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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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These two views of a section of a transgenic liver replicating the hepatitis B virus dramatically demonstrate how cytotoxic T lymphocytes (CTLs) control infection. The cells are stained for the viral core protein, and the abundant red splotches in the top section are evidence of widespread viral replication before CTLs are added. The bottom panel shows the same section after CTLs have been added. The dramatic disappearance of virus is due to the antiviral effect of interferon gamma produced by the CTLs after they recognize the virus in the liver.