A kinder, gentler war against hepatitis B.

Virologists have long known that cells called cytotoxic T lymphocytes (CTLs) battle viruses by latching onto an infected cell and delivering the kiss of death-an outburst of compounds that destroys both the cell and its infectious cargo.

Now, investigators are realizing that these immune cells may sometimes have a gentler bedside manner. In fighting the hepatitis B virus, for example, these lymphocytes appear to secrete compounds that provoke infected cells into destroying the viral molecules being produced inside them. This activity suppresses the infection without harming the infected cells.

"This appears to be a mechanism vertebrates have evolved to deal with infections without killing themselves," says Francis V. Chisari of the Scripps Research Institute in La Jolla, Calif.

For the last 2 decades, Chisari has studied how the immune system combats the hepatitis B virus. Though an effective vaccine for the virus exists, its distribution is limited and an estimated 300 million people worldwide are already infected. Since the virus infects liver cells called hepatocytes, these people face a significant risk of cancer or long-term liver damage, says Chisari.

Because it doesn't infect the mouse, the animal most widely used in biomedical research, hepatitis B virus has been a difficult infectious agent to study. To bypass the problem, Chisari and his colleagues have gradually added all the genes from the virus into the mouse genome. As if infected by hepatitis B itself, the liver cells of such a mouse turn into viral factories, producing new copies of the virus and secreting them into the animal's bloodstream. Working with these mice, Chisari, Luca G. Guidotti of Scripps, and their colleagues have recently discovered that they can completely eliminate the hepatitis B virus from a mouse's bloodstream by injecting CTLs that target the hepatocytes producing viral proteins.

Because the CTL injections killed only about 5 percent of the hepatocytes, the investigators began to suspect that CTLs do more than slay cells, says Chisari. His group then found that when CTLs recognize infected cells, they secrete two soluble compounds, tumor necrosis factor-alpha and interferon-gamma. These compounds diffuse through the liver and stimulate antiviral activity in distant liver cells.

Chisari's group has described the nature of that activity in several reports over the last few years, including articles in the Dec. 15, 1995 Proceedings of the National Academy of Sciences and the January Immunity.

In their first response, stimulated liver cells produce proteins that degrade the molecules that would make up hepatitis B's protective viral shells. Shortly afterward, these liver cells make proteins that interfere with the replication of the virus' genetic material. In order to create new viruses, some of the viral genes in the mice produce RNA, a molecule similar to DNA. The new liver proteins appear to destroy specifically the viral RNA.

Chisari contends that human liver cells may attempt to suppress hepatitis B in a similar manner. In addition to identifying the antiviral proteins produced by hepatocytes, his group would like to develop methods to stimulate the hepatocytes' antiviral response directly.

Chisari also suggests that what his group has learned about how CTLs confront hepatitis B may help researchers tackling other viruses, including the AIDS- causing HIV. "It gives us a little more information on how cytotoxic T cells can contribute to defense by causing cells themselves to become more resistant," agrees Barry T. Rouse, a viral immunologist at the University of Tennessee in Knoxville.