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Nobel Prize in Physiology or Medicine 2020

This collection of research, review and comment from Nature Research celebrates the 2020 Nobel Prize in Physiology or Medicine awarded to Harvey J. Alter, Michael Houghton and Charles M. Rice "for the discovery of hepatitis C virus". Chronic viral hepatitis is a global health concern and is a major cause of cirrhosis and liver cancer. Work by the prize-winning scientists demonstrated that an unknown virus was the cause of unexplained cases of chronic hepatitis, isolated the viral genetic sequence that led to its identification as hepatitis C virus and provided the final proof that this virus alone could cause hepatitis. This work led to blood tests that improved global health and antiviral drugs that mean the disease can now be cured and perhaps one day eradicated. 

From the winners

The development of therapies for hepatitis C virus (HCV) infection has been hampered by the lack of a small-animal model of the disease. Now Alexander Ploss and colleagues describe the first immunocompetent rodent model for hepatitis C virus infection, using adenoviruses expressing four human factors to enable entry of HCV into mouse cells. These vectors were then used to transduce the livers of mice, which then became susceptible to HCV infection. Although the model does not enable a complete virus replication cycle, it should be useful for the evaluation of HCV vaccines and entry inhibitors.

Letter | | Nature

The development of an effective vaccine and specific antiviral therapies against hepatitis C virus (HCV), a leading cause of liver disease, has been hampered by the lack of a convenient small animal model. With the identification of the gap junction protein occludin as the fourth and final key component of the hepatitis C virus cell-entry receptor, that elusive lab model may have come a step nearer. In addition to human occludin, viral infection of murine cells requires expression of the previously identified HCV entry factors CD81, scavenger receptor class B type I, and claudin-1.

Letter | | Nature

Claudin-1, a tight junction protein expressed in human liver, has been identified as an essential entry co-factor for hepatitis C virus. Like the CD81 co-receptor, claudin-1 spans the cell membrane four times with two extracellular loops. It functions in the hepatitis C virus entry process at a post-binding and pre-fusion step. This discovery provides insights into the mechanism of viral entry into liver cells, and a potential new target for antiviral drugs.

Letter | | 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.

Letter | | Nature

This study reports the use of cell culture models to scan an extensive interferon-stimulated gene (ISG) library for activity against a broad spectrum of viruses. The scan reveals that positive-sense single-stranded (ss)RNA viruses are more susceptible to ISG activities than negative-sense ssRNA viruses or a DNA virus. The DNA sensor cyclic GMP-AMP synthase (cGAS) is shown to inhibit several RNA viruses. The authors also generated cGAS knockout mice and showed an in vivo requirement for cGAS in antiviral responses.

Letter | | Nature

There is growing interest in antiviral interferon-stimulated genes (ISGs), such as IFITM3 and BST2 (also known as tetherin), because of their potential as drug targets. An overexpression screen has been used to assess the impact of several hundred ISGs on the replication of a number of viruses, including HIV-1 and hepatitis C virus. Combinations of validated antiviral ISGs were found to have additive effects and to converge on translational inhibition. Surprisingly, some ISGs actually enhance the replication of certain viruses, underlining the complexity of the response to interferon.

Letter | | Nature

Over 150 million people are infected with hepatitis C virus, there is no vaccine, and current therapies are not always effective. More efficient antivirals are much sought after, so the report of the crystal structure of the NS2 autoprotease of hepatitis C virus is a major advance. The structure, which reveals NS2 as a dimeric cysteine protease, will help in elucidating NS2's role in the viral life cycle, and it may aid the design of new drugs.

Letter | | Nature

Hepatitis C virus (HCV) is a positive-strand RNA virus that causes significant pathology in humans. Here, Lindenbach and Rice discuss recent insights into the unique properties of HCV particles and then review HCV entry and assembly, with a focus on the viral and host factors involved.

Review Article | | Nature Reviews Microbiology

A new wave of antivirals to fight hepatitis C infection has helped patients achieve a good quality of life, but drug resistance, side effects and a lack of pan-viral genotype coverage still remains a problem. This Review discusses current clinical studies and potential targets of the virus life cycle to tackle these issues and puts forward a paradigm to develop second-generation effective antivirals and drug combinations for achieving the ideal regimen of an all-oral, interferon-free therapeutic cocktail.

Review Article | | Nature Medicine

The development of direct-acting antiviral agents to treat chronic hepatitis C virus (HCV) infection, much needed clinically, has focused largely on inhibitors of two viral enzymes, the protease NS3 and NS5B, an RNA-dependent RNA polymerase essential for HCV replication. BMS-790052, identified using chemical genetics as a powerful specific HCV inhibitor, is a small-molecule inhibitor of a third viral molecule that has no known enzyme activity, the non-structural protein 5A (NS5A). A research team from Bristol-Myers Squibb this week reports on the discovery and virological profile of BMS-790052 and discloses clinical trial observations with this compound in normal healthy volunteers and HCV-infected subjects. These results establish proof-of-concept for HCV NS5A inhibition as a clinically relevant mechanism. In vitro data point to synergistic interactions with known HCV inhibitors, suggesting that cocktails of antiviral agents may be a viable therapeutic approach.

