scholarly journals Inhibition of NF-κB Activation in Combination with Bcl-2 Expression Allows for Persistence of First-Generation Adenovirus Vectors in the Mouse Liver

1998 ◽  
Vol 72 (11) ◽  
pp. 9267-9277 ◽  
Author(s):  
André Lieber ◽  
Chen-Yi He ◽  
Leonard Meuse ◽  
Charis Himeda ◽  
Christopher Wilson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Transgenic Mice ◽  
Transcriptional Activation ◽  
First Generation ◽  
Viral Gene ◽  
Gene Products ◽  
Antiviral Immune Response ◽  
Innate Defense ◽  
Adenovirus Vectors

ABSTRACT NF-κB is a key regulator of the innate antiviral immune response, due in part to its transcriptional activation of cytokines and adhesion molecules, which, in turn, function in chemotaxis and activation of inflammatory cells. We reported earlier that viral gene expression in hepatocytes transduced with first-generation (E1-deleted) adenoviruses induced NF-κB activation, elevation of serum cytokines, and hepatocellular apoptosis during the first days postinfusion. These events did not occur in mice infused with an adenovirus vector deleted for E1, E2, E3, and late gene expression. In the present study, we used an adenovirus expressing an IκBα supersuppressor (Ad.IκBM) andbcl-2 transgenic mice to unravel the role of virus-induced NF-κB activation and apoptosis in the clearance of recombinant adenovirus vectors from the liver. The combined action of IκBM and Bcl-2 allowed for vector persistence in livers of C57BL/6 × C3H mice. In the absence of Bcl-2, IκBM expression in mouse livers significantly reduced NF-κB activation, cytokine expression, leukocyte infiltration, and the humoral immune response against the transgene product; however, this was not sufficient to prevent the decline of vector DNA in transduced cells. Infusion of Ad.IκBM caused extended apoptosis predominantly in periportal liver regions, indicating that NF-κB activation may protect transduced hepatocytes from apoptosis induced by adenovirus gene products. To confer vector persistence, bcl-2 transgene expression was required to block virus-induced apoptosis if NF-κB protection was inactivated by IκBM. Expression of gene products involved in early stages of apoptotic pathways was up-regulated in response to virus infusion inbcl-2 transgenic mice, which may represent a compensatory effect. Our study supports the idea that the suppression of innate defense mechanisms improves vector persistence.

scholarly journals The E4-6/7 Protein Functionally Compensates for the Loss of E1A Expression in Adenovirus Infection

2000 ◽  
Vol 74 (13) ◽  
pp. 5819-5824 ◽  
Author(s):  
Robert J. O'Connor ◽  
Patrick Hearing
Keyword(s):  
Gene Expression ◽  
Transcriptional Activation ◽  
Promoter Region ◽  
Cultured Cells ◽  
Recombinant Adenovirus ◽  
Viral Gene ◽  
Gene Products ◽  
E1a Gene

ABSTRACT The E1A gene products are required and sufficient for activation of adenovirus gene expression in cultured cells. The E4-6/7 gene product induces the binding of the cellular transcription factor E2F to the viral E2a promoter region. The induction of E2F binding to the E2a promoter in vitro is directly correlated with transcriptional activation of the E2a promoter in vivo. The E2 region encodes the viral replication proteins, yet adenoviruses lacking E4-6/7 function demonstrate no defective phenotype in infected cells. Here we show that the E4-6/7 protein can functionally compensate for E1A expression in virus infection. In the absence of the E1A gene products, expression of the E4-6/7 protein is sufficient to displace retinoblastoma protein family members from E2Fs, activate expression of early region 2 via induction of E2F DNA binding to the E2a promoter region, and significantly enhance replication of an E1A-defective adenovirus. These results have implications in the regulation of viral gene expression and for the development of recombinant adenovirus vectors.

scholarly journals Viral-Mediated mRNA Degradation for Pathogenesis

Biomedicines ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 111
Author(s):  
Shujuan Du ◽  
Xiaoqing Liu ◽  
Qiliang Cai
Keyword(s):  
Gene Expression ◽  
Current Knowledge ◽  
Immune Surveillance ◽  
Viral Gene Expression ◽  
Mrna Degradation ◽  
Vital Role ◽  
Viral Gene ◽  
Antiviral Immune Response ◽  
Successful Infection ◽  
The Stability

Cellular RNA decay machinery plays a vital role in regulating gene expression by altering the stability of mRNAs in response to external stresses, including viral infection. In the primary infection, viruses often conquer the host cell’s antiviral immune response by controlling the inherently cellular mRNA degradation machinery to facilitate viral gene expression and establish a successful infection. This review summarizes the current knowledge about the diverse strategies of viral-mediated regulatory RNA shutoff for pathogenesis, and particularly sheds a light on the mechanisms that viruses evolve to elude immune surveillance during infection.

