Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Modulators of innate immunity as novel therapeutics for treatment of chronic hepatitis B.

ABSTRACT: The first line defense mechanisms against viral infection are mediated by the innate immune system. Viral components are detected by infected cells and/or innate immune cells that express different sensory receptors. They in turn mediate induction of direct antiviral mechanisms and further modulation of innate and adaptive immune responses. For evading the innate system, most viruses have evolved efficient mechanisms to block sensing and/or antiviral functions of the innate response. Interestingly, hepatitis B virus (HBV) seems to act like a stealth virus that escapes cell intrinsic antiviral mechanisms through avoiding recognition by the innate system rather than blocking its effector functions. In line with this concept, agonistic activation of innate immunity has emerged as a promising novel anti-HBV therapy approach with several compounds having advanced to the clinical stage.

SUBMITTER: Suslov A

PROVIDER: S-EPMC5988934 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Modulators of innate immunity as novel therapeutics for treatment of chronic hepatitis B.

Suslov Aleksei A Wieland Stefan S Menne Stephan S

Current opinion in virology 20180220

The first line defense mechanisms against viral infection are mediated by the innate immune system. Viral components are detected by infected cells and/or innate immune cells that express different sensory receptors. They in turn mediate induction of direct antiviral mechanisms and further modulation of innate and adaptive immune responses. For evading the innate system, most viruses have evolved efficient mechanisms to block sensing and/or antiviral functions of the innate response. Interesting ...[more]

PMID: 29444493

Similar Datasets

Peg-Interferon Lambda Treatment Induces Robust Innate and Adaptive Immunity in Chronic Hepatitis B Patients.

Project description:IFN-lambda (IFNλ) is a member of the type III IFN family and is reported to possess anti-pathogen, anti-cancer, and immunomodulatory properties; however, there are limited data regarding its impact on host immune responses in vivo. We performed longitudinal and comprehensive immunosurveillance to assess the ability of pegylated (peg)-IFNλ to augment antiviral host immunity as part of a clinical trial assessing the efficacy of peg-IFNλ in chronic hepatitis B (CHB) patients. These patients were pretreated with directly acting antiviral therapy (entecavir) for 12 weeks with subsequent addition of peg-IFNλ for up to 32 weeks. In a subgroup of patients, the addition of peg-IFNλ provoked high serum levels of antiviral cytokine IL-18. We also observed the enhancement of natural killer cell polyfunctionality and the recovery of a pan-genotypic HBV-specific CD4+ T cells producing IFN-γ with maintenance of HBV-specific CD8+ T cell antiviral and cytotoxic activities. It was only in these patients that we observed strong virological control with reductions in both viral replication and HBV antigen levels. Here, we show for the first time that in vivo peg-IFNλ displays significant immunostimulatory properties with improvements in the main effectors mediating anti-HBV immunity. Interestingly, the maintenance in HBV-specific CD8+ T cells in the presence of peg-IFNλ is in contrast to previous studies showing that peg-IFNα treatment for CHB results in a detrimental effect on the functionality of this important antiviral T cell compartment.Clinical trial registrationClinicalTrials.gov NCT01204762.

| S-EPMC5446997 | biostudies-literature

Viral dUTPases: Modulators of Innate Immunity.

Project description:Most free-living organisms encode for a deoxyuridine triphosphate nucleotidohydrolase (dUTPase; EC 3.6.1.23). dUTPases represent a family of metalloenzymes that catalyze the hydrolysis of dUTP to dUMP and pyrophosphate, preventing dUTP from being incorporated into DNA by DNA polymerases, maintaining a low dUTP/dTTP pool ratio and providing a necessary precursor for dTTP biosynthesis. Thus, dUTPases are involved in maintaining genomic integrity by preventing the uracilation of DNA. Many DNA-containing viruses, which infect mammals also encode for a dUTPase. This review will summarize studies demonstrating that, in addition to their classical enzymatic activity, some dUTPases possess novel functions that modulate the host innate immune response.

| S-EPMC8961515 | biostudies-literature

Endogenous Retroviruses as Modulators of Innate Immunity.

