Research sheds light on response of the hepatitis C virus to targeted therapeutics

Hepatitis C Antiviral Resistance Revealed

Scientists at the Icahn School of Medicine at Mount Sinai (ISMMS) say recent research has shed light on the response of the hepatitis C virus (HCV) to targeted therapeutics and provided new insights about HCV’s role in cancer development. Their work (“Hepatitis C virus genetics affects miR-122 requirements and response to miR-122 inhibitors”), published in Nature Communications, focused on microRNA genes, a type of regulatory gene, and used whole-genome sequencing of the virus to challenge conventional wisdom about how the virus responds to emerging therapies.

Their findings, note the researchers, may contribute to more effective development of hepatitis C drugs in the future and to more personalized treatment for patients.

According to the Centers for Disease Control and Prevention, HCV is widespread, affecting some 3% of the world’s population and more than 3 million people in the United States alone. Recent CDC reports indicate that hepatitis C infections are on the rise among young people and are increasingly the cause of death among baby boomers.

The vast majority of people who get HCV will suffer chronic infection, which can lead to liver inflammation, cirrhosis, and liver cancer. Highly effective new treatments have been launched recently, but their high prices have caused public outcry and limited widespread use. There is no commercially available vaccine for hepatitis C.

In this new study, Mount Sinai researchers examined HCV response to an experimental treatment that targets and blocks the supply of a microRNA (miR-122) that the virus needs for infection of human cells. Contrary to expectations, they found that depleting the supply of miR-122 could trigger drug resistance with the emergence of HCV strains able to infect cells with negligible levels of the microRNA. This information could be used for more effective dosing of drugs targeting this gene, as well as for pre-treatment analysis to determine which patients may respond best to this class of drugs.

“This effort, which was made possible by innovative microRNA analysis, offers significant progress toward precision medicine in treating HCV patients,” said Matthew Evans, Ph.D., assistant professor of microbiology at the ISMMS and a co-author of the study. “There is a critical need for more weapons in our arsenal to fight HCV, particularly for affordable, effective treatment as we try to stay a step ahead of this virus and prevent it from developing the kind of drug resistance we’re seeing in the bacterial realm.”

In another key finding, the scientists uncovered knowledge that may help answer the longstanding question of how HCV leads to cancer. The study demonstrated that HCV hijacks the miR-122 gene, diminishing its normal activity in liver cells. Since this microRNA is known to be a potent tumor repressor, it is possible that HCV robs cells of their natural defenses against uncontrolled growth. Such an outcome could contribute to cancers that arise from chronic HCV infection.

“We found that HCV itself reduces miR-122’s activity in the cell, possibly through binding and sequestering miR-122,” wrote the investigators. “Our study provides insight into the interaction between miR-122 and HCV, including viral adaptation to reduced miR-122 bioavailability, and has implications for the development of anti-miR-122-based HCV drugs.”

“Our study offers broader implications for this class of microRNA genes and their interaction with targets, which may be useful for a number of diseases in addition to hepatitis C,” said Brian Brown, Ph.D., associate professor of genetics and genomic sciences at the ISMMS and a co-author of the study. “We are also intrigued by this new information that may shed light on the link between HCV and the onset of cancer and look forward to future efforts to explore this theory.”

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Cocaine use may increase HIV vulnerability

Cocaine use may increase HIV vulnerability

New research published in the Journal of Leukocyte Biology suggests that cocaine makes quiescent CD4 T cells susceptible to HIV resulting in significant infection and new virus production

Bethesda, MD -- Cocaine use may increase one's vulnerability to HIV infection, according to a new research report published in the Journal of Leukocyte Biology. In the report, scientists show that cocaine alters immune cells, called "quiescent CD4 T cells," to render them more susceptible to the virus, and at the same time, to allow for increased proliferation of the virus.

"We ultimately hope that our studies will provide a better understanding of how drugs of abuse impact how our body defends itself against disease," said Dimitrios N. Vatakis, Ph.D., the study's senior author and a scientist with UCLA's Department of Medicine, Division of Hematology-Oncology and the UCLA AIDS Institute. "Such discovery can significantly improve the quality of life of drug users."

To make this discovery, scientists collected blood from healthy human donors and isolated quiescent CD4 T cells, and exposed them to cocaine and subsequently infected them with HIV. Following infection, researchers monitored the progression of HIV's life cycle and compared this progression against that of untreated cells. They found that cocaine rendered this subset of CD4 T cells susceptible to HIV, resulting in significant infection and new virus production.