scholarly journals Impact of Tat Genetic Variation on HIV-1 Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-28 ◽  
Author(s):  
Luna Li ◽  
Satinder Dahiya ◽  
Sandhya Kortagere ◽  
Benjamas Aiamkitsumrit ◽  
David Cunningham ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Transcriptional Activation ◽  
Viral Gene Expression ◽  
Functional Domains ◽  
Viral Gene ◽  
Molecular Architecture ◽  
Viral Transactivator ◽  
Hiv Drugs ◽  
Hiv 1

The human immunodeficiency virus type 1 (HIV-1) promoter or long-terminal repeat (LTR) regulates viral gene expression by interacting with multiple viral and host factors. The viral transactivator protein Tat plays an important role in transcriptional activation of HIV-1 gene expression. Functional domains of Tat and its interaction with transactivation response element RNA and cellular transcription factors have been examined. Genetic variation withintatof different HIV-1 subtypes has been shown to affect the interaction of the viral transactivator with cellular and/or viral proteins, influencing the overall level of transcriptional activation as well as its action as a neurotoxic protein. Consequently, the genetic variability withintatmay impact the molecular architecture of functional domains of the Tat protein that may impact HIV pathogenesis and disease. Tat as a therapeutic target for anti-HIV drugs has also been discussed.

B-Catenin Signaling Regulates the In Vivo Distribution of Hepatitis B Virus Biosynthesis across the Liver Lobule

2021 ◽  
Author(s):  
Grant Tarnow ◽  
Alan McLachlan
Keyword(s):  
Gene Expression ◽  
Transgenic Mice ◽  
Viral Replication ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Central Vein ◽  
Liver Lobule ◽  
Liver Gene ◽  
Mice Liver

β-catenin (Ctnnb1) supports high levels of liver gene expression in hepatocytes in proximity to the central vein functionally defining zone 3 of the liver lobule. This region of the liver lobule supports the highest levels of viral biosynthesis in wildtype HBV transgenic mice. Liver-specific β-catenin-null HBV transgenic mice exhibit a stark loss of high levels of pericentral viral biosynthesis. Additionally, viral replication that does not depend directly on β-catenin activity appears to expand to include hepatocytes of zone 1 of the liver lobule in proximity to the portal vein, a region of the liver that typically lacks significant HBV biosynthesis in wildtype HBV transgenic mice. While the average amount of viral RNA transcripts does not change, viral DNA replication is reduced approximately three-fold. Together, these observations demonstrate that β-catenin signaling represents a major determinant of HBV biosynthesis governing the magnitude and distribution of viral replication across the liver lobule in vivo. Additionally, these findings reveal a novel mechanism for the regulation of HBV biosynthesis that is potentially relevant to the expression of additional liver-specific genes. IMPORTANCE Viral biosynthesis is highest around the central vein in the HBV transgenic mouse model of chronic infection. The associated HBV biosynthetic gradient across the liver lobule is primarily dependent upon β-catenin. In the absence of β-catenin, the gradient of viral gene expression spanning the liver lobule is absent and HBV replication is reduced. Therefore, therapeutically manipulating β-catenin activity in the liver of chronic HBV carriers may reduce circulating infectious virions without greatly modulating viral protein production. Together, these change in viral biosynthesis might limit infection of additional hepatocytes while permitting immunological clearance of previously infected cells, potentially limiting disease persistence.

scholarly journals IFN-I Independent Antiviral Immune Response to Vesicular Stomatitis Virus Challenge in Mouse Brain

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 326
Author(s):  
Anurag R. Mishra ◽  
Siddappa N. Byrareddy ◽  
Debasis Nayak
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Vesicular Stomatitis Virus ◽  
Antiviral Response ◽  
Type I ◽  
Immune Gene ◽  
Antiviral Immune Response ◽  
Virus Challenge ◽  
Vesicular Stomatitis ◽  
Ifn Γ

