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A viral cloaking device
Date:7/18/2008

evolved to evade T cells by keeping MHC from reaching the cell surface. In turn, the immune system recruited other hunters to search for cells that don't show MHC proteins.

Sometime along its treacherous evolutionary path, HCMV stole a class 1 MHC molecule from its host and modified it for supreme stealth. "This is a decoy," Bjorkman says. She and Yang analyzed the structure of the mimic, called UL18, to compare how similar it is to the real thing. They found that despite a mere 23 percent match in genetic sequences, UL18 looks almost exactly the same as a true class 1 MHC.

The same immune cells that search for missing MHC proteins are designed to bind to them when they find them, thereby inhibiting an immune response. Yang and Bjorkman found that UL18 happens to bind 1,000 times tighter to these inhibitory receptors than real MHC molecules do. "This is exactly what the virus wants--to avoid being recognized by T cells, but to engage inhibitory receptors to turn off immune cells," Yang notes. "Only a small number of UL18 molecules are required to have the same inhibitory effect as a large number of MHC class I molecules."

"What I find astounding is that the virus stole this gene and kept it almost identical but improved upon its binding," Bjorkman says.

UL18 didn't stop there. "It also binds peptides--that's unique to this MHC mimic. We don't know why," Bjorkman adds. The peptide is obscured from killer cells by yet another shield, Yang says. In a trait it shares with HIV proteins, HCMV's UL18 covers itself with carbohydrates, which are unrecognizable to the immune system. A real class 1 MHC molecule has one site for adding carbohydrates; the fake has 13, Bjorkman notes. The only place where it's not covered is where it binds to the inhibitory receptor.

All its efforts have made UL18 virtually undetectable. "It's a good example of a viral protein that evolved from its host ancestor to block unwanted interactions," Yang sa
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Contact: Elisabeth Nadin
enadin@caltech.edu
626-395-3631
California Institute of Technology
Source:Eurekalert

Page: 1 2 3

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