"The co-epidemics of elicit drug use and infectious disease are well documented, though typically this connection is thought to occur through lifestyle choices and increased exposure," said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. "What often does not come to mind is that drugs such as cocaine may be helping to fuel infections in this high-risk population by altering the immune system. These new studies are an important advance documenting how cocaine use may increase a person's vulnerability to HIV and further highlighting the need for improved education for both HIV prevention and drug abstinence."

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The Journal of Leukocyte Biology publishes peer-reviewed manuscripts on original investigations focusing on the cellular and molecular biology of leukocytes and on the origins, the developmental biology, biochemistry and functions of granulocytes, lymphocytes, mononuclear phagocytes and other cells involved in host defense and inflammation. The Journal of Leukocyte Biology is published by the Society for Leukocyte Biology.

Details: Sohn G. Kim, James B. Jung, Dhaval Dixit, Robert Rovner, Jr., Jerome A. Zack, Gayle C. Baldwin, and Dimitrios N. Vatakis. Cocaine exposure enhances permissiveness of quiescent T cells to HIV infection. J Leukoc Biol, October 2013 94:835-843; doi:10.1189/jlb.1112566 ; http://www.jleukbio.org/content/94/4/835.abstract

Hepatitis C- Accurate, clinically relevant information for patients with viral hepatitis

Hepatitis C Information

Learning about HCV or deciding on a treatment plan after being diagnosed can be an overwhelming task.

Hours and hours of searching the Internet for accurate easy to understand information often ensues. Finding the right creditable web site with relevant information is invaluable.

Here are a few links pointing you in the right direction, starting with Clinical Care Options (CCO)

CCO Hepatology in Practice™ is a unique Web site designed to provide easy access to accurate, clinically relevant information to improve care for patients with viral hepatitis. The program was launched in 2011 and the contents are reviewed and updated on an ongoing basis.

This site is available for use after a free, one-time registration.
Click here register

The information available to patients at CCO is abundant, here are just a few topics of interest.

Hepatology - Management of Hepatitis C Infection

Released: 12/13/11

Last Reviewed: 12/13/11

In patients with chronic hepatitis C virus (HCV) infection, the goal of therapy is virologic cure. Eradication of HCV RNA, which persists long-term off therapy, is referred to as a sustained virologic response (SVR). Although SVR is equivalent to virologic cure, the term cure has traditionally been avoided. Initially, there was concern that despite undetectable HCV RNA following treatment, there might potentially be dormant virus that could return in the future. However, long-term follow-up data show that patients with an SVR following treatment with peginterferon and ribavirin have a relapse rate < 1% after a mean of 1.8 years from the end of antiviral treatment,^{[Swain 2010]} and early data with protease inhibitor–based triple therapy indicate that SVR achieved in patients treated with telaprevir plus peginterferon and ribavirin is durable (< 1% relapse) through a median of 21 months of follow-up.^{[Sherman 2011b]} A further concern with the term cure is that underlying liver disease may not be fully reversed even if HCV infection is eradicated. Obtaining SVR is associated with decreases in all-cause mortality,^{[Backus 2011]} liver-related death, liver-related complications, the need for liver transplantation, and in the incidence of hepatocellular cancer.^{[Morgan 2010; Veldt 2007]} In patients without advanced fibrosis before treatment, SVR represents cure. For those with advanced fibrosis, particularly cirrhosis, SVR is a virologic cure associated with improved outcomes, but adverse events, particularly the development of liver cancer, may still occur. The positive outcomes observed are an effect of permanent HCV RNA eradication, as viral suppression by long-term HCV therapy without SVR does not have the same impact on clinical outcomes.[Shiffman 2009]

