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| Open AccessBTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion
Acute-on-chronic liver failure (ACLF) is characterized by rapid deterioration of liver function in patients with chronic liver disease. Here, the authors show that BTLA expression in CD4+ T cells is associated with disease severity and inflammation in hepatitis B virus-related ACLF.
- Xueping Yu
- , Feifei Yang
- & Jiming Zhang
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Article
| Open AccessA hepatic network of dendritic cells mediates CD4 T cell help outside lymphoid organs
Here, English et al. show that after expanding in lymphoid tissues, CD4+ and CD8+ T cells recognising hepatic antigens migrate into specialised vascular liver areas where CD4+ T cells locally license hepatic dendritic cells and further expand CD8+ T cell numbers.
- Kieran English
- , Rain Kwan
- & Patrick Bertolino
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| Open AccessDirect-acting antiviral resistance of Hepatitis C virus is promoted by epistasis
This study reveals that mutations of the hepatitis C virus act collectively to confer resistance against direct-acting antiviral drugs. This can aid the development of drugs that are less prone to resistance.
- Hang Zhang
- , Ahmed Abdul Quadeer
- & Matthew R. McKay
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| Open AccessInterferon stimulated immune profile changes in a humanized mouse model of HBV infection
There is increasing evidence that treatment of hepatitis B with interferon alpha can be beneficial. Here, Wang et al, present a type 1 interferon receptor humanized mouse model and characterize it as a platform in which to study interferon function in vivo.
- Yaping Wang
- , Liliangzi Guo
- & Feng Li
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| Open AccessTargeted viral adaptation generates a simian-tropic hepatitis B virus that infects marmoset cells
Hepatitis B virus is an almost uniquely human-tropic pathogen for which model systems are scarce. Here, the authors determine key residues within the HBV receptor that form a barrier in the HBV life cycle in primates and identify marmosets as a model candidate for infection with simian-tropic HBV.
- Yongzhen Liu
- , Thomas R. Cafiero
- & Alexander Ploss
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| Open AccessMolecular imaging of liver inflammation using an anti-VCAM-1 nanobody
Here, the authors present a noninvasive tool to detect liver inflammation using nuclear imaging, as an alternative to biopsy. The prove the diagnostic power of this tool to detect liver inflammation in preclinical models of chronic liver disease.
- Maxime Nachit
- , Christopher Montemagno
- & Pascale Perret
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| Open AccessSystematic review and individual-patient-data meta-analysis of non-invasive fibrosis markers for chronic hepatitis B in Africa
Authors carry out a systematic review and meta-analysis to evaluate the performance of fibrosis biomarkers for the diagnosis of fibrosis and cirrhosis in patients with chronic hepatitis B virus infection living in sub-Saharan Africa.
- Asgeir Johannessen
- , Alexander J. Stockdale
- & Maud Lemoine
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| Open AccessNeutralization of hepatitis B virus with vaccine-escape mutations by hepatitis B vaccine with large-HBs antigen
The hepatitis B vaccine is recognised as the most effective approach in reducing hepatitis-B-related morbidity; vaccine-escape mutations are however capable of infecting vaccinated individuals. In this work, authors aim to establish a hepatitis B vaccine candidate, which they assess in rhesus macaques in terms of efficacy and safety.
- Ayaka Washizaki
- , Asako Murayama
- & Takanobu Kato
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Article
| Open AccessComputational identification of HCV neutralizing antibodies with a common HCDR3 disulfide bond motif in the antibody repertoires of infected individuals
Identifying determinants of broadly neutralizing antibodies against hepatitis C virus (HCV) may guide HCV vaccine design. Here, the authors discover new anti-HCV antibodies using computational screening and analyze the amino acid composition and sequence-structure relationships in this antibody family.
- Nina G. Bozhanova
- , Andrew I. Flyak
- & Jens Meiler
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Article
| Open AccessThe impact of the timely birth dose vaccine on the global elimination of hepatitis B
The timely hepatitis B birth dose vaccination is recommended for all new-borns by the WHO, but coverage is inconsistent. Here, the authors model the impact of scaling-up coverage in 110 low and middle income countries and assess how it may be affected by delays for example caused by the COVID-19 pandemic.
- Margaret J. de Villiers
- , Shevanthi Nayagam
- & Timothy B. Hallett
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| Open AccessTargeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint
Shared metabolic pathways could allow simultaneous manipulation of T cells, viruses and tumours. Here the authors show targeting cholesterol esterification restrains hepatitis B in vitro, whilst bolstering exhausted antigen-specific T cell responses from human liver and hepatocellular carcinoma.
- Nathalie M. Schmidt
- , Peter A. C. Wing
- & Mala K. Maini
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Article
| Open AccessHepatitis B virus cccDNA is formed through distinct repair processes of each strand
HBV covalently closed circular DNA (cccDNA) enables and persists in chronic infection, but the molecular mechanism of its formation is unclear. Here, Wei and Ploss elucidate the detailed kinetics and biochemical steps by which the relaxed circular DNA is converted into cccDNA.
