La Jolla, CA. April 30, 1999 -- A study published in today's issue of Science by Drs. Luca G. Guidotti and Francis V. Chisari at The Scripps Research Institute (TSRI) demonstrates a new paradigm in viral immunology, namely that the immune system can cure viral infections without destroying the infected cells. Until now, scientists believed that viral clearance was due to the destruction of infected cells by cytotoxic T cells. But the article, "Viral Clearance Without Destruction of Infected Cells During Acute HBV Infection," demonstrates that nondestructive antiviral mechanisms can contribute to viral clearance by eliminating a virus from inside the cell without killing it.
According to Dr. Chisari, Professor, Department of Molecular and Experimental Medicine, and Director, General Clinical Research Center, "The immune system has evolved a defense mechanism that allows it to cure certain viral infections by instructing the infected cells to stop producing virus and to accelerate viral elimination. This appears to be a survival strategy to control infections of vital organs that would be destroyed if the only way to control the infection was to kill all of the infected cells."
Hepatitis B is one of the most common, serious infectious diseases in the world. More than 350 million people worldwide are chronic carriers of the virus (HBV) and it has infected 1-1.25 million Americans. The leading cause of liver cancer, the World Health Organization estimates that the infection leads to more than one million deaths every year. Each year approximately 300,000 people will become infected with the Hepatitis B virus. Although there is a safe and effective vaccine for the prevention of HBV, it is of no value to those already infected. While treatments are currently available for the infection, they have considerable limitations in terms of toxicity and long-term benefits.
In this study, the authors demonstrate that the DNA of the Hepatitis B virus disappears from the liver and the blood of acutely infected animals long before the onset of disease and the peak of T cell infiltration, suggesting that nondestructive antiviral mechanisms, triggered by inflammatory cytokines secreted by the first wave of inflammatory cells that enter the liver, contribute to clearance of the virus. According to Dr. Guidotti, these cytokines -- proteins that are secreted by cells of the immune system -- attach to receptors on infected cells and trigger them to purge themselves of the virus. This significant decrease in viral load reduces the number of cells that must be killed, thereby preserving the function of the organ while the virus is removed.
The scientific basis for the current study is the result of work conducted by Drs. Guidotti and Chisari over the past five years using a transgenic mouse model. In these experiments HBV replication was completely eliminated by inflammatory cytokines under conditions in which there was no injury to the liver.
Chisari commented, "If we can harness the curative function of the immune response in patients with chronic HBV, it may be possible to cure these patients. No treatments are available today either to trigger the production of cytokines or to deliver them to the livers of infected patients in sufficient quantities or in enough time for elimination. This work provides fundamental new insights into the immunological mechanisms of infection control."
The study was funded by the National Institutes of Health.
Journal
Science