A5026233059- Hepatitis C virus research
- Hepatitis B Virus Studies
- Hepatitis Viruses Studies and Epidemiology
- Viral gastroenteritis research and epidemiology
- Viral Infections and Immunology Research
- Liver Disease Diagnosis and Treatment
- interferon and immune responses
- Animal Virus Infections Studies
- Animal Disease Management and Epidemiology
- Systemic Lupus Erythematosus Research
- RNA and protein synthesis mechanisms
- Monoclonal and Polyclonal Antibodies Research
- RNA Research and Splicing
- MicroRNA in disease regulation
- Influenza Virus Research Studies
- Liver Disease and Transplantation
- RNA modifications and cancer
- Zoonotic diseases and public health
- Respiratory viral infections research
- Liver Diseases and Immunity
- Immune Cell Function and Interaction
- HIV/AIDS drug development and treatment
- RNA regulation and disease
- Viral Infections and Outbreaks Research
- Viral-associated cancers and disorders
University of North Carolina at Chapel Hill
2016-2025
Office of Infectious Diseases
1990-2018
UNC Lineberger Comprehensive Cancer Center
2010-2018
Segeberger Kliniken
2012-2018
Texas Biomedical Research Institute
2001-2017
Nationwide Children's Hospital
2017
University of North Carolina Health Care
2015
The University of Texas Medical Branch at Galveston
2003-2014
Communities In Schools of Orange County
1979-2013
University of Milan
2013
MicroRNAs are small RNA molecules that regulate messenger (mRNA) expression. MicroRNA 122 (miR-122) is specifically expressed and highly abundant in the human liver. We show sequestration of miR-122 liver cells results marked loss autonomously replicating hepatitis C viral RNAs. A genetic interaction between 5′ noncoding region genome was revealed by mutational analyses predicted microRNA binding site ectopic expression containing compensatory mutations. Studies with replication-defective...
Toll-like receptors (TLRs) bind pathogen-specific ligands early in infection, initiating signaling pathways that lead to expression of multiple protective cellular genes. Many viruses have evolved strategies block the effector mechanisms induced through these pathways, but viral interference with critical proximal receptor interactions has not been described. We show here NS3/4A serine protease hepatitis C virus (HCV), a notorious for its ability establish persistent intrahepatic causes...
ABSTRACT Virus-responsive signaling pathways that induce alpha/beta interferon production and engage intracellular immune defenses influence the outcome of many viral infections. The processes trigger these their effect upon host permissiveness for specific pathogens are not well understood. We show structured hepatitis C virus (HCV) genomic RNA activates regulatory factor 3 (IRF3), thereby inducing in cultured cells. This response is absent cells selected HCV replication. Studies including...
Persistent infections with hepatitis C virus (HCV) are likely to depend on viral inhibition of host defenses. We show that the HCV NS3/4A serine protease blocks phosphorylation and effector action interferon regulatory factor-3 (IRF-3), a key cellular antiviral signaling molecule. Disruption function by mutation or ketoamide peptidomimetic inhibitor relieved this blockade restored IRF-3 after challenge an unrelated virus. Furthermore, dominant-negative constitutively active mutants,...
Hepatitis C virus (HCV) is a major human pathogen that infects 170 million people. A hallmark of HCV its ability to establish persistent infections reflecting the evasion host immunity and interference with alpha/beta-IFN innate immune defenses. We demonstrate disruption retinoic acid-inducible gene I (RIG-I) signaling by viral NS3/4A protease contributes control antiviral RIG-I was essential for or RNA-induced IFN-beta promoter in hepatoma cells. This disrupted activity NS3/4A, which...
A pairwise comparison of the nucleic acid sequence 168 bases from 152 wild-type or unique cell culture-adapted strains hepatitis virus (HAV) revealed that HAV can be differentiated genetically into seven genotypes (I to VII). In general, nucleotide viruses in different differs at 15 25% positions within this segment genome. Viruses four (I, II, III and VII) were recovered cases humans, whereas other three (IV, V VI) isolated only simian species developing a A-like illness during captivity....
Background and Aims: The aim of this study was to determine whether expression hepatitis C virus proteins alters hepatic morphology or function in the absence inflammation. Methods: Transgenic C57BL/6 mice with liver-specific RNA encoding complete viral polyprotein (FL-N transgene) structural (S-N were compared nontransgenic littermates for altered liver function. Results: FL-N transcripts detectable only by reverse-transcription polymerase chain reaction, S-N identified Northern blots....