- Lei Wei
- & Alexander Ploss
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Article
| Open AccessHepatitis B virus rigs the cellular metabolome to avoid innate immune recognition
RIG-I is a cytosolic antiviral nucleic acid sensor that signals via MAVS to produce type 1 interferons. Here the authors show that hepatits B virus can repress this pathway by activating glycolysis and lactate production, enabling accumulated lactate to bind MAVS and prevent its mitochondrial localization.
- Li Zhou
- , Rui He
- & Shi Liu
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Article
| Open AccessA genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor
Here the authors perform a gain-of-function screen and identify CDKN2C as a host factor for HBV replication, inducing cell cycle arrest and expression of HBV transcription enhancers. CDKN2C expression correlates with disease progression suggesting a potential role in HBV-induced liver disease.
- Carla Eller
- , Laura Heydmann
- & Thomas F. Baumert
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| Open AccessElectrical pulse-induced electrochemical biosensor for hepatitis E virus detection
Detection of viral biomarkers is important for disease treatment and prevention. Here, the authors report on a system that uses an electrical pulse-induced electrochemical sensor for the detection of hepatitis E virus, and demonstrate potential application of the device.
- Ankan Dutta Chowdhury
- , Kenshin Takemura
- & Enoch Y. Park
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| Open AccessRecapitulation of HDV infection in a fully permissive hepatoma cell line allows efficient drug evaluation
Hepatitis delta virus (HDV) depends on the envelope proteins of hepatitis B virus (HBV) for virion production. Here, Lempp et al. produce a cell line expressing HBV envelope proteins and their receptor, which allows continuous secretion of infectious progeny HDV and testing of antiviral drugs.
- Florian A. Lempp
- , Franziska Schlund
- & Stephan Urban
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Article
| Open AccessSuppression of a broad spectrum of liver autoimmune pathologies by single peptide-MHC-based nanomedicines
Immune response against tissue-specific antigens is a hallmark of autoimmunity. Here the authors show that a single autoantigen-based nanomedicine can ameliorate pathology in a broad range of liver autoimmunity models without impairing host defenses, suggesting organ-wide tolerization.
- Channakeshava Sokke Umeshappa
- , Santiswarup Singha
- & Pere Santamaria
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Article
| Open AccessEnveloped viruses distinct from HBV induce dissemination of hepatitis D virus in vivo
Hepatitis D virus (HDV) relies on a helper virus to package and transmit its ribonucleoprotein (RNP). Here, Perez-Vargas et al. show that HDV can use envelope proteins from HBV-unrelated viruses, including HCV and flaviviruses, to propagate in vitro and in humanized mice.
- Jimena Perez-Vargas
- , Fouzia Amirache
- & François-Loïc Cosset
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Article
| Open AccessNKG2A is a NK cell exhaustion checkpoint for HCV persistence
Immune cells may become less responsive, or ‘exhausted’, upon chronic viral infection, but the underlying mechanism and crosstalk are still unclear. Here the authors show that, upon chronic hepatitis C virus (HCV) infection, natural killer cell exhaustion is induced by NKG2A signalling to instruct downstream exhaustion of CD8+ T cells and HCV persistence.
- Chao Zhang
- , Xiao-mei Wang
- & Hong Tang
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| Open AccessBreakdown of adaptive immunotolerance induces hepatocellular carcinoma in HBsAg-tg mice
Chronic hepatitis B virus (HBV) infection is a risk factor for hepatocellular carcinoma (HCC) and is associated with immune tolerance to HBV. Here the authors show, in a transgenic mouse model, that rescuing T cells function via inhibition of co-inhibitory receptor TIGIT results in HCC development via supporting inflammation.
- Lu Zong
- , Hui Peng
- & Zhigang Tian
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Article
| Open AccessChronic hepatitis C virus infection irreversibly impacts human natural killer cell repertoire diversity
Natural killer (NK) cells are important immune cells for mediating antiviral immunity. Here the authors show that chronic hepatitis C virus infection in human can imprint lasting functional phenotypes in NK cells to increase their inter-individual but decrease intra-individual diversity.
- Benedikt Strunz
- , Julia Hengst
- & Niklas K. Björkström
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Article
| Open AccessOncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion
Blocking PD-1 function on T cells is thought to be a viable strategy to prevent virus-induced or tumor-induced T cell exhaustion. Here the authors link the zinc-finger transcription factor SALL4 with miR-200c inhibition of PD-L1 expression by hepatocytes in patients with HBV-induced hepatocellular carcinoma.