Project description:Endogenous retroviruses (ERVs), or LTR retrotransposons, are a class of transposable elements that are highly represented in mammalian genomes. Human ERVs (HERVs) make up roughly 8.3% of the genome and over the course of evolution, HERV elements underwent positive selection and accrued mutations that rendered them non-infectious; thereby, the genome could co-opt them into constructive roles with important biological functions. In the past two decades, with the help of advances in sequencing technology, ERVs are increasingly considered to be important components of the innate immune response. While typically silenced, expression of HERVs can be induced in response to traumatic, toxic, or infection-related stress, leading to a buildup of viral transcripts and under certain circumstances, proteins, including functionally active reverse transcriptase and viral envelopes. The biological activity of HERVs in the context of the innate immune response can be based on the functional effect of four major viral components: (1) HERV LTRs, (2) HERV-derived RNAs, (3) HERV-derived RNA:DNA duplexes and cDNA, and (4) HERV-derived proteins and ribonucleoprotein complexes. In this review, we will discuss the implications of HERVs in all four contexts in relation to innate immunity and their association with various pathological disease states.

| S-EPMC9963469 | biostudies-literature

Antiviral Efficacy and Host Innate Immunity Associated with SB 9200 Treatment in the Woodchuck Model of Chronic Hepatitis B.

Project description:SB 9200, an oral prodrug of the dinucleotide SB 9000, is being developed for the treatment of chronic hepatitis B virus (HBV) infection and represents a novel class of antivirals. SB 9200 is thought to activate the viral sensor proteins, retinoic acid-inducible gene 1 (RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) resulting in interferon (IFN) mediated antiviral immune responses in virus-infected cells. Additionally, the binding of SB 9200 to these sensor proteins could also sterically block the ability of the viral polymerase to access pre-genomic RNA for nucleic acid synthesis. The immune stimulating and direct antiviral properties of SB 9200 were evaluated in woodchucks chronically infected with woodchuck hepatitis virus (WHV) by daily, oral dosing at 15 and 30 mg/kg for 12 weeks. Prolonged treatment resulted in 2.2 and 3.7 log10 reductions in serum WHV DNA and in 0.5 and 1.6 log10 declines in serum WHV surface antigen from pretreatment level with the lower or higher dose of SB 9200, respectively. SB 9200 treatment also resulted in lower hepatic levels of WHV nucleic acids and antigen and reduced liver inflammation. Following treatment cessation, recrudescence of viral replication was observed but with dose-dependent delays in viral relapse. The antiviral effects were associated with dose-dependent and long-lasting induction of IFN-?, IFN-? and IFN-stimulated genes in blood and liver, which correlated with the prolonged activation of the RIG-I/NOD2 pathway and hepatic presence of elevated RIG-I protein levels. These results suggest that in addition to a direct antiviral activity, SB 9200 induces antiviral immunity during chronic hepadnaviral infection via activation of the viral sensor pathway.

| S-EPMC4995001 | biostudies-literature

Double-Stranded RNA Sensors and Modulators in Innate Immunity.

Project description:Detection of double-stranded RNAs (dsRNAs) is a central mechanism of innate immune defense in many organisms. We here discuss several families of dsRNA-binding proteins involved in mammalian antiviral innate immunity. These include RIG-I-like receptors, protein kinase R, oligoadenylate synthases, adenosine deaminases acting on RNA, RNA interference systems, and other proteins containing dsRNA-binding domains and helicase domains. Studies suggest that their functions are highly interdependent and that their interdependence could offer keys to understanding the complex regulatory mechanisms for cellular dsRNA homeostasis and antiviral immunity. This review aims to highlight their interconnectivity, as well as their commonalities and differences in their dsRNA recognition mechanisms.

| S-EPMC7136661 | biostudies-literature

Hepatocyte-targeted RNAi therapeutics for the treatment of chronic hepatitis B virus infection.

Project description:RNA interference (RNAi)-based therapeutics have the potential to treat chronic hepatitis B virus (HBV) infection in a fundamentally different manner than current therapies. Using RNAi, it is possible to knock down expression of viral RNAs including the pregenomic RNA from which the replicative intermediates are derived, thus reducing viral load, and the viral proteins that result in disease and impact the immune system's ability to eliminate the virus. We previously described the use of polymer-based Dynamic PolyConjugate (DPC) for the targeted delivery of siRNAs to hepatocytes. Here, we first show in proof-of-concept studies that simple coinjection of a hepatocyte-targeted, N-acetylgalactosamine-conjugated melittin-like peptide (NAG-MLP) with a liver-tropic cholesterol-conjugated siRNA (chol-siRNA) targeting coagulation factor VII (F7) results in efficient F7 knockdown in mice and nonhuman primates without changes in clinical chemistry or induction of cytokines. Using transient and transgenic mouse models of HBV infection, we show that a single coinjection of NAG-MLP with potent chol-siRNAs targeting conserved HBV sequences resulted in multilog repression of viral RNA, proteins, and viral DNA with long duration of effect. These results suggest that coinjection of NAG-MLP and chol-siHBVs holds great promise as a new therapeutic for patients chronically infected with HBV.

| S-EPMC3666629 | biostudies-literature

Targeting Host Innate and Adaptive Immunity to Achieve the Functional Cure of Chronic Hepatitis B.

