Hepatitis C Virus Faces New Weapon from Scientists

[Guest guest]

http://www.infectioncontroltoday.com/news/2010/09/hepatitis-c-virus-faces-new-we\

apon-from-scientists.aspx

Hepatitis C Virus Faces New Weapon from Scientists

In recent human trials for a promising new class of drug designed to target the

hepatitis C virus (HCV) without shutting down the immune system, some of the HCV

strains being treated exhibited signs of drug resistance.

In response, an interdisciplinary team of Florida State University biologists,

chemists and biomedical researchers devised a novel genetic screening method

that can identify the drug-resistant HCV strains and the molecular-level

mechanisms that make them that way –– helping drug developers to tailor specific

therapies to circumvent them.

The potentially life-saving technology also works when screening other viruses

with drug-resistance issues, notably human immunodeficiency virus (HIV) and

influenza.

More than 170 million people worldwide are infected with HCV, which leads to

both acute and chronic liver diseases.

“In collaboration with pharmaceutical firm Gilead Sciences and researchers from

the University of Heidelberg (Germany), what our research team discovered was

how the latest drug for HCV works and what changes in the virus that makes it

resistant to this unique therapy,” says Hengli Tang, a Florida State University

molecular biologist.

“This is knowledge that is essential to drug developers focused on HCV,” says

Tang, “but equally important is that our method, which we call ‘CoFIM’

(Cofactor-independent mutant) screening, can also be applied to other drug

targets and other viruses. And, since we now understand how this latest class of

drug works and what causes resistance to it, we can better select other classes

of drugs with distinct mechanisms –– in other words, those that target other

parts of the virus –– in order to craft a combination therapy, which is the

future of HCV therapy and the key to overcoming drug resistance.”

The groundbreaking research is described in a paper published online in the

September 2010 issue of the journal PLoS Pathogens.

Florida State biology doctoral student Feng Yang led the research team. The

award-winning scholar earned her PhD in August 2010 and is now a postdoctoral

associate at Yale University. Yang designed the CoFIM screening methodology with

fellow FSU graduate students, postdoctoral associates and distinguished faculty

colleagues –– including associate professor Tang; chemistry/biochemistry

professor M. Logan, director of FSU’s Institute of Molecular Biophysics;

and Research Assistant Professor Ewa A. Bienkiewicz, of the FSU College of

Medicine, where she directs the Biomedical Proteomics Laboratory.

Driving the team’s development of CoFIM screening was the need to identify key

“cellular cofactors” and their mechanisms of action –– a fundamental aspect of

virus-host interaction research.

“’Cellular cofactors’ are proteins that normally exist in host cells that have

been hijacked by viruses to facilitate viral replication.” Tang says. “They

became accomplices to the invading viruses. “Our research team was the first to

show that ‘cyclophilin A’ (CyPA) is an essential cellular cofactor for hepatitis

C virus infection and the direct target of a new class of clinical anti-HCV

compounds, which include cyclosporine A (CsA)-based drugs that are devoid of

immunosuppressive function,” Tang adds. “In addition, we went a step further

than other research teams by employing our newly developed CoFIM screening

method, which we used to demonstrate not only HCV’s dependence on cellular

cofactor cyclophilin A and susceptibility to cyclosporine A drugs but also to

uncover the molecular-level regulators that determine those two traits in the

virus.”

Those molecular-level regulators are known as “small interfering RNA libraries”

–– collections of molecules so named for their size and ability to suppress gene

expression. They act to individually suppress every gene in the cell, resulting

in different consequences depending upon which gene is suppressed by a given

member in the library.

The CoFIM screening method involves inducing or “coaxing” the HCV virus to

mutate by itself, in vitro, absent the replication assistance it normally

receives from a particular cellular cofactor. Then, CoFIM tracks the changes in

the virus’s response both to CsA-based drugs and any other drug designed to

inhibit the cofactor.

Funding for the research conducted at Florida State University came in largest

part from a $1.4 million grant awarded by the National Institutes of Health

(NIH). And, because chronic liver disease caused by HCV can lead to liver

cancer, a grant from the American Cancer Society provided additional support.