- Cheng Sun
- , Peixiang Lan
- & Zhigang Tian
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Article
| Open AccessZinc is a potent and specific inhibitor of IFN-λ3 signalling
Lambda interferons (IFNL) are involved in the immune response to viral infection. Here the authors show that zinc can interfere with IFNL signalling, and that in HCV patients the rs12979860 polymorphism regulates blood zinc levels and, subsequently, the hepatic immune response.
- Scott A. Read
- , Kate S. O’Connor
- & Golo Ahlenstiel
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| Open AccessTCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation
Virus-specific CD8+T cells lose effector function over the course of chronic infection, a process called ‘exhaustion’, but the fate of these cells after treatment-induced antigen elimination is unknown. Here the authors show that exhausted cells persist in patients even after direct-acting antiviral therapy removes antigen exposure, and that these cells are responsive on re-exposure to antigen.
- Dominik Wieland
- , Janine Kemming
- & Robert Thimme
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Article
| Open AccessHepatitis C virus has a genetically determined lymphotropism through co-receptor B7.2
Infection of B cells by hepatitis C virus (HCV) is poorly understood, but is thought to result in lymphoproliferative disorders. Here, Chenet al. identify CD86 as co-receptor for lymphotropic HCV and show that HCV infection inhibits memory B-cell function.
- Chia-Lin Chen
- , Jeffrey Y. Huang
- & Keigo Machida
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| Open AccessMBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C
Chronic Hepatitis C infection is associated with a broad spectrum of liver pathologies, ranging from inflammation to fibrosis and liver cancer. Here Thabet et al. identified a polymorphism in the gene MBOAT7 that is associated with increased hepatic inflammation and higher risk of fibrosis development and progression.
- Khaled Thabet
- , Anastasia Asimakopoulos
- & Rosanna Santaro
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| Open AccessSeptin 9 induces lipid droplets growth by a phosphatidylinositol-5-phosphate and microtubule-dependent mechanism hijacked by HCV
The accumulation of lipid droplets is often observed in hepatitis C virus infection, but the mechanism of their formation is not known. Here the authors show that septin 9 expression is increased in infected livers, and a septin 9/phosphatidylinositol 5-phosphate signalling pathway regulates the growth of lipid droplets.
- Abdellah Akil
- , Juan Peng
- & Ama Gassama-Diagne
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Article
| Open AccessMAIT cells are activated during human viral infections
Mucosal Associated Invariant T cells have been implicated in response to bacterial pathogens. Here the authors show that in human viral infections, these cells are activated by IL-18 in cooperation with other pro-inflammatory cytokines, producing interferon gamma and granzyme B.
- Bonnie van Wilgenburg
- , Iris Scherwitzl
- & Paul Klenerman
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| Open AccessPre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination
Ageing is associated with poor responses to vaccines but the underlying mechanism remains unclear. Here the authors use a systems-based approach to define molecular signatures present before vaccination that correlate with non-responsiveness to hepatitis B vaccination in healthy, elderly adults.
- Slim Fourati
- , Razvan Cristescu
- & Rafick-Pierre Sékaly
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Article
| Open AccessTrained immunity in newborn infants of HBV-infected mothers
The ability to fight infections matures after birth and is thus termed ‘trained immunity’. Here the authors show that cord blood cells from hepatitis B virus-infected mothers respond more strongly to bacterial infections, suggesting that viral exposure in uteropromotes trained immunity in newborns.
- Michelle Hong
- , Elena Sandalova
- & Antonio Bertoletti
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Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity
Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma displaying biliary phenotypes are aggressive cancers. Fujimoto et al. characterize the mutational profile of chronic hepatitis and identify mutations in KRAS and IDHassociated with poor survival.
- Akihiro Fujimoto
- , Mayuko Furuta
- & Hidewaki Nakagawa
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| Open AccessUnexpected structure for the N-terminal domain of hepatitis C virus envelope glycoprotein E1
Hepatitis C virus (HCV) gains entry into host cells via envelope glycoproteins E1 and E2. Here, El Omari et al.present the crystal structure of the N terminus of the E1 ectodomain of HCV and show that it adopts a different fold than predicted.
- Kamel El Omari
- , Oleg Iourin
- & David I. Stuart
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Emergent properties of the interferon-signalling network may underlie the success of hepatitis C treatment
The standard treatment for hepatitis C virus (HCV) infection, combining interferon (IFN) α and ribavirin, fails in a number of patients. Here, the authors use a mathematical model of the IFN signalling network in the presence of HCV to explain the success or failure of hepatitis C treatment.
- Pranesh Padmanabhan
- , Urtzi Garaigorta
- & Narendra M. Dixit
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Convergence and coevolution of Hepatitis B virus drug resistance
Lamivudine treatment of hepatitis B is associated with drug-resistance mutations in the virus’ DNA polymerase. In this study, 11 patients with drug resistance are investigated and the primary mutation in the DNA polymerase shown to be essential but not sufficient for establishing drug resistance.
- Hong Thai
- , David S. Campo
- & Yury Khudyakov