News & Views | | Nature

Hepatitis C virus causes severe liver disease. Initial trials of a newly developed agent that prevents the virus reproducing itself look promising. But what are the future prospects for this treatment?

News & Views | | Nature

Most research prizes in biomedicine, from the Nobels to the Laskers, are restricted to three recipients. But in an age of big science, when much larger teams are generally needed to make important research discoveries, all the people who provide seminal contributions deserve to be awarded.

Opinion | | Nature Medicine

Reviews and comments

Hepatitis C virus infection can cause acute and chronic hepatitis C, which are both characterized by inflammation of the liver. In this Primer, Manns et al. describe the latest developments against the global hepatitis C epidemic in the era of highly effective therapies.

Primer | | Nature Reviews Disease Primers

This Review describes the epidemiology and mechanisms underlying the reciprocal relationship between hepatitis C virus (HCV) infection and chronic kidney disease (CKD). The authors also discuss recommended treatment approaches for patients with HCV infection and CKD, and outline remaining issues in the field.

Review Article | | Nature Reviews Nephrology

The past 10 years have witnessed incredible developments in the treatment of hepatitis C. From an era in which the standard of care was PEG-IFN and ribavirin back in 2004, various interferon-free regimens with direct-acting antivirals are now available or will be soon. Here, major milestones in the hepatitis C treatment revolution are outlined.

News & Views | | Nature Reviews Gastroenterology & Hepatology

Direct-acting antiviral agents (DAAs) have revolutionized the management of chronic hepatitis C, but their use in acute infection is unclear. This Review outlines the epidemiology, diagnosis and management of acute HCV infection, providing insights into the use of DAAs in at-risk populations (such as people who inject drugs).

Review Article | | Nature Reviews Gastroenterology & Hepatology

Chronic HCV infection is a global health problem. In this Review, the authors describe the global burden of hepatitis C and HCV-related disease, including hepatocellular carcinoma, cirrhosis and extrahepatic manifestations. How the new direct-acting antiviral agents might influence disease burden is also discussed.

Review Article | | Nature Reviews Gastroenterology & Hepatology

Late presentation to hepatitis B virus and hepatitis C virus care is common, hindering global efforts to reduce the morbidity and mortality associated with liver disease. Models of care promoting and simplifying early testing of viral hepatitis are needed if we are to eliminate viral hepatitis as a major public health threat by 2030.

Comment | | Nature Reviews Gastroenterology & Hepatology

Cryoglobulinaemia is characterized by the presence of precipitable immunoglobulins in the serum and can lead to a clinical syndrome called cryoglobulinaemic vasculitis. This Primer describes the underlying mechanisms, diagnosis and management of cryoglobulinaemia.

Primer | | Nature Reviews Disease Primers

A growing body of evidence suggests that chronic hepatitis C infection is associated with an increased rate of extrahepatic cancers. In this Review, the authors summarize epidemiological studies exploring this relationship and provide insights into the potential mechanisms underlying a causal link.

Review Article | | Nature Reviews Gastroenterology & Hepatology

New national hepatitis C virus (HCV) screening guidance from the United States Preventive Services Task Force includes a recommendation for one-time testing for all adults aged 18 to 79 years. Implicit in the new guidance is that all people diagnosed with chronic HCV infection should be offered HCV treatment.

News & Views | | Nature Reviews Gastroenterology & Hepatology

Research

The development of direct-acting antiviral agents to treat chronic hepatitis C virus (HCV) infection, much needed clinically, has focused largely on inhibitors of two viral enzymes, the protease NS3 and NS5B, an RNA-dependent RNA polymerase essential for HCV replication. BMS-790052, identified using chemical genetics as a powerful specific HCV inhibitor, is a small-molecule inhibitor of a third viral molecule that has no known enzyme activity, the non-structural protein 5A (NS5A). A research team from Bristol-Myers Squibb this week reports on the discovery and virological profile of BMS-790052 and discloses clinical trial observations with this compound in normal healthy volunteers and HCV-infected subjects. These results establish proof-of-concept for HCV NS5A inhibition as a clinically relevant mechanism. In vitro data point to synergistic interactions with known HCV inhibitors, suggesting that cocktails of antiviral agents may be a viable therapeutic approach.

Letter | | Nature

Organs from donors with transmissible viral infections, such as hepatitis C virus (HCV), are not offered for transplantation due to a high risk of transmission. Here, Galasso et al. develop a method for treatment of HCV-infected human donor lungs that is safe and prevents HCV transmission in the pig model.

Article | Open Access | | Nature Communications

Treatment options for hepatitis C virus (HCV) infection have limited efficacy and high toxicity, resulting in poor adherence and, thus, viral resistance. Identifying previously unrecognized pathways involved in HCV infection may aid the development of new therapeutics. Using an RNAi screen, Lupberger et al. have identified cellular kinases involved in HCV infection of liver cells and have tested the ability of approved inhibitors to block viral entry both in vitro and in vivo.

Article | | Nature Medicine