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Researchers discover how herpes tricks the immune system


Herpes viruses enter the body and hide away in cells, often re-emerging later to cause illnesses such as shingles, genital herpes and cancer. How these viruses evade the immune system remains poorly understood, but researchers at Washington University School of Medicine in St. Louis discovered that a mouse herpes virus uses molecules that mimic a cell’s own proteins to help thwart an immune attack.

The findings also suggest that a branch of the immune system known as the complement system may play a more important role in controlling herpes virus infections than previously thought. The study is published in the August issue of the journal Immunity.

"These findings reveal another molecular mechanism by which viruses evade the immune system," says study leader Herbert W. Virgin, M.D., Ph.D., professor of pathology and immunology and of molecular microbiology. "By targeting this viral protein or by manipulating the complement system, perhaps someday we can develop better treatments for herpes virus infections."

The complement system consists of about 20 different proteins that are transported in the bloodstream. When activated by certain disease-causing organisms, the proteins unite and collect on viruses or on the membranes of virus-infected cells and kill them by punching holes in the membranes. To help prevent the inadvertent and dangerous triggering of this complement reaction, healthy cells produce molecules known as regulators of complement activation (RCA).

Virgin’s team found that one type of herpes virus makes its own version of RCA to trick the immune system and evade destruction by complement, but that the RCA mimic proteins help the virus only during acute infection.

The researchers used a mouse virus called gamma-herpes virus 68 (gHV68), which is similar to Epstein Barr virus and the herpes virus that causes Kaposi’s sarcoma, a cancer that occurs in some people with immune deficiency. The team engineered a mutant strain of the mouse virus that lacked the RCA mimic protein. They compared the effects of the normal virus and the mutant virus on normal mice versus mice that lacked a key complement protein, C3.

The researchers found that viruses lacking an RCA mimic were far less virulent than the normal virus: It took 100 times more of the mutant virus to cause disease in healthy mice compared to normal virus. The mutant virus also grew 27 times slower than normal, and it failed to spread to other organs during acute infection. This showed that the RCA mimic proteins were necessary for the virus to thrive.

Next, the researchers tested the mutant virus in mice lacking C3. In this case, the mutant virus was just as virulent as normal viruses in normal mice. Without C3 in the infected animal, the virus did not need to disguise itself with RCA in order to thrive. This implies that, in normal mice, the mimic protein enabled the virus to escape detection by the complement system.

The investigators then explored the role of complement and RCA during persistent and chronic infections. Historically, scientists believed that the body uses the complement system only during the initial, or acute, phase of herpes virus infection. Chronic stages of infection, they thought, were fought by immune system components such as T cells, B cells and interferons.

Persistent infection occurs when the virus continues to replicate beyond the period of acute infection. It is most clearly seen when the immune system is seriously impaired. Latent infection occurs when the virus resides inactively in cells, but it can be reactivated to generate infectious virus.

The researchers found that while healthy mice infected with gHV68 rarely showed signs of persistent infection, this condition readily occurred in C3-deficient mice. This was evidence that complement helped control this phase of infection.

They also discovered that complement helps control latent infection. Using special tests that reactivate latent viruses, the team found that three to five times more virus could be reactivated in C3-deficient mice than in normal mice.

"Our findings explicitly show that complement plays a role during persistent and latent infection, and that was unexpected," says Virgin. "They also emphasize that we can’t study a viral protein during just one part of a virus’s life cycle and assume we understand the function of that protein. It’s important to look at it during all phases of infection."

Kapadia SB, Levine B, Speck SH, Virgin HW IV. Critical role of complement and viral evasion of complement in acute, persistent, and latent g-herpes virus infection. Immunity, 17, 1-20, August 2002.

Funding from the National Institute of Allergy and Infectious Diseases, the National Cancer Institute and a training grant from the Cancer Research Institute supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Darrell E. Ward | EurekAlert!
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