Why is HCV So Resilient?

[Guest guest]

Why is HCV So Resilient?

by C.

Article Date: 03-02-05

One of the reasons it's so challenging to treat people with

hepatitis C successfully is due to the virus' resilience in the

body. While our immune systems are inherently designed to fight off

foreign substances like bacteria and viruses almost as soon as they

enter the body, hepatitis C (HCV) has a built-in evasive mechanism

that helps protect it from an otherwise devastating and irreparable

blow. It's like a military submarine that sends out decoys to throw

off an impending torpedo. As a result, HCV is able to successfully

replicate, or make copies of itself.

Because of its seemingly omnipotent nature, HCV can persist in the

body for decades after an initial infection, sometimes causing so

much damage to a person's liver that their only option in the end is

a liver transplant operation.

Uncovering HCV's Resilience

So, why is the hepatitis C virus able to evade the immune system?

Scientists at two universities in Texas think they may have found

the answer. In a study published online in the journal The

Proceedings of the National Academy of Sciences,1 researchers

explain how HCV is able to shut down two key elements of the immune

response through a protein the virus uses called NS3/4A protease.

Essentially, HCV is able to circumvent the immune response by

preventing the production of signaling molecules in the immune

system, which signal other immune cells to go after foreign invaders

in the body.

In an additional paper,2 the same scientists described the process

by which the hepatitis virus blocks signaling molecules in the

immune system from calling up other immune system cells to launch an

attack against HCV. In the second study, the scientists showed that

certain liver cells allow HCV replication to occur due to an

abnormal inactivation of an immune system signaling molecule known

as retinoic acid-inducible gene I (RIG-I).

Blocking HCV Replication Through Medicine

This research comes on the heels of preliminary results of clinical

trials testing the effectiveness of medications that target HCV's

ability to circumvent an immune attack. It's been suggested that

these drugs called protease inhibitors block hepatitis C's ability

to make copies of itself once it infects the liver particularly by

blocking the virus' immune system evasion.3,4

The medications work similarly to protease inhibitors for HIV. Those

drugs block the activity of a protein that the AIDS virus uses to

make copies of itself.5

" At least one protease inhibitor has had extraordinary activity

against hepatitis C in human clinical trials, but we're going to

need to improve on it in a number of ways, including reducing the

potential for the virus to become resistant to it, " said Stanley

Lemon, MD, a senior author on the paper, and director of the

Hepatitis C Research Center at the University of Texas Medical

Branch at Galveston.

" A better understanding of how NS3/4A does its work in blocking the

immune response will help make that possible, " said Lemon, who is

also Professor and Dean of Medicine in the departments of

Microbiology & Immunology and Internal Medicine.

An 'Impressive' Drug in This Class

One experimental medication in this class has been named BILN 2061.6

The medication, given to patients orally, has shown an " impressive "

ability to reduce levels of the hepatitis C virus, according to

experts.7

Youla Tsantrizos, PhD, a senior research scientist at pharmaceutical

manufacturer Boehringer-Ingelheim, Ltd., wrote: " Oral administration

of BILN 2061 to patients infected with the hepatitis C genotype 1

virus resulted in an impressive reduction of viral RNA levels,

establishing proof-of-concept for HCV NS3 protease inhibitors as

therapeutic agents in humans. " 7

1. Foy E, Sumpter R Jr, Loo YM et al. Control of antiviral defenses

through hepatitis C virus disruption of retinoic acid-inducible gene-

I signaling. Proc Natl Acad Sci USA 2005 Feb 22;102(8):2986-91. Epub

2005 Feb 14.

2. Sumpter R Jr, Loo YM, Foy E et al. Regulating intracellular

antiviral defense and permissiveness to hepatitis C virus RNA

replication through a cellular RNA helicase, RIG-1. J Virol 2005

Mar;79(5):2689-99.

3. Lemon SM, Yi M, Li K. " Strong reasons make strong actions " – The

antiviral efficacy of NS3/4A protease inhibitors. Hepatology 2005

Feb 18;41(3):671-4. [Epub ahead of print].

4. Hinrichsen H, Benhamon Y, Wedemeyer H et al. Short-term antiviral

efficacy of BILN 2061, a hepatitis C virus serine protease

inhibitor, in hepatitis C genotype 1 patients. Gastroenterology 2004

Nov;127(5):1347-55.

5. AIDSInfo. U.S. Department of Health and Human Services (HHS).

Protease Inhibitors. Available at:

http://aidsinfo.nih.gov/other/cbrochure/english/cbrochure_en.html#05.

Accessed March 2, 2005.

6. Lamarre D, PC, M et al. An NS3 protease inhibitor

with antiviral effects in humans infected with hepatitis C virus.

Nature 2003 Nov 13;426(6963):186-9. Epub 2003 Oct 26.

7. Tsantrizos YS. The design of a potent inhibitor of the hepatitis

C virus NS3 protease: BILN 2061—from the NMR tube to the clinic.

Biopolymers 2004;76(4):309-23.

is a long-time health journalist and an editor for

Priority Healthcare. His credits include coverage of health news for

the website of Fox Television's The Health Network, and articles for

the New York Post and other consumer and trade publications.