Scientist show how viruses co-opt cell defenses to cause chronic infections likethose from HIV and Hepatitis B and C

October 11, 1999

Scientists at the University of California, San Francisco and the UCSF-affiliated San Francisco General Medical Center have developed a model to study at the cellular level how viruses like HIV and Hepatitis B and C evade and co-opt the defense strategies of the cells they invade to cause chronic infections.

In a study reported in the Proceedings of the National Academy of Sciences, a group led by Allan Lau, and Michael Yeung, scientists in the Department Of Pediatrics at UCSF, has shown that a virus can establish a persistent infection if it can overcome cell suicide, an important host defense. And they have shown that once the virus establishes a lasting presence in the host's cells, physiological changes begin. The cells grow more slowly and the virus becomes less infectious over time -- evidence of co-evolution for the virus and its host.

The discovery could lead to methods to find new antiviral agents, to boost the effectiveness of antiviral drugs - and possibly to end Hepatitis C and other persistent viral infections.

Most viral infections begin with a virulent phase straight out of science fiction: The virus invades and kills cells, the immune system mounts a response to keep it from invading further and the infected person suffers misery as a result. Some viruses later change their tactics from invader to dominator. The virus takes over part of the cell's machinery and dwells there, becoming a persistent infection. Persistent viral infections can continue for life and wreak slow havoc, as HIV does to the immune system and Hepatitis B and C do to the liver.

Now Lau, Yeung and their colleagues have taken a virulent, cell-killing virus and converted it to a persistently infective virus. They turned off the host cell's last-ditch defense mechanism, which normally attempts to stop the viral invasion by a process of programmed destruction called apoptosis -- cell suicide.

In the initial experiments that led to this model, Lau said, the scientists expected that suppressing cell suicide would allow the virus to produce more copies of itself and spread more effectively. "What we didn't expect was that this would cause the virus to become less of a killer, and to convert to a persistent infectious agent."

A persistent infection is "heaven" for a virus, Lau explained. It means that instead of being defeated by the immune system or killing its host, the organism has succeeded in invading a host that will live for a long time.

Lau is a UCSF associate professor of pediatrics who conducts research in the Moses Grossman Infectious Disease Laboratory at the UCSF-affiliated San Francisco General Hospital Medical Center. Yeung is an assistant research biologist with Lau's group. They study immune defenses against viral infection.

In two previous papers published in PNAS, they have described a dual role in antiviral control and apoptosis regulation for an enzyme in normal cells called PKR, a protein kinase activated by RNA.

The PKR gene produces this enzyme when it recognizes double-stranded RNA -- a sign that a virus has entered the cell, and a trigger for cell suicide to stop the virus from spreading through the host. PKR is a mediator of interferon antiviral activity and thus boosts cell immunity. Also it mediates the cell-killing action of tumor necrosis factor. Thus, Lau's group found, if PKR is over-produced, it plays a pivotal role in the steps that lead to apoptosis or programmed cell death. If PKR is suppressed in a cell, that delays cell death.

The scientists tested what would happen if they suppressed the action of PKR in a group of cells and exposed them to encephalitis-causing virus (EMCV). This is a virulent -- that is, rapidly spreading -- virus that normally takes over cellular machinery to make new copies of itself. When the host cell mounts a defense, programming its own death through apoptosis, the virus normally must move on to infect other cells, or to be killed by agents in the host's immune system.

In the PKR-suppressed cells in Lau's laboratory, EMCV changed its behavior. As long as apoptosis was delayed, the virus established itself as a parasite, living on in the cell where it would be safe from most immune system defenses.

As the scientists grew the cell-virus complex in laboratory dishes over time, they observed that the host cells also showed physiological changes, including slower growth. When the cells died, the virus infected other cells. However, over time, the virus became gradually less infectious -- that is, less effective at sending out copies of itself. Its success as a virus now was ensured by its ability to live without killing its host.

There are other viruses that have evolved strategies to foil cell suicide. Lau and Yeung postulate that some version of this strategy may be used by the viruses that cause Hepatitis B, Hepatitis C and AIDS as they become persistent infections. These deadly but chronic viruses may inhibit some step in the process that normally allows cells to recognize a viral invader by its double-stranded RNA and, with the mediation of PKR, to program cell suicide in response.

Lau said there are several potential practical applications of his team's discoveries about PKR. For example:Lau's and Yeung's co-authors on the article in the Proceedings of the National Academy of Sciences are Danny L. Chang and Randell E. Camantigue, both former UCSF research technicians now attending medical school elsewhere. The research was communicated to PNAS by J. Robert Lehman of Stanford University School of Medicine.

The research was supported in part by grants from Pasteur Merieux Connaught, the Rhone-Poulenc Group, France, and from the Department of Pediatrics, University of California, San Francisco.

The PNAS article is accompanied by a commentary, "PKR mediates virus-induced apoptosis: a new role for an old actor," by Randal J. Kaufman of the University of Michigan Medical Center.

University of California - San Francisco

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