Many viruses possess mechanisms to evade the immune system. Forexample, HIV mutates so much that the immune system can't quiteget a handle on it.
Researchers from Seattle have discovered that among the methodsused by cytomegalovirus (CMV) includes one that protects a singleviral protein from the efforts of the immune system.
"This is a very novel mechanism which is selective for a specificprotein," said assistant professor Mark Gilbert, of the University ofWashington-Seattle and the Fred Hutchinson Cancer Research Centerand lead author of the study that appeared in the Oct. 24 Nature. And,it is a mechanism that Gilbert said could open up new avenues ingene therapy.
In some areas of the country 90 percent of people have been infectedwith CMV, usually when the were children. Unlike cold viruses, forinstance, CMV sets up a latent infection and becomes a permanentresident once it has infected a person. Usually, the virus staysinactive, but it is always lurking about waiting for an opportunity toreactivate should the immune system begin to falter. This is the casein AIDS patients: it causes blindness and those who have had bonemarrow transplants are susceptible to CMV pneumonia.
In order to remain as a latent infection, CMV had to become a realpro at circumventing the eradication efforts of the immune system.The immune system identifies infected cells after these cells degradesome viral protein into small pieces and load those pieces ontoantigen presenting molecules called MHC1. Several CMV geneshave been found that specifically prevent CMV peptides from beingloaded onto MHC1. Other viral genes shut down all MHC1 activity.
Most of these genes are expressed late in the virus life cycle. But, inorder to evade the immune system, the virus must also avoid noticewhen it first infects a cell. Gilbert and colleagues identified just sucha mechanism.
The Seattle researchers found that a protein which is part of theinfecting viral particle called pp65 can render viral protein immunefrom degradation by the cell it infects. Pp65 adds phosphates onto theCMV early-immediate protein _ a vital virus protein. As a result, theimmediate early protein cannot be broken up into pieces that the cellscould present to the immune system as foreign invaders.
"For CMV, this mechanism prevents the immediate-early proteinfrom being presented," said Gilbert. "This may also be a method thatother viruses or even human cells use to avoid the immune system."
If this is the case, Gilbert speculated that it may offer a solution toone of the larger problems associated with attempts at gene therapy.Currently, when researchers try to introduce genes into T cells, theimmune system wipes those altered T cells out because they areproducing foreign protein.
"That has been a huge Achilles heel for gene therapy," said Gilbert."Potentially, we could use pp65 and the sequences found in [theimmediate-early protein] to protect other molecules frompresentation."
But Gilbert cautioned it is possible that such a method would onlywork for proteins that, like the immediate-early protein, are located inthe nucleus. He noted, "We really have little understanding of theprocessing that antigens undergo _ it is really a black box." n
-- Lisa Seachrist Washington Editor
(c) 1997 American Health Consultants. All rights reserved.