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Overcoming barriers to effective Hepatitis C treatment

Among viruses, the Hepatitis C virus is extremely persistent – a patient sometimes cannot get rid of the virus after infection, and it remains in their cells over long periods of time. The standard HCV treatment is effective over time only in half the patients, making Hepatitis C the bane of doctors and scientists worldwide.

Researchers at the Therapeutic Engineering Lab at the Department of Chemical Engineering, Indian Institute of Science, think they may know more about why the disease is persistent. Using simulations, they found that the Hepatitis C virus and the body’s immune system get into a deadlock when the body is fighting the virus.

The Hepatitis C Virus (HCV) survives by replicating itself. The virus itself also produces its own protein army, which is used for virus replication. After getting infected by a virus, cells release proteins called interferons, proteins that are a battle response to virus invasion. Interferons start a cascade of reactions that produce “antiviral” proteins that block replication of the virus. The virus proteins in turn block the antiviral proteins.  

“Interferon controls HCV, HCV controls interferon”, says Pranesh Padmanabhan, first author of the paper. It seems like a battle scenario where either is equally poised to win. A consequence of this “bi-stable” or steady state is that the virus can persist -- despite the body producing interferons and other proteins to attack it. This is the first discovery of a virus inducing this kind of bi-stability in the immune system.

The study used simulations to reproduce patterns of viral infection in patients, by varying the fraction of cells resistant or sensitive to interferons. The simulation was programmed such that in some cells, virus replication was high and antiviral protein production low. In other cells, the situation was reversed, and in still others, the levels were equal.

The simulation results showed a range of responses depending on the proportion of cells resistant to interferons. If many cells were resistant, treatment failed; and it failed even if cells produced high levels of interferons.

This can make reliance on interferons alone an ineffective cure. Current treatment regimes for hepatitis C include direct action drugs, which directly target the virus unlike interferons which prod our immune system. They lower HCV levels sufficiently enough to tip the balance, destroy the bi-stable state and improve the chances for interferons to take control.

“Now that we know about this bi-stability, the solution to treatment failure is to simply tweak the system”, says Padmanabhan. Patients may not respond to interferon treatment or to direct action drugs alone. But direct action drugs in combination with interferons will improve response significantly. 

The reason why no one understands why the Hepatits C virus is extremely persistent is because they aren’t looking at the whole picture, explains Padmanabhan. The reason cannot be found by looking at the molecular interactions of the virus, but by looking at the entire system of interaction.

He also reckons there are two ways forward. “We now know what needs to be manipulated to improve the efficacy of direct action drugs that are based on enhancing interferon activity. Follow-on work will aim to identify important points of target in the body’s interferon-signaling network, or the HCV life cycle, to further improve the interferon responsiveness of cells,” said Padmanabhan.

Author information

Narendra Dixit is an Associate Professor heading the Therapeutic Engineering Lab at the Department of Chemical Engineering at IISc. Pranesh Padmanabhan is his PhD student. They have collaborated with Urtzi Garaigorta from The Scripps Research Institute in California.

Link to the paper: http://www.nature.com/ncomms/2014/140516/ncomms4872/full/ncomms4872.html