Type I interferon (IFN-I) plays a pivotal role during viral infection response in the central nervous system (CNS). The IFN-I can orchestrate and regulate most of the innate immune gene expression and myeloid cell dynamics following a noncytopathic virus infection. However, the role of IFN-I in the CNS against viral encephalitis is not entirely clear. Here we have implemented the combination of global differential gene expression profiling followed by bioinformatics analysis to decipher the CNS immune response in the presence and absence of the IFN-I signaling. We observed that vesicular stomatitis virus (VSV) infection induced 281 gene changes in wild-type (WT) mice primarily associated with IFN-I signaling. This was accompanied by an increase in antiviral response through leukocyte vascular patrolling and leukocyte influx along with the expression of potent antiviral factors. Surprisingly, in the absence of the IFN-I signaling (IFNAR−/− mice), a significantly higher (1357) number of genes showed differential expression compared to the WT mice. Critical candidates such as IFN-γ, CCL5, CXCL10, and IRF1, which are responsible for the recruitment of the patrolling leukocytes, are also upregulated in the absence of IFN-I signaling. The computational network analysis suggests the presence of the IFN-I independent pathway that compensates for the lack of IFN-I signaling in the brain. The analysis shows that TNF-α is connected maximally to the networked candidates, thus emerging as a key regulator of gene expression and recruitment of myeloid cells to mount antiviral action. This pathway could potentiate IFN-γ release; thereby, synergistically activating IRF1-dependent ISG expression and antiviral response.

scholarly journals HLA-A*0201, HLA-A*1101, and HLA-B*0702 transgenic mice recognize numerous poxvirus determinants from a wide variety of viral gene products.

2005 ◽  
Vol 175 (12) ◽  
pp. 8440.2-8440
Author(s):  
V. Pasquetto ◽  
H.-H. Bui ◽  
R. Giannino ◽  
F. Mirza ◽  
J. Sidney ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Viral Gene ◽  
Gene Products

scholarly journals MicroRNA miR-21 Attenuates Human Cytomegalovirus Replication in Neural Cells by Targeting Cdc25a

2014 ◽  
Vol 89 (2) ◽  
pp. 1070-1082 ◽  
Author(s):  
Ya-Ru Fu ◽  
Xi-Juan Liu ◽  
Xiao-Jun Li ◽  
Zhang-zhou Shen ◽  
Bo Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Stem Cells ◽  
Birth Defects ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Gene Products ◽  
Hcmv Replication

ABSTRACTCongenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, primarily manifesting as neurological disorders. HCMV infection alters expression of cellular microRNAs (miRs) and induces cell cycle arrest, which in turn modifies the cellular environment to favor virus replication. Previous observations found that HCMV infection reduces miR-21 expression in neural progenitor/stem cells (NPCs). Here, we show that infection of NPCs and U-251MG cells represses miR-21 while increasing the levels of Cdc25a, a cell cycle regulator and known target of miR-21. These opposing responses to infection prompted an investigation of the relationship between miR-21, Cdc25a, and viral replication. Overexpression of miR-21 in NPCs and U-251MG cells inhibited viral gene expression, genome replication, and production of infectious progeny, while shRNA-knockdown of miR-21 in U-251MG cells increased viral gene expression. In contrast, overexpression of Cdc25a in U-251MG cells increased viral gene expression and production of infectious progeny and overcame the inhibitory effects of miR-21 overexpression. Three viral gene products—IE1, pp71, and UL26—were shown to inhibit miR-21 expression at the transcriptional level. These results suggest that Cdc25a promotes HCMV replication and elevation of Cdc25a levels after HCMV infection are due in part to HCMV-mediated repression of miR-21. Thus, miR-21 is an intrinsic antiviral factor that is modulated by HCMV infection. This suggests a role for miR-21 downregulation in the neuropathogenesis of HCMV infection of the developing CNS.IMPORTANCEHuman cytomegalovirus (HCMV) is a ubiquitous pathogen and has very high prevalence among population, especially in China, and congenital HCMV infection is a major cause for birth defects. Elucidating virus-host interactions that govern HCMV replication in neuronal cells is critical to understanding the neuropathogenesis of birth defects resulting from congenital infection. In this study, we confirm that HCMV infection downregulates miR-21 but upregulates Cdc25a. Further determined the negative effects of cellular miRNA miR-21 on HCMV replication in neural progenitor/stem cells and U-251MG glioblastoma/astrocytoma cells. More importantly, our results provide the first evidence that miR-21 negatively regulates HCMV replication by targeting Cdc25a, a vital cell cycle regulator. We further found that viral gene products of IE1, pp71, and UL26 play roles in inhibiting miR-21 expression, which in turn causes increases in Cdc25a and benefits HCMV replication. Thus, miR-21 appears to be an intrinsic antiviral factor that represents a potential target for therapeutic intervention.

scholarly journals Immune Responses of HIV-1 Tat Transgenic Mice to Mycobacterium Tuberculosis W-Beijing SA161