Project description:Despite the availability of an effective preventive vaccine for hepatitis B virus (HBV) for over 38 years, chronic HBV (CHB) infection remains a global health burden with around 257 million patients. The ideal treatment goal for CHB infection would be to achieve complete cure; however, current therapies such as peg-interferon and nucleos(t)ide analogs are unable to achieve the functional cure, the newly set target for HBV chronic infection. Considering the fact functional cure has been accepted as an endpoint in the treatment of chronic hepatitis B by scientific committee, the development of alternative therapeutic strategies is urgently needed to functionally cure CHB infection. A promising target for future therapeutic strategies is immune modulation to restore dysfunctional HBV-specific immunity. In this review, we provide an overview of the progress in alternative therapeutic strategies, including immune-based therapeutic approaches that enhance host innate and adaptive immunity to achieve and increase the functional cure from CHB infection.

| S-EPMC7349973 | biostudies-literature

Innate immunity: a new chapter for hepatitis C.

Project description:The immune response to hepatitis C virus (HCV) and the mechanisms leading to successful resolution are complex. Much work has been done on understanding the adaptive immune response to HCV due to the imperative of trying to find a vaccine. However the importance of the innate immune system is being increasingly recognized. This has culminated in the discovery of IL-28B as a key genetic element in recovery from HCV in diverse populations. This association is one of the strongest in anti-viral immunity and represents a paradigm shift in how we view the immune response to HCV infection.

| S-EPMC3959377 | biostudies-literature

Novel bile acid therapeutics for the treatment of chronic liver diseases.

Project description:Recent developments in understanding the role of bile acids (BAs) as signalling molecules in human metabolism and inflammation have opened new avenues in the field of hepatology research. BAs are no longer considered as simple molecules helping in fat digestion but as agents with real therapeutic value in treating complex autoimmune and metabolic liver diseases. BAs and their receptors such as farnesoid X receptor, transmembrane G protein-coupled receptor 5 and peroxisome proliferator-activated receptor have been identified as novel targets for drug development. Some of these novel pharmaceuticals are already in clinical evaluation with the most advanced drugs having reached phase III trials. Chronic liver diseases such as primary biliary cholangitis, primary sclerosing cholangitis and nonalcoholic fatty liver disease, for which there is no or limited pharmacotherapy, are most likely to gain from these developments. In this review we discuss recent and the most relevant basic and clinical research findings related to BAs and their implications for novel therapy for chronic liver diseases.

| S-EPMC4830100 | biostudies-literature

Sofosbuvir: A novel treatment option for chronic hepatitis C infection.

Project description:Hepatitis C currently infects more than 170 million people around the world, leading to significant morbidity and mortality. The current standard of care for HCV infection, including one of the two protease inhibitors, telaprevir or boceprevir, for 12-32 weeks, along with pegylated interferon alfa-2a (PEG-IFN-?) and ribavirin for up to 48 weeks, is unsatisfactory in many cases, either because of lack of efficacy or because of treatment-related adverse effects. There is an urgent need of new drugs with improved efficacy as well as a safety profile. Sofosbuvir, a recently approved nucleotide analog, is a highly potent inhibitor of the NS5B polymerase in the Hepatitis C virus (HCV), and has shown high efficacy in combination with several other drugs, with and without PEG-INF, against HCV. It offers many advantages due to its high potency, low side effects, oral administration, and high barrier to resistance. The efficacy and safety were demonstrated in many large and well-designed phase 2 and phase 3 clinical trials like NEUTRINO, PROTON, ELECTRON, ATOMIC, COSMOS, FUSION, FISSION, NUCLEAR, POSITRON, and the like. It is generally well-tolerated. Adverse events that occurred include: Headache, insomnia, fatigue, nausea, dizziness, pruritis, upper respiratory tract infections, rash, back pain, grade 1 anemia, and grade 4 lymphopenia; however, the exact safety profile can only be judged when this drug is actually used on a large scale.

| S-EPMC4231565 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data