Scientists Probe How HCV Evades the Immune System
by John C. Martin
Article Date: 06-22-05

Scientists at Johns Hopkins University are probing deep into the workings of the
hepatitis C virus to better understand how it effectively evades the body's
immune system onslaught at the earliest stages of infection. Their findings are
published in a pair of studies this month.1,2

The findings could form the basis of an HCV vaccine in the future, the
investigators say.

Viral Evolution: Evading Immune Attack
In both studies, teams of scientists analyzed the virus' transition from acute
to chronic infection. During this phase, they say, it evolves, causing changes
in its genes as the immune system launches its attack. These changes weaken the
body's immune response, and at that moment, the virus' genes then revert back to
their original form.

These genetic changes are known as mutations. "In a newly infected person, the
virus may need to adopt new mutations to escape recognition by the immune
system's T cells, which fight infection, but it may need to lose the mutations
that had protected it in someone else," explained Stuart Ray, MD, an associate
professor of Medicine in the department of Infectious Diseases at Johns Hopkins
University, and the lead investigator of the second study.2 "Despite pressure to
change, the virus is always restoring its shape."

A Mostly Chronic Infection
Hepatitis C is believed to infect nearly 4 million Americans, of whom about
two-and-a-half million have chronic, or long-term, infection. Most infections
are caused by illegal injection drug use, experts say. But the per-year
infection rate has declined since the 1980s from about 240,000 to about 30,000
in 2003, the latest year from which statistics are available.

Symptoms that hint HCV may be present include jaundice, fatigue, darkly-colored
urine, abdominal pain, loss of appetite, and nausea.

Up to 20 percent of those with the disease may develop liver cirrhosis over 20
to 30 years and nearly three-quarters may develop chronic liver disease,
according to estimates. HCV is a leading indicator for liver transplantation in
this country.3

Solving a Viral Mystery
The Hopkins findings are believed to be the first description of the precise
gene changes in the virus that take place during the acute phase of infection,
when HCV initially escapes the body's defenses and establishes itself in the
body. It is at the point at which the chronic phase of the infection begins that
the immune system weakens and is no longer effectively able to fight off the
infection. While that is well known, the reasons underlying this were not, Ray
and his team wrote.

"Hepatitis C is extremely difficult to treat if it becomes chronic," said
infectious disease specialist Andrea Cox, MD, PhD, Assistant Professor of
Medicine at Hopkins and the lead author of the first study.1 "While
approximately 30 percent of patients have a strong enough immune response to rid
themselves of the virus during the acute phase, and current treatments are 90%
effective at treating any remaining acute infections, these treatments are only
50% effective against chronic infections, which otherwise persist for life and
can cause death."

Cox says the virus can change the structure of its genes very rapidly; it
possesses some 2 to 3 times more genetic variability than HIV, the virus whose
infection causes AIDS. It can also reproduce some 100 times faster than HIV, she
said. To compound that problem, there are generally few symptoms during the
acute phase of HCV infection, making it less likely that people will be
diagnosed early when it is easiest to treat.

Previously, scientists believed the hepatitis C virus changed its genes at
random. But these new studies revealed that the changes are pre-selected; that
is, they are made so that the genes can more effectively fend off an immune
attack. Once the immune system invasion subsides, the virus' genes revert to
their original state—known as the consensus sequence.

But that's not the whole story, Ray told Priority Healthcare. "It is also likely
that HCV uses other tools, like its ability to undermine the innate immune
response, to weaken support for the T cell response."

Genetic Mutation Analysis
In the study led by Ray, researchers isolated viral genes from a group of newly
infected patients, all of whom had been offered treatment. Each was taking part
in a larger, unrelated study of infectious diseases in IV drug users. One
patient self-recovered during the study, and the rest went on to chronic
infection.

Ray's team also collected blood samples from the patients to study the function
of their immune system cells during this initial, acute phase of infection. They
found that no changes in the genetic makeup of the virus had taken place in the
patient who eventually self-recovered. But, in contrast, there were many changes
in the viral genes in those who went on to chronic infection, the scientists
learned.

During the initial stages of infection, immune system T cells recognize the
hepatitis virus as foreign, which prompts the production of a protein known as
interferon gamma whose primary role is to alert many other immune system cells
to launch an attack. But Ray and his group noted that production of interferon
gamma had decreased in the patients who went on to chronic infection, indicating
that the immune system's ability to fight off the virus had weakened, mostly
likely in response to the virus' genetic changes.

Meanwhile, in the study headed by Cox, researchers had collected blood samples
for 22 chronically infected women who had contracted the virus nearly 30 years
ago by a tainted blood product. Using computer analysis, the researchers
compared the activity of each patient's immune system cells in the blood samples
against the genetic changes in the hepatitis C virus.

As in the Ray study, the researchers confirmed that changes in HCV RNA occurred
as a strategy to fight off an immune attack, and then the virus reverted to its
original genetic makeup.

New Therapeutic Strategy?
These findings could someday form the basis of a new vaccine against the virus,
the researchers point out. Said David Thomas, MD, a professor of Medicine at
Hopkins and an investigator in the Ray study: "If we can focus vaccine
development on the common genetic element in chronically infected patients, then
we may be able to make a more effective vaccine."

Such a vaccine would target the virus in its original, or preferred state prior
to its genetic immune-eluding changes that occur, Ray explained. It is in this
state that HCV can replicate more effectively. Thus, a vaccine that forces it to
move away from this preferred state by causing changes in its genes will make it
more difficult for the virus to replicate. "We believe that making immune escape
very costly for the virus [by making it difficult to make copies of itself] will
enhance the effectiveness of the vaccine," he said.

In the meantime, Ray says he and his colleagues want to better understand why
one-quarter of HCV-infected people spontaneously clear the virus during the
first year. "We think they probably have more "help" from CD4 cells, based on
studies of HCV-infected chimpanzees," he said.

1. Cox AL, Mosbruger T, Mao Q et al. Cellular immune selection with hepatitis C
virus persistence in humans. J Exp Med 2005 Jun 6;201(11):1741-52.
2. Ray SC, Fanning L, Wang XH, Netski DM, Kenny-Walsh E, Thomas DL. Divergent
and convergent evolution after a common-source outbreak of hepatitis C virus. J
Exp Med 2005 Jun 6;201(11):1753-9.
3. Centers for Disease Control and Prevention (CDC). Frequently Asked Questions
About Hepatitis C. Available at:
http://www.cdc.gov/ncidod/diseases/hepatitis/c/faq.htm#1a. Accessed June 15,
2005.





Sandra Tara Balduf (Ane)

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