Modeling the helicase to understand hepatitis C

NS3 behaves like a 'caterpillar' and helps the virus to replicate

NS3 is an enzyme specific to the hepatitis C virus. If developed, a drug capable of recognizing and selectively attacking it could fight the disease without side effects for the body. However, to be able to develop one we need to know more about the behavior of this important protein in the virus replication process. Some SISSA scientists have provided a detailed and comprehensive view of the behavior of NS3. The study has been published in the journal Nucleic Acids Research.

According to the WHO, a good 140 million people are affected by hepatitis C (3/4 million new cases per year). This is still a subtle disease which, in the event of chronic infection, heavily affects the patients' quality of life and whose complications can lead to death. One of the molecules involved in the reproduction mechanism of the virus in the body is a helicase, NS3, an enzyme that interacts with the RNA (the viral genome, which is not like our DNA) by climbing onto it and helping the pathogen's replication process.

"By knowing in detail how this helicase works, in the future we could try to block the viral replication, and thus stop the disease from proliferating in the body" explains Giovanni Bussi, SISSA professor and among the study authors. NS3 facilitates the work of the polymerases, the molecules that build a replica of the RNA strand, by "opening" and preparing the RNA to the action of the second enzyme. "NS3 crawls along the RNA strand contracting and extending like a caterpillar and, as it does so, it releases the part of the virus to which the polymerase then attaches" explains Andrea Pérez-Villa, SISSA student and first author of the paper. "We decided to analyze this protein because, unlike others, it is only present in the hepatitis C virus. This way, any drug capable of targeting its interaction with the RNA would not damage other proteins, for example, those belonging to the body being attacked by the virus. This means that, theoretically, the drug would have no side effects".

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Expression of a single gene lets scientists easily grow hepatitis C virus in the lab

 "What prevents non-mutated HCV from replicating in laboratory-grown cell lines?"

In a study published in Nature on August 12, scientists led by The Rockefeller University’s Charles M. Rice, Maurice R. and Corinne P. Greenberg Professor in Virology and head of the Laboratory of Virology and Infectious Disease, report that when they overexpressed a particular gene in human liver cancer cell lines, the virus could easily replicate. This discovery allows study of naturally occurring forms of hepatitis C virus (HCV) in the lab.

“Being able to easily culture HCV in the lab has many important implications for basic science research,” says Rice. “There is still much we don’t understand about how the virus operates, and how it interacts with liver cells and the immune system.”

Scientists have long attempted to understand what makes HCV tick, and in 1999 a group of German scientists succeeded in coaxing modified forms of the virus to replicate in cells in the laboratory. However, it was soon discovered that these forms of the virus were able to replicate because they had acquired certain “adaptive” mutations.

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Cooperation among viral variants helps hepatitis C survive immune system attacks

Warring armies use a variety of tactics as they struggle to gain the upper hand. Among their tricks is to attack with a decoy force that occupies the defenders while an unseen force launches a separate attack that the defenders fail to notice.

A study published earlier this month in the journal Proceedings of the National Academy of Sciences suggests that the Hepatitis C virus (HCV) may employ similar tactics to distract the body's natural defenses. After infecting patients, Hepatitis C evolves many variants, among them an "altruistic" group of viral particles that appears to sacrifice itself to protect other mutants from the body's immune system.

The findings, reported by researchers from the Georgia Institute of Technology and the Centers for Disease Control and Prevention (CDC), could help guide development of future vaccines and treatments for the virus, which affects an estimated 170 million people in the world. Developing slowly over many years and often without symptoms, Hepatitis C can cause severe liver damage and cancer. There are currently no vaccines for the disease.

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Scientists identify crucial step in helping to prevent Hepatitis C virus replicating

New research from the University of Southampton has identified how changes in the cell membrane play a pivotal role in how the Hepatitis C virus replicates.

By understanding this process, the researchers hope to investigate how to prevent the changes and potentially develop therapeutic drugs to combat the Hepatitis C virus (HCV), which infects an estimated 170 million people globally.

When HCV infects a cell it uses one of its proteins, NS4B, to form a lipid-rich structure called the 'membranous web'. This structure contains 'reaction centres', where the virus can replicate protected from the host cell's antivirus defences.

More information: "Interaction between the NS4B amphipathic helix, AH2, and charged lipid headgroups alters membrane morphology and AH2 oligomeric state—Implications for the Hepatitis C virus life cycle," Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1848, Issue 8, August 2015, Pages 1671-1677, ISSN 0005-2736, dx.doi.org/10.1016/j.bbamem.2015.04.015

Read more at: http://phys.org/news/2015-05-scientists-crucial-hepatitis-virus-replicating.html#jCp

Study details microRNA's role as a double agent during Hep C infection

In the battle between a cell and a virus, either side may resort to subterfuge. Molecular messages, which control the cellular machinery both sides need, are vulnerable to interception or forgery. New research at Rockefeller University has revealed the unique twist on just such a strategy deployed by the liver-infecting Hepatitis C virus - one that may help explain the progression of liver disease and that the researchers suspect may be found more widely in the world of disease-causing viruses.

Led jointly by Charles Rice, the Maurice R. and Corinne P. Greenberg Professor in Virology and head of the Laboratory of Virology and Infectious Disease and Robert Darnell, Senior Attending Physician, Robert and Harriet Heilbrunn Professor, and head of the Laboratory of Molecular Neuro-oncology, the research is described today (March 12) in Cell. It employed a powerful combination of techniques to map the interactions between the virus and a small piece of genetic material - known as miRNA-122 - that is produced almost exclusively by liver cells, which normally use it to regulate expression of their own genes.

"It is well known that once inside a liver cell, the hepatitis C virus must bind to miRNA-122 in order to establish a persistent infection. We found an unanticipated consequence of this interaction: By binding to miRNA-122, the virus acts like a sponge, soaking up these gene-regulating molecules," says first author Joseph Luna, a graduate student with a joint appointment in the labs. "Our experiments showed this has the effect of skewing gene activity in infected liver cells."

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Hot on the trail of the hepatitis-liver cancer connection

Using whole genomic sequencing, scientists from RIKEN in Japan have for the first time demonstrated the profound effect that chronic hepatitis infection and inflammation can have on the genetic mutations found in tumors of the liver, potentially paving the way to a better understanding of the mechanisms through which these chronic infections can lead to cancer. Primary liver cancer is the third leading cause of cancer death worldwide, and recent studies have shown that particularly in Asia, infection with either hepatitis B or C is often associated with such cancers.

For the study, which was published in Nature Communications, the group performed whole genomic sequencing on 30 individual tumors classified as liver cancer displaying a biliary phenotype. This type of cancer originates in the liver, but is different from hepatocellular carcinoma, the dominant form of primary liver cancer, and is generally more aggressive, with poorer prognosis. They compared the data with 60 of the more-common hepatocellular carcinoma tumors. To study gene expression, they then examined RNA sequencing data from 25 of the biliary-phenotype cancers and 44 hepatocellular cancers.

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