Learning How a Virus Evades the First Line of Immune Defense

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Learning How a Virus Evades the First Line of Immune

Defense

Provided by AScribe Newswire on 7/1/2004

by Howard Hughes Medical Institute

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CHEVY CHASE, Md., June 24 (AScribe Newswire) --

Researchers have uncovered the first evidence that a

virus can mutate to evade the body's first line of

immune defense. The discovery may help explain why

people with AIDS or others with compromised immunity

may suffer severe infections from viruses that they

would otherwise defeat.

 

In studies published in the June 2004 issue of the

journal Immunity, the researchers found that the mouse

version of cytomegalovirus (MCMV) is capable of

mutating to evade natural killer (NK) cells. NK cells

are major weapons of the innate immune system, the

component of the immune system that attacks infections

first. This more generalized component of the immune

system quickly springs into action to knock down

infections. In the process, it buys precious time for

the immune system's more specific second line of

defense, known as acquired immunity, which must adapt

and proliferate to target a particular invading virus

or microorganism.

 

Howard Hughes Medical Institute investigator Wayne M.

Yokoyama at Washington University School of Medicine

in St. Louis led the research group. Yokoyama and his

colleagues collaborated with researchers from the Max

von Pettenkoffer-Institute in Germany and the

University of Rijeka in Croatia. Although it has long

been known that viruses such as HIV can mutate to

evade the immune system, those mutations permit the

virus to circumvent acquired immunity, said Yokoyama.

Previous studies suggested that only RNA viruses

underwent mutation and escaped, rather than the DNA

viruses, whose replication is believed to be less

prone to rapid mutation.

 

In earlier studies with mice, Yokoyama and his

colleagues had shown how MCMV triggers NK cells to

attack and kill cells infected with the virus. They

demonstrated that the virus makes a protein called

m157. The presence of this viral protein on the

surface of an infected cell allows NK cells to

recognize and destroy it.

 

In the experiments described in the Immunity article,

the researchers exposed mice lacking an acquired

immune system -- but with normal NK cells -- to MCMV.

They discovered that although the mice survived

initially, they died within several weeks of

infection.

 

" That was a surprising finding, and it raised many

questions about what the virus was doing during this

period, " said Yokoyama. " Our subsequent analysis

revealed that the viruses that grew out at three to

four weeks after infection were not the same

genetically as the ones that we put in. "

 

The researchers found that the MCMV virus that

eventually overcame the innate immunity of the mice

had developed mutations in the gene for m157 that

rendered the virus essentially " invisible " to NK

cells.

 

One question, however, was whether the mutant m157

pre-existed in a small percentage of the viruses in

the initial infection or whether the virus produced

new mutations as it replicated, said Yokoyama. To show

that the virus could, indeed, produce new mutations,

the researchers infected mice with a viral culture

that they knew contained no mutant m157. They found

that there were different m157 mutations in each

mouse, suggesting that mutations were independently

developing in each infected mouse, allowing the

viruses to escape detection by NK cells.

 

" These findings strongly support the idea that there

are mutations that occur in the course of a single

infection and these mutants escape immune control as a

result of selection pressure, " said Yokoyama. " We

believe this is a new concept because, although such

viral escape has been described before, it has been in

RNA viruses, which have a high propensity for

mutation. Whereas, for double-stranded DNA viruses

such as CMV, it has been thought that the mutation

frequency was much lower. "

 

" The other important aspect of this work is that, to

my knowledge, this is the first example of a virus

mutating to escape innate immunity, " said Yokoyama.

 

According to Yokoyama, the new findings may help

explain why people with damaged acquired immunity --

such as those with AIDS, autoimmune diseases or

transplant recipients who are on immune-suppressing

drugs -- often suffer severe CMV infections.

 

" For example, AIDS patients with significantly

depressed CD4 T-cell counts often get severe CMV

infections, even though most people have had CMV

infections that do not cause such severe disease, "

said Yokoyama. " As a physician, I've taken care of

many of these patients, and it never dawned on me that

there was something different about their virus that

could produce such infections. "

 

Yokoyama also noted that transplant patients

frequently develop CMV infections that may be due to

presence of the virus in the transplanted organ. He

said the infections tend to occur about a month after

the transplant.

 

Given this clinical experience, Yokoyama and his

colleagues now seek to extrapolate their findings to

human CMV to determine whether the virus is undergoing

the same type of mutation to evade the innate immune

system. Such findings in humans, he said, could lead

to new treatment strategies to combat viral

infections.

 

The Howard Hughes Medical Institute was established in

1953 by the aviator-industrialist. HHMI's principal

mission is conducting basic biomedical research, which

it carries out in collaboration with more than 66

universities, medical centers and other research

institutions throughout the United States. Its more

than 300 investigators, along with a scientific staff

of more than 3,000, work at these institutions in

Hughes laboratories. The Institute also has a

philanthropic grants program that is strengthening

science education and training, from elementary school

through graduate and medical school. It also supports

the work of biomedical researchers in many countries

around the globe.

 

HHMI is one of the largest philanthropies in the

world, with an endowment of more than $12 billion. Its

headquarters are located in Chevy Chase, Md., just

outside Washington, D.C.

 

MEDIA CONTACT:

 

Jim Keeley, Howard Hughes Medical Institiute,

301-215-8858; keeleyj

 

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