Fwd: Learning How a Virus Evades the First Line of Immune Defense

July 2, 2004

Frank <califpacific wrote:

alternative_medicine_forum From: Frank Fri, 2 Jul 2004 05:00:30 -0700 (PDT) Learning How a Virus Evades the First Line of Immune Defensehttp://www.healthy.net/scr/news.asp?Id=9403Learning How a Virus Evades the First Line of ImmuneDefenseProvided by AScribe Newswire on 7/1/2004by Howard Hughes Medical InstituteBack to Healthy NewsxoCHEVY CHASE, Md., June 24 (AScribe Newswire) --Researchers have uncovered the first evidence that avirus can mutate to evade the body's first line ofimmune defense. The discovery may help explain whypeople with AIDS or others with compromised immunitymay suffer severe infections from viruses that theywould otherwise defeat.In studies published in the June 2004 issue of

thejournal Immunity, the researchers found that the mouseversion of cytomegalovirus (MCMV) is capable ofmutating to evade natural killer (NK) cells. NK cellsare major weapons of the innate immune system, thecomponent of the immune system that attacks infectionsfirst. This more generalized component of the immunesystem quickly springs into action to knock downinfections. In the process, it buys precious time forthe immune system's more specific second line ofdefense, known as acquired immunity, which must adaptand proliferate to target a particular invading virusor microorganism.Howard Hughes Medical Institute investigator Wayne M.Yokoyama at Washington University School of Medicinein St. Louis led the research group. Yokoyama and hiscolleagues collaborated with researchers from the Maxvon Pettenkoffer-Institute in Germany and theUniversity of Rijeka in Croatia. Although it has longbeen known that viruses

such as HIV can mutate toevade the immune system, those mutations permit thevirus to circumvent acquired immunity, said Yokoyama.Previous studies suggested that only RNA virusesunderwent mutation and escaped, rather than the DNAviruses, whose replication is believed to be lessprone to rapid mutation.In earlier studies with mice, Yokoyama and hiscolleagues had shown how MCMV triggers NK cells toattack and kill cells infected with the virus. Theydemonstrated that the virus makes a protein calledm157. The presence of this viral protein on thesurface of an infected cell allows NK cells torecognize and destroy it.In the experiments described in the Immunity article,the researchers exposed mice lacking an acquiredimmune system -- but with normal NK cells -- to MCMV.They discovered that although the mice survivedinitially, they died within several weeks ofinfection."That was a surprising finding,

and it raised manyquestions about what the virus was doing during thisperiod," said Yokoyama. "Our subsequent analysisrevealed that the viruses that grew out at three tofour weeks after infection were not the samegenetically as the ones that we put in."The researchers found that the MCMV virus thateventually overcame the innate immunity of the micehad developed mutations in the gene for m157 thatrendered the virus essentially "invisible" to NKcells.One question, however, was whether the mutant m157pre-existed in a small percentage of the viruses inthe initial infection or whether the virus producednew mutations as it replicated, said Yokoyama. To showthat the virus could, indeed, produce new mutations,the researchers infected mice with a viral culturethat they knew contained no mutant m157. They foundthat there were different m157 mutations in eachmouse, suggesting that mutations were

independentlydeveloping in each infected mouse, allowing theviruses to escape detection by NK cells."These findings strongly support the idea that thereare mutations that occur in the course of a singleinfection and these mutants escape immune control as aresult of selection pressure," said Yokoyama. "Webelieve this is a new concept because, although suchviral escape has been described before, it has been inRNA viruses, which have a high propensity formutation. Whereas, for double-stranded DNA virusessuch as CMV, it has been thought that the mutationfrequency was much lower.""The other important aspect of this work is that, tomy knowledge, this is the first example of a virusmutating to escape innate immunity," said Yokoyama.According to Yokoyama, the new findings may helpexplain why people with damaged acquired immunity --such as those with AIDS, autoimmune diseases ortransplant recipients who

are on immune-suppressingdrugs -- often suffer severe CMV infections."For example, AIDS patients with significantlydepressed CD4 T-cell counts often get severe CMVinfections, even though most people have had CMVinfections that do not cause such severe disease,"said Yokoyama. "As a physician, I've taken care ofmany of these patients, and it never dawned on me thatthere was something different about their virus thatcould produce such infections."Yokoyama also noted that transplant patientsfrequently develop CMV infections that may be due topresence of the virus in the transplanted organ. Hesaid the infections tend to occur about a month afterthe transplant.Given this clinical experience, Yokoyama and hiscolleagues now seek to extrapolate their findings tohuman CMV to determine whether the virus is undergoingthe same type of mutation to evade the innate immunesystem. Such findings in humans, he

said, could leadto new treatment strategies to combat viralinfections.The Howard Hughes Medical Institute was established in1953 by the aviator-industrialist. HHMI's principalmission is conducting basic biomedical research, whichit carries out in collaboration with more than 66universities, medical centers and other researchinstitutions throughout the United States. Its morethan 300 investigators, along with a scientific staffof more than 3,000, work at these institutions inHughes laboratories. The Institute also has aphilanthropic grants program that is strengtheningscience education and training, from elementary schoolthrough graduate and medical school. It also supportsthe work of biomedical researchers in many countriesaround the globe.HHMI is one of the largest philanthropies in theworld, with an endowment of more than $12 billion. Itsheadquarters are located in Chevy Chase, Md., justoutside