Elements (SINEs). ncRNAs are increasingly being implicated in diverse functional roles especially during conditions of stress. These stress responses are driven through diverse mediators, inclusive of long and short ncRNAs. ncRNAs such as MALAT1, GAS5, miR-204 and miR-199a-5p have been functionally involved during oxidative stress, endoplasmic reticulum (ER) stress and unfolded protein response (UPR). Also, within SINEs, Alu RNAs derived from primate-specific Alu repeats with ~11% human genome contribution, playing a significant role. Pathogenic diseases, including the recent COVID-19, leads to differential regulation of ncRNAs. Although, limited evidence suggests the need for an inquest into the role of ncRNAs in determining the host response towards pathogen challenge.

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The Immunogenicity in Mice of HCV Core Delivered as DNA Is Modulated by Its Capacity to Induce Oxidative Stress and Oxidative Stress Response

Cited by 5 publications

References 121 publications

Reciprocal Inhibition of Immunogenic Performance in Mice of Two Potent DNA Immunogens Targeting HCV-Related Liver Cancer

Reciprocal Inhibition of Immunogenic Performance in Mice of Two Potent DNA Immunogens Targeting HCV-Related Liver Cancer

Flaviviridae Viruses and Oxidative Stress: Implications for Viral Pathogenesis

Noncoding RNAs: modulators and modulatable players during infection-induced stress response

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