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

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.

The attached image
shows molecular dynamics
simulation showing the aggregation
of the NS4B protein on the bilayer surface

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.

Within NS4B, the AH2 peptide plays a crucial role in remodelling lipid membranes to form the membranous web. However, it is not understood how AH2 causes these changes.

Using nuclear magnetic resonance (NMR) spectroscopy in conjunction with molecular dynamics (MD), Southampton researchers showed that AH2 interacts with negatively charged lipid membranes within the cell. It causes them to become more malleable, a property almost certainly important in reaction centre formation. When introduced into membranes with non-charged lipids, AH2 behaved differently, forming larger complexes resulting in limited deformation of the membrane, consistent with a separate role in early steps of membranous web formation.

Co-author of the study Dr Phil Williamson, Lecturer in Biological Sciences, says: "Now we begin to understand at the molecular level how HCV hijacks cellular membranes to aid its replications, we can use this information to help identify novel sites for therapeutic intervention to target HCV and similar viruses."

Co-author Dr Chris McCormick, from Medicine at the University of Southampton, adds: "This gives us an important lead on how changes in lipid content in the membranous web help drive membrane remodelling. The challenge for us now is to use the same interdisciplinary approach to link these activities with other maturation events seen inside the infected cell."

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The research, which was produced by undergraduate students from the University's Centre for Biological Sciences as part of an interdisciplinary team of researchers from Biological Sciences, Chemistry and Medicine, is published in BBA Biomembranes.

Virology Blog - Review cell proteins essential for entry of hepatitis C

Podcast-TWiV 166: Breaking and entering

Vincent, Dickson, Rich, and Alan review cell proteins essential for entry of hepatitis C, Ebola, and measles viruses.

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Life Cycle Of The Hepatitis C Virus

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The hepatitis C virus must attach to and infect liver cells in order to carry out its life cycle and reproduce - this is why it is associated with liver disease. While little is known about the exact natural processes of hepatitis C, like other viruses, it must complete eight key steps to carry out its life cycle:

1. The virus locates and attaches itself to a liver cell. Hepatitis C uses particular proteins present on its protective lipid coat to attach to a receptor site (a recognizable structure on the surface of the liver cell).

2. The virus's protein core penetrates the plasma membrane and enters the cell. To accomplish this, hepatitis C utlilizes its protective lipid (fatty) coat, merging its lipid coat with the cellÕs outer membrane (the coat is in fact composed of a fragment of another liver cell's plasma membrane). Once the lipid coat has successfully fused to the plasma membrane, the membrane engulfs the virus - and the viral core is inside the cell.

3. The protein coat dissolves to release the viral RNA in the cell. This may be accomplished during penetration of the cell membrane (it is broken open when it is released into the cytoplasm), or special enzymes present in liver cells may be used to dissolve the casing.

4. The viral RNA then coopts the cell's ribosomes, and begins the production of materials necessary for viral reproduction. Because hepatitis C stores its information in a "sense" strand of RNA, the viral RNA itself can be directly read by the host cell's ribosomes, functioning like the normal mRNA present in the cell. As it begins producing the materials coded in its RNA, the virus also probably shuts down most of the normal functions of the cell, conserving its energy for the production of viral material, although it occasionally appears that hepatitis C will stimulate the cell to reproduce (presumably to create more cells that can produce viruses), which is why hepatitis C is often associated with liver cancer. The viral RNA first synthesizes the RNA transcriptase it will need for reproduction.

5. Once there is adequate RNA transcriptase, the viral RNA creates an antisense version (the paired opposite) of itself as a template for the creation of new viral RNA. The viral RNA is now copied hundreds or thousands of times, making the genetic material for new viruses. Some of this new RNA will contain mutations.

6. Viral RNA then directs the production of protein-based capsomeres (the building blocks for the virus's protective protein coat). Ribosomes create the proteins and
release them for use.

7. The completed capsomeres assemble around the new viral RNA into new viral particles. The capsomeres are designed to attract each other and fit together in a certain way. When enough capsomeres are brought together, they self-assemble to form a spherical shell, called a capsid, that fully encapsulates the virus's RNA. The completed particle is called a nucleocapsid.

8. The newly formed viruses travel to the inside portion of the plasma membrane and attach to it, creating a bud. The plasma membrane encircles the virus and then releases it - providing the virus with its protective lipid coat, which it will later use to attach to another liver cell. This process of budding and release of new viruses continues for hours at the cell surface until the cell dies from exhaustion.

Each surviving virus - those which are not destroyed by the immune system or other environmental factors - can produce hundreds or thousands of offspring. Over time, this endless cycle of reproduction results in significant damage to the liver, as millions upon millions of cells are destroyed by viral reproduction or by the immune system's attacks on infected cells.

Dartmouth Medical School

Fat droplets are critically involved in the HCV lifecycle

At first glance, the HCV lifecycle is fairly simple. The virus enters the cell. One large protein is produced and cut into several smaller viral enzymes and proteins that build the virus. The RNA genome is copied, and the new RNAs and structural proteins are used to make new virus particles that are released into the blood stream for to infect more cells. These processes were thought to occur at specialized membranes inside the cell. However, recently it has been shown that fat droplets are critically involved

The hepatitis C virus (HCV)is triggered off in its infectious activity by an enzyme connected to the fat that is stored in the liver, conclude scientists.

This discovery may offer a new strategy for treating the infection.

The study by the researchers at the Gladstone Institute of Virology and Immunology (GIVI) shows that the enzyme DGAT1 is a key factor in HCV infection.

With several potential DGAT1 inhibitors already in the drug-development pipeline, a treatment for HCV may be possible in the near future.

"Our results reveal a potential 'Achilles heel' for HCV infection," Nature quoted Melanie Ott, senio r author on the study, as saying.

"Several DGAT1 inhibitors are already in early clinical trials to treat obesity-associated diseases. They might also work against HCV," said Ott.

It has been recently shown that fat droplets are critically involved in the HCV lifecycle and DGAT1 helps in their formation.

The Gladstone team discovered that HCV infection and viral particle production are severely impaired in liver cells that lack DGAT1 activity.

"We found that HCV specifically relies on one DGAT enzymes, DGAT1. Whe we inhibit DGAT1 with a drug, the liver still produces fat droplets through another DGAT enzyme but these droplets cannot be used by HCV," said lead author Eva Herker.hey found that DGAT1 interacts with one viral protein, the viral nucleocapsid core protein, required for viral particle assembly.

The core protein normally associates with the surface of fat droplets but cannot do so when DGAT1 is inhibited or missing in infected cells.

The study was published in the journal Nature Medicine.

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Read more: Hepatitis C Virus Infection Contributed by Liver's Fat Enzyme http://www.medindia.net/news/Hepatitis-C-Virus-Infection-Contributed-by-Livers-Fat-Enzyme-75290-1.htm#ixzz12CpPRtCh