The theme for the 2017 World Hepatitis Day is "ELIMINATE HEPATITIS" — a simple and direct call to arms. Achieving this ambitious goal will necessitate tremendous efforts across many domains, from prevention via widespread vaccination to cure with safe and efficacious new treatments. Convincing governments to invest in elimination efforts remains the biggest hurdle to removing viral hepatitis as a public health threat, but it is a hurdle that can be substantially lowered through ongoing research that promises cheaper, safer, and more effective drugs, tests and vaccines, amongst other tools. In turn, the development of these tools relies on more detailed knowledge of disease mechanisms. Although HCV can now be effectively cured, and HBV infection can be prevented by vaccination, eliminating viral hepatitis will be far more feasible with an expanded and diverse armamentarium against all hepatitis viruses.
This mini-collection brings together selected recent (<2 years old) papers from across Nature journals that have substantially contributed to the understanding of viral hepatitis or have advanced research areas that bring elimination of these disease closer to reality. I am very grateful for the help of fellow editors at Nature Microbiology, Nature, Nature Medicine, Nature Genetics, Nature Communications, Nature Biotechnology and Nature Reviews Immunology, Nature Reviews Disease Primers, who recommended these articles and described their importance. Articles are grouped loosely by topic.
Background – review articles providing an overview of viral hepatitis aspects
- Manns et al. (2017) Hepatitis C virus infection. Nature Reviews Disease Primers.
- In this Primer, Manns et al. describe the latest developments against the global hepatitis C epidemic in the era of highly effective therapies.
- Lempp et al. (2016) Hepatitis delta virus: insights into a peculiar pathogen and novel treatment options. Nature Reviews Gastroenterology & Hepatology.
- Here, the authors summarize current knowledge of the epidemiology, pathogenesis and molecular biology of hepatitis delta virus. Existing treatment options and novel treatment regimens under clinical development are also discussed.
- Shin et al. (2016) Immune responses and immunopathology in acute and chronic viral hepatitis. Nature Reviews Immunology.
- This Review describes the similarities and differences in immune responses against HAV, HBV and HCV infections and the immunopathogenesis of these diseases, which may explain the distinct courses and outcomes of each hepatitis virus infection.
- Li et al. (2015) The yin and yang of hepatitis C: synthesis and decay of hepatitis C virus RNA. Nature Reviews Microbiology.
- HCV is an unusual RNA virus that has a striking capacity to persist for the remaining life of the host in the majority of infected individuals. In order to persist, HCV must balance viral RNA synthesis and decay in infected cells. In this Review, Lemon and colleagues describe the interactions of the RNA genome of hepatitis C virus with various host proteins and microRNAs, and discuss how these interactions affect viral RNA synthesis and decay, and how they influence the long-term persistence of the virus.
- Patel et al. (2017) HBV RNA pre-genome encodes specific motifs that mediate interactions with the viral core protein that promote nucleocapsid assembly. Nature Microbiology.
- This paper demonstrates that sequence-specific interactions between the HBV pre-genome and the core protein define the nucleocapsid assembly pathway and trigger virus-like particle formation, further shedding light on the HBV lifecycle.
- Geller et al. (2016) Highly heterogeneous mutation rates in the hepatitis C virus genome. Nature Microbiology.
- In this study, high-fidelity, ultra-deep sequencing of a modified replicon system reveals >1000-fold differences in mutation rate across the hepatitis C virus genome, with extreme variation in rate even between adjacent nucleotides.
Virus–host interaction and immunology
- Decorsière et al. (2016) Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor. Nature.
- Expression of hepatitis B virus X (HBx) protein is known to stimulate transcription from the viral DNA episome. Michael Strubin and colleagues show that HBx does this by hijacking the host's ubiquitin machinery to target for degradation the Smc5/6 complex, which has a broad role in chromosome organization. They show that the Smc5/6 complex appears to act as a restriction factor, binding to the viral genome to block its transcription. This work suggests new targets for therapeutic intervention against hepatitis B virus infection, and raises the possibility that other DNA viruses might also be restricted by the Smc5/6 complex.
- Ansari et al. (2017) Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus. Nature Genetics.
- In this study, Ansari et al. show that the innate and adaptive arms of the host immune system are critical drivers of viral evolution; viral load is also found to be a function of patient IFNL4 genotype in a manner dependent on the presence of serine at residue 2414 in HCV NS5A protein.
- Jarret et al. (2016) Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling. Nature Medicine.