Protease Inhibitors

Released: 12/13/11

Last Reviewed: 12/13/11

In 2011, the novel agents boceprevir and telaprevir were approved by the US Food and Drug Administration and the European Medicines Agency for use in combination with peginterferon/ribavirin in treatment-naive and treatment-experienced patients chronically infected with genotype 1 hepatitis C virus (HCV). Both of these agents are NS3/4A inhibitors and act against an HCV-encoded serine protease that is required for cleavage of the viral polyprotein during and after translation. By preventing this important step in the viral lifecycle, both of these drugs potently inhibit HCV replication. Unfortunately, single mutations in the viral genome lead to high-level resistance to these agents, and so their use as monotherapy is not an option; boceprevir and telaprevir must each be given with peginterferon and ribavirin. The efficacy of each agent is discussed later, and indirect comparisons are made, as there have been no head-to-head trials comparing these 2 agents. For patients with non–genotype 1 HCV, the current standard of care remains dual therapy with peginterferon/ribavirin.......click here to continue

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CCO-Latest Hepatology Updates

1/12/12 - Hepatitis C Management in Special Populations
Updated to include new data on the pharmacokinetics of boceprevir coadministration with cyclosporine or tacrolimus

12/13/11 - Hepatitis C Virus Epidemiology, Pathogenesis, Diagnosis, and Natural History
Now available: Francesco Negro, MD, provides an in-depth review of past and current HCV transmission trends, the latest understanding of HCV pathogenesis, key assays and recommendations for the diagnosis of HCV, and the natural history of both acute and chronic HCV infection.

12/13/11 - Other Viruses That Affect the Liver
Now available: Joshua Levitsky, MD, MS, and Lisa B. VanWagner, MD, MS, outline the epidemiology, clinical presentation, diagnosis, and clinical management of the secondary and exotic hepatotropic viruses in patients with solid organ transplantations.

The Liver Meeting® 2011 Educational Webcast of selected sessions 
If you haven't yet explored the "LiverLearning" section available @ the AASLD web site you're missing out on the November meeting webcasts, video podcasts, abstracts and more. Free registration is required, start the process by clicking Here. 

Once this is accomplished click here to view webcasts and more.

Other HCV Sites:
These links will take you to the premier Hepatitis C sites and keep you informed with breaking news, clinical studies, new drugs, podcasts, newsletters, support, personal experiences, chat rooms, forums and more.

Research sheds light on virus life cycle

U of A medical researchers discover how a common virus cheats death
By Raquel Maurier February 17, 2011


Tom Hobman and Ing Swie Goping discovered how a common virus can cheat death.
(Edmonton) A team of researchers in the Faculty of Medicine & Dentistry at the University of Alberta has taken an important step forward in the study of virology by discovering how a common virus cheats death by allowing the viral disease to spread throughout the body.
Now the team wants to see if similar viruses work the same way. Their findings could have major implications for improving the health of millions and may prevent deaths, since this discovery could arm medical scientists with the ability to shut down many viruses at an earlier stage.


Viruses invade host cells and replicate inside them. One of the body’s immune responses is to trigger cells to “commit suicide” if they are infected or sick. However, Tom Hobman and his fellow researchers, Carolina Ilkow and Ing Swie Goping, found out how the rubella virus, responsible for German measles, blocks cell death, thereby allowing the virus to spread. Rubella virus, a type of RNA virus, is responsible for more birth defects worldwide than any other infectious agent. These viruses cause the vast majority of viral diseases in humans, including AIDS, influenza, hepatitis C, West Nile disease and Dengue fever.


Hobman’s team suspected that RNA viruses block the pathways in cells that lead to cell suicide. This was the opposite of what many scientists would have expected. The U of A research team found that when cells are infected with rubella virus, cell suicide is delayed or blocked. They also discovered that a protein, which is generally thought to function only as a building block, actually plays a key role in stopping the process that triggers cell death. This so-called “capsid” protein in the virus acts like a sponge and soaks up a protein in the cell known as Bax, which is crucial in the process triggering the cell to commit suicide.


“This discovery was surprising but gratifying at the same time,” says Hobman. “Previously, no one had given any thought to any potential function of this capsid protein.”
Hobman’s team then decided to conduct some reverse genetic experiments and mutated the capsid protein. This impaired the ability of the virus to replicate itself, because cells committed suicide much earlier in the infection process and more often.


The team’s findings have been published in the journal PLoS Pathogens.
Hobman and his colleagues are now studying the West Nile and Dengue fever viruses to see if those viruses prevent cell suicide in a similar fashion. He hopes the team’s discovery will one day lead to viral infections being limited and shut down at an earlier stage.
Hobman is an authority on host-virus interactions in cells infected with rubella and West Nile viruses. He wrote the chapter on rubella in a widely used textbook on viruses.

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