2011 ◽  
Vol 5 (1) ◽  
pp. 86-95 ◽  
Author(s):  
Jennifer R Honda ◽  
Shaobin Shang ◽  
Crystal A Shanley ◽  
Megan L Caraway ◽  
Marcela Henao-Tamayo ◽  
...  
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Transgenic Mice ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Intracellular Cytokine Staining ◽  
Infectious Agent ◽  
Microbial Pathogens ◽  
Viral Gene ◽  
Alveolar Cells

Background:Mycobacterium tuberculosisremains among the leading causes of death from an infectious agent in the world and exacerbates disease caused by the human immunodeficiency virus (HIV). HIV infected individuals are prone to lung infections by a variety of microbial pathogens, includingM. tuberculosis. While the destruction of the adaptive immune response by HIV is well understood, the actual pathogenesis of tuberculosis in co-infected individuals remains unclear. Tat is an HIV protein essential for efficient viral gene transcription, is secreted from infected cells, and is known to influence a variety of host inflammatory responses. We hypothesize Tat contributes to pathophysiological changes in the lung microenvironment, resulting in impaired host immune responses to infection byM. tuberculosis.Results:Herein, we show transgenic mice that express Tat by lung alveolar cells are more susceptible than non-transgenic control littermates to a low-dose aerosol infection ofM. tuberculosisW-Beijing SA161. Survival assays demonstrate accelerated mortality rates of the Tat transgenic mice compared to non-transgenics. Tat transgenic mice also showed poorly organized lung granulomata-like lesions. Analysis of the host immune response using quantitative RT-PCR, flow cytometry for surface markers, and intracellular cytokine staining showed increased expression of pro-inflammatory cytokines in the lungs, increased numbers of cells expressing ICAM1, increased numbers of CD4+CD25+Foxp3+ T regulatory cells, and IL-4 producing CD4+ T cells in the Tat transgenics compared to infected non-tg mice.Conclusions:Our data show quantitative differences in the inflammatory response to the SA161 clinical isolate ofM. tuberculosisW-Beijing between Tat transgenic and non-transgenic mice, suggesting Tat contributes to the pathogenesis of tuberculosis.

scholarly journals Viral DNA-Dependent Induction of Innate Immune Response to Hepatitis B Virus in Immortalized Mouse Hepatocytes

2015 ◽  
Vol 90 (1) ◽  
pp. 486-496 ◽  
Author(s):  
Xiuji Cui ◽  
Daniel N. Clark ◽  
Kuancheng Liu ◽  
Xiao-Dong Xu ◽  
Ju-Tao Guo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Innate Immune Response ◽  
Viral Gene Expression ◽  
Innate Immune ◽  
Viral Gene ◽  
Viral Dna ◽  
B Virus

ABSTRACTHepatitis B virus (HBV) infects hundreds of millions of people worldwide and causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HBV is an enveloped virus with a relaxed circular (RC) DNA genome. In the nuclei of infected human hepatocytes, conversion of RC DNA from the incoming virion or cytoplasmic mature nucleocapsid (NC) to the covalently closed circular (CCC) DNA, which serves as the template for producing all viral transcripts, is essential to establish and sustain viral replication. A prerequisite for CCC DNA formation is the uncoating (disassembly) of NCs to expose their RC DNA content for conversion to CCC DNA. We report here that in an immortalized mouse hepatocyte cell line, AML12HBV10, in which RC DNA exposure is enhanced, the exposed viral DNA could trigger an innate immune response that was able to modulate viral gene expression and replication. When viral gene expression and replication were low, the innate response initially stimulated these processes but subsequently acted to shut off viral gene expression and replication after they reached peak levels. Inhibition of viral DNA synthesis or cellular DNA sensing and innate immune signaling diminished the innate response. These results indicate that HBV DNA, when exposed in the host cell cytoplasm, can function to trigger an innate immune response that, in turn, modulates viral gene expression and replication.IMPORTANCEChronic infection by hepatitis B virus (HBV) afflicts hundreds of millions worldwide and is sustained by the episomal covalently closed circular (CCC) DNA in the nuclei of infected hepatocytes. Release of viral genomic DNA from cytoplasmic nucleocapsids (NCs) (NC disassembly or uncoating) is a prerequisite for its conversion to CCC DNA, which can also potentially expose the viral DNA to host DNA sensors and trigger an innate immune response. We have found that in an immortalized mouse hepatocyte cell line in which efficient CCC DNA formation was associated with enhanced exposure of nucleocapsid-associated DNA, the exposed viral DNA indeed triggered host cytoplasmic DNA sensing and an innate immune response that was able to modulate HBV gene expression and replication. Thus, HBV can, under select conditions, be recognized by the host innate immune response through exposed viral DNA, which may be exploited therapeutically to clear viral persistence.

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