The RNA genomes of human hepatitis C virus (HCV) and the animal pestiviruses responsible for bovine viral diarrhea (BVDV) hog cholera (HChV) have relatively lengthy 5′ nontranslated regions (5′NTRs) sharing short segments conserved primary nucleotlde sequence. functions these 5′NTRs are poorly understood. By comparative sequence analysis thermodynamic modeling multiple BVDV HChV strains, we developed models secondary structures RNAs. These pestiviral highly structurally, despite substantial...
Viral signaling through retinoic acid-inducible gene-I (RIG-I) and its adaptor protein, IFN promoter-stimulator 1 (IPS-1), activates regulatory factor-3 (IRF-3) the host IFN-alpha/beta response that limits virus infection. The hepatitis C (HCV) NS3/4A protease cleaves IPS-1 to block RIG-I signaling, but how this regulation controls HCV is not known. Moreover, endogenous cleavage has been demonstrated in context of infection vitro or vivo. Here, we show transiently induces RIG-I-...
ABSTRACT Dicistronic, selectable subgenomic replicons derived from the Con1 strain of hepatitis C virus (HCV) are capable autonomous replication in cultured Huh7 cells (Lohmann et al., Science 285:110-113, 1999). However, adaptive mutations NS3, NS5A, and/or NS5B proteins required for efficient these RNAs and increase by orders magnitude numbers G418-resistant colonies selected following transfection cells. Here, we demonstrate that a replicon (NNeo/3-5B) an infectious molecular clone second...
MicroRNAs (miRNAs) are small noncoding RNAs that regulate eukaryotic gene expression by binding to regions of imperfect complementarity in mRNAs, typically the 3′ UTR, recruiting an Argonaute (Ago) protein complex usually results translational repression or destabilization target RNA. The translation and decay mRNAs closely linked, competing processes, whether miRNA-induced silencing (RISC) acts primarily reduce stability mRNA remains controversial. miR-122 is abundant, liver-specific miRNA...
Innate cellular antiviral defenses are likely to influence the outcome of infections by many human viruses, including hepatitis B and C agents that frequently establish persistent infection leading chronic hepatitis, cirrhosis, liver cancer. However, little is known pathways which hepatocytes, cell type within these replicate, sense infection, initiate protective responses. We show cultured hepatoma cells, Huh7 do not activate interferon (IFN)-beta promoter in response extracellular...
Infections with hepatitis C virus (HCV) are marked by frequent viral persistence, chronic liver disease, and extraordinary genetic diversity. Although much has been learned about HCV since its discovery, progress slowed a lack of permissive cell culture systems supporting replication. Productive infections have achieved recently genotype 2a virus, but cirrhosis cancer typically associated 1 HCV, which is more prevalent relatively resistant to IFN therapy. We describe production infectious 1a...
Journal Article FREQUENCY OF ILLNESS ASSOCIATED WITH EPIDEMIC HEPATITIS A VIRUS INFECTIONS IN ADULTS Get access WAYNE M. LEDNAR, LEDNAR 1Division of Preventive Medicine, Walter Reed Army Institute ResearchWashington, DC Reprint requests to Dr. Wayne Lednar at current address: Medicine Service, Madigan Medical Center, Tacoma, WA 98431 Search for other works by this author on: Oxford Academic PubMed Google Scholar STANLEY LEMON, LEMON 2Division Infectious Diseases, University North Carolina...
Mitochondrial antiviral signaling protein (MAVS) is an essential component of virus-activated pathways that induce protective IFN responses. Its localization to the outer mitochondrial membrane suggests important yet unexplained role for mitochondria in innate immunity. Here, we show hepatitis A virus (HAV), a hepatotropic picornavirus, ablates type 1 responses by targeting 3ABC precursor its 3C(pro) cysteine protease where it colocalizes with and cleaves MAVS, thereby disrupting activation...
miR-122 is a liver-specific microRNA that positively regulates hepatitis C virus (HCV) RNA abundance and essential for production of infectious HCV. Using genetic approach, we show its ability to enhance yields dependent upon two miR-122-binding sites near the 5' end HCV genome, S1 S2. Viral with base substitutions in both S2 failed produce transfected cells, while was rescued near-wild-type levels cells supplemented complementary mutant. A comparison mutants only one site revealed be...
Hepatitis C virus (HCV) replication is dependent on microRNA 122 (miR-122), a liver-specific that recruits Argonaute 2 to the 5′ end of viral genome, stabilizing it and slowing its decay both in cell-free reactions infected cells. Here we describe RNA degradation pathways against which miR-122 provides protection. Transfected HCV degraded by exonuclease Xrn1 3′ exosome complex, whereas replicating within cells primarily with no contribution from exosome. Consistent this, sequencing ends...
Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn IFN-α/β-dependent intrinsic viral diseases. Both types IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria related intramacrophagic pathogens. These have no history severe disease, despite exposure to many viruses, including...