A mini-collection of research on viral hepatitis

Nature Research editors present a collection of the best recent papers on viral hepatitis, selected from across Nature journals.
A mini-collection of research on viral hepatitis

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, NatureNature Medicine, Nature GeneticsNature 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.
  • 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.


  • 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.

Mechanisms of disease


  • Sun et al. (2015) Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5ANature.
    • 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.


  • Saeed et al. (2015) SEC14L2 enables pan-genotype HCV replication in cell cultureNature.
    • 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.
  • 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 systemNature 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 countriesNature 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.

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