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Chronic Infections
Chronic hepatitis is a “smoldering” infection,
in which the body fails to clear the virus from all the infected
cells. What the body does do, however, is to unleash its killer
T cells in an attempt to clear the infection. However, for
reasons that are not entirely clear, the T cell response isn’t
vigorous enough to eliminate the infection. Indeed, the number
of HBV-specific T cells produced by these patients is 100
to 1000 fold lower than in patients who clear the infection.
This leads to a slow, progressive process in which the outnumbered
T cells are able to kill some of the infected hepatocytes,
but not enough of them to terminate the infection of a large
organ like the liver.
However, what they can do is continue killing... and that
sets the stage for the rest of the story.
The antiviral effect may be essentially unrecognizable,
but the cumulative destruction can lead to a serious condition
known as cirrhosis. Cirrhosis is caused by progressive destruction
and regeneration of hepatocytes, inflammation, and scarring.
“This terribly compromises the function of the liver
and shortens the life of the patient if the disease is severe,
and it can progress to cancer,” says Chisari.
The scar tissue impedes blood flow in the liver. The decreased
blood flow can then cause a number of other complications
to the body, including jaundice, which can be seen as a yellow
coloring of the eyes and skin because of the release of bile
into the bloodstream. Cirrhosis itself often kills chronically
infected patients, and even when it does not it can lead to
cancer of the liver.
Cancer is caused by the exposure of the liver to mutagens
released by the inflammatory cells and to an increased probability
of random point mutations due to the active regeneration spurred
on by the continual CTL activity.
"[People with chronic hepatitis] have a 100- to 200-fold
increased risk for developing liver cancer," says Chisari.
"By comparison, heavy smokers have a 10-fold higher risk
of developing lung cancer."
In all, 15 to 25 percent of people who are chronically infected
with HBV die from liver disease. In the United States, liver
diseases related to HBV infections claim about 5,000 lives
a year. Worldwide, this number is 1 million per year.
The situation is particularly dire for children. Nine out
of ten infants who are infected with HBV will suffer a chronic
infection, whereas only two to five percent of individuals
who are infected as adults will become chronically infected.
In fact, the CDC estimates that 20 to 30 percent of the 1.25
million Americans who are chronically infected with HBV were
infected as children.
A Less Vigorous Defense
HBV infections are more serious in chronically infected
patients because their immune systems mount a quantitatively
inadequate defense. That’s why infants are at a dramatically
increased risk of acquiring a chronic infection if they are
infected by their mothers through neonatal transmission when
their immune systems are immature. The virus establishes itself
in this immunologically immature population and tolerizes
them so that they will not make an adequate immune response.
When the viral infection spreads, so does the amount of
viral antigen in the blood. The immune system recognizes specific
antigens, or epitopes and uses this recognition as the basis
of a targeted attack. Chisari’s group first discovered
in the late 1980s that people who clear the infection make
a polyclonal, vigorous response to many different epitopes
from all the viral proteins.
"It’s a profound and effective immune response
directed at so many elements that mutational escape [is not
possible]," says Chisari.
In chronically infected patients, on the other hand, the
response is rather weak. Several years ago, Chisari looked
at the immune response in infected humans by comparing virus-specific
cytotoxic T cells with characteristics of the disease. When
he looked at the blood of chronically infected patients, Chisari
saw few cytotoxic T lymphocytes and the ones that were there
were specific for very few epitopes. This profound difference,
suggests Chisari, is the basis for chronic infection.
"Chronically infected patients develop an ineffective
immune response," he says. "If we can find some
way to boost this immune response that they are, in fact,
capable of making but are not, maybe they would then be cured."
Current treatment for chronic HBV involves taking antivirals,
which control but do not eliminate the infection. As soon
as the course of medicine is stopped, the HBV rebounds. Chisari
and his collaborators are now looking for ways to couple antiviral
therapy with immune stimulation.
The General Clinical Research Center
Significantly, Chisari carries out a number of his studies
at the General Clinical Research Center (GCRC), which he also
directs.
"If there is one thing you can do in this article,"
Chisari says to me, "bring the GCRC to the attention
of the TSRI faculty and postdoctoral fellows."
The GCRC is a TSRI-managed clinical research facility located
in the Green Hospital. The center is open to any TSRI-affiliated
investigator or postdoctoral fellow who is interested in clinical
studies involving humans, and it provides substantial financial
assistance for these studies by providing for the care, monitoring,
and testing of patients.
"[Investigators] don’t need to seek additional
funding to pay for the patient-related costs," says Chisari.
In fact, the GCRC enables TSRI investigators to determine
definitively the bearing of their discoveries on human biology.
It brings together basic scientists with physicians and nurses
who are trained to take care of patients and collect valuable
samples. The center has a laboratory, directed by TSRI Associate
Professor Daniel Salomon, that processes samples to stabilize
them for further study. The center also has a large database
to track samples and draws upon the talents of TSRI Professor
James Koziol, a biostatistician.
"It has been used very effectively by a number of TSRI
investigators and also by a large number of clinical investigators,"
says Chisari, who is the GCRC director. Associate Professor
Bruce Zuraw is associate director. Professor Ernest Beutler,
Chair of the Department of Molecular and Experimental Medicine,
is the principal investigator on the grant from the National
Institutes of Health, which provides the majority of the GCRC’s
funding and provides strict guidelines designed to protect
the rights and safety of patients in any human trial.
Any researcher who wishes to conduct a study in the GCRC
must submit a protocol to the TSRI Human Subjects Committee,
which is independent of the GCRC. This committee reviews the
safety, ethical, and human-protection aspects of the study.
If the protocol passes, it is then reviewed by the GCRC Scientific
Advisory Committee, which meets every month or so to evaluate
proposed studies for scientific merit.
Chisari notes that this procedure is supportive of scientists
while rigorously enforcing National Institutes of Health guidelines.
“Investigators who are using the GCRC will be alerted
to any risks and provided with education and guidance on how
they can be avoided,” he says.
TSRI researchers who are interested in using the facilities
establish a collaboration with a clinician who has admitting
privileges to the hospital, and the studies are carried out
by this licensed physician.
Investigators use the GCRC for a number of purposes, the
simplest of all being to safely obtain blood for their investigations.
The center tracks blood donors and screens all blood for HIV
and hepatitis B and C viruses.
A slightly more involved study might find a TSRI investigator
correlating some marker in blood or other bodily fluid with
the manifestation of a disease. The investigator might, for
instance, ask the doctors and nurses at the GCRC to conduct
clinical exams of a study group to monitor patients' progress,
at the same time as collecting samples. Clinical exams can
range from routine interviews and X-rays to magnetic resonance
imaging and spinal taps.
At the highest level, the GCRC provides a way to bring together
patients with diseases and conditions for which there is no
known cure with investigators who have potential therapies.
And during such clinical investigations, the center can monitor
the procedures for beneficial or adverse effects, drug levels
in the blood, pharmacokinetics, and toxicology.
"It could be an important outlet for chemists who make
small molecules they think could be important in the life
of a cell or the life of an organism," says Chisari.
"A treatment can be administered to the patient in the
setting of the GCRC once approval is obtained by [TSRI’s
Institutional Review Board] and by the U.S. Food and Drug
Administration."
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