These changes probably took place thousands of years ago, yet actually fairly recently in terms of evolutionary time, said Lewis Lanier, PhD, UCSF professor of microbiology and immunology and senior author on the paper. When we first found the activating receptor that binds to the viral protein and destroys it, we thought, Why hasnt the virus evolved a way to get rid of this protein? Thats when we started to wonder if the receptor was an adaptation of the immune system to the arms war a counter attack to the virus ability to exploit the inhibitory response, he said.

In their research, the scientists used a panel of mutant viruses to identify a single gene responsible for the activating receptor in the MCMV-resistant mice strain. Mice lacking that single gene were no longer protected and were susceptible to the virus.

Most mice lack the gene that provides resistance to MCMV, so it is probably a relatively recent development, the scientists reason. They suspect the activating receptor evolved from the inhibitory receptor because the two proteins are about 95 percent identical.

The receptor is one of many, both inhibitory and activating, encoded by the Ly49 family of genes. Their functional counterparts in humans are called KIR (Killer cell Ig-like receptors). As in the Ly49 family in mice, the KIR receptor family has inhibitory receptors that recognize self molecules on normal host cells to prevent autoimmunity, and also deploy activating receptors, suggesting that the same strategy is operational in humans to counter viral infections. Besides smallpox and Epstein-Barr, the human cytomegalovirus is related to the herpesvirus that causes Kaposis sarcoma.

It had long seemed a paradox to researchers, Lanier says, that inhibitory and activating receptors could be so similar. With receptors involved in a
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Contact: Wallace Ravven
wravven@pubaff.ucsf.edu
415-476-2557
University of California - San Francisco
11-Apr-2002