- Jarret and colleagues demonstrate in this study that HCV-induced miRNAs downregulate hepatocyte type 1 IFN signalling, shedding light on how HCV modulates host antiviral responses.
- Li et al. (2016) Genome-wide association study identifies 8p21.3 associated with persistent hepatitis B virus infection among Chinese. Nature Communications.
- This genome-wide association study in Chinese patients with persistent hepatitis B virus (HBV) infection confirms previously associated genetic loci and discovers a novel protective locus on 8p21.3. The study also demonstrates that the nearby gene INST10 suppresses HBV replication in vitro.
Mechanisms of disease
- Thabet et al. (2016) MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C. Nature Communications.
- Chronic hepatitis C infection is associated with a broad spectrum of liver diseases, ranging from inflammation to fibrosis and liver cancer. Here the authors identify a polymorphism in the gene MBOAT7 that is associated with increased hepatic inflammation and higher risk of fibrosis development and progression.
- Saito et al. (2016) p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nature Communications.
- Dysregulation of p62 has been implicated in tumorigenesis. Here the authors show that p62 promotes hepatocellular carcinoma associated with HCV by reprogramming glucose and glutamine metabolism through NRF2, and present a novel compound that can inhibit p62 action thus sensitizing cancer cells to chemotherapy
- Sun et al. (2015) Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A. Nature.
- Daclatasivir can reduce viral load in patients infected with hepatitis C virus (HCV) by inhibiting the virus's non-structural protein 5A (NS5A) replication complex, although HCV NS5A inhibitor resistance mutations can arise. Min Gao and colleagues show that daclatasivir with an NS5A analogue can enhance daclatasivir potency, and the combination overcomes resistance in vitro and in a mouse model. The authors develop a model to show that inhibitor binding to one resistant NS5A causes a conformational change that is transmitted to adjacent NS5A molecules, restoring drug sensitivity.
- Fisicaro et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nature Medicine.
- After showing that HBV-specific CD8 T cells from individuals with chronic HBV infections have substantial mitochondrial dysfunction, which contributes to impaired antiviral activity, Carlo Ferrari and colleagues demonstrate that antioxidants improve mitochondrial and antiviral T cell function.
- Saeed et al. (2015) SEC14L2 enables pan-genotype HCV replication in cell culture. Nature.
- Hepatitis C virus (HCV) cannot replicate in cell culture unless it possesses adaptive mutations. Charles Rice and colleagues show here that expression of a host cellular factor, SEC14L2, allows replication of all HCV genotypes in several hepatoma cell lines by enhancing vitamin E-mediated protection against lipid peroxidation. Importantly, the SEC14L2-expressing cells could also support replication of HCV following inoculation with patient sera. This finding is a step towards the development of culture systems in which natural HCV isolates can be propagated and antiviral agents tested.
- Harak et al. (2016) Tuning a cellular lipid kinase activity adapts hepatitis C virus to replication in cell culture. Nature Microbiology.
- Harak et al. find that HCV tunes host lipid levels to mediate it’s replication. This result explains why we can’t really get HCV to replicate well in some cultured cells. The findings are useful for understanding disease pathogenesis but also applicable for researchers to establish in vitro assays for HCV.
- Mailly et al. (2015) Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody. Nature Biotechnology.
- A monoclonal antibody specific for the tight junction protein claudin-1 eliminates chronic HCV infection without detectable toxicity. This paper is important because it showed that an antibody targeting a virus receptor can cure chronic viral infection and identified tight junction proteins as targets for antiviral therapy.
- Levy et al. (2015) Long-term culture and expansion of primary human hepatocytes. Nature Biotechnology.
- This paper devised a method to produce differentiated hepatocytes that were able to support HCVcc infection and made possible the assessment of patient-to-patient variability in the response to drug therapy, and provided insight into the idiosyncratic toxicity of drugs.
- Winer et al. (2017) Long-term hepatitis B infection in a scalable hepatic co-culture system. Nature Communications
- In this study, Winer et al. develop a platform for modeling persistent HBV infection, including patient-derived viruses, in scalable cell culture. This article is the subject of a fascinating Behind the paper feature.
- Allain & Opare-Sem (2016) Screening and diagnosis of HBV in low-income and middle-income countries. Nature Reviews Gastroenterology & Hepatology.
- Allain and Opare-Sem discuss the diagnosis and management of HBV in low and middle income countries, in which HBV can be a very significant disease burden. They also cover factors affecting the treatment and monitoring of HBV-related liver disease.