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One of the first signs of trouble was a barking cough that resounded through a North Carolina farm in August 1998.Every pig in an operation of 2400 animalssickened, with symptoms similar to thosecaused by the human flu: high fever, poorappetite, and lethargy. Pregnant sowswere hit hardest, and almost 10% abortedtheir litters, says veterinary virologistGene Erickson of the Rollins AnimalDisease Diagnostic Laboratory inRaleigh. Many piglets that survived inutero were later born small and weak, andsome 50 sows died.

The culprit, a new strain of swine in-fluenza to which the animals had little im-munity, left veterinarians and virologistsalike puzzled. Although related flu strains in

birds, humans, and pigs outside NorthAmerica constantly evolve, only one in-fluenza subtype had sickened NorthAmerican pigs since 1930. That spell wassuddenly broken about 4 years ago, and aquick succession of new flu viruses has beensweeping through North Americas 100 mil-lion pigs ever since. This winter, for exam-

ple, up to 15% of the 4- to 7-week-oldpiglets on a large Minnesota farm died, eventhough their mothers had been vaccinatedagainst swine flu, says veterinary pathologistKurt Rossow of the University ofMinnesota, Twin Cities.

It seems that after years of stability, the North American swine flu virus has jumped onto an evolutionary fast track,churning out variants every year. Changesin animal husbandry, including increasedvaccination, may be spurring this evolu-tionary surge. And researchers say that theresulting slew of dramatically differentswine flu viruses could spell danger forhumans, too. The evolving swine flu in-creases the likelihood that a novel viruswill arise that is transmissible among hu-mans, says Richard Webby, a molecularvirologist at St. Jude Childrens ResearchHospital in Memphis, Tennessee.

Because people have no immunity tomany viruses from other species, strainsthat on rare occasions leap the species bar-rier can have deadly consequences (seesidebar, p. 1504). And pigs are consideredmixing vessels in which swine, avian,

and human influenza viruses mix andmatch. Scientists believe, for example, thatthe last two flu pandemics, or worldwideepidemics, in 1957 and 1968, occurredwhen avian flu and human flu virusesswapped genes in pigs, creating a new, hy-

brid virus that then spread to humans. Ineach case, the new virus appeared first inSoutheast Asia, then around the globe. The1918 Spanish flu, which claimed upwardof 40 million lives, may also have arisenfirst in pigs. We used to think that theonly important source of genetic change inswine influenza was in Southeast Asia,says Christopher Olsen, a molecular virol-ogist at the University of Wisconsin (UW),Madison. Now we need to look in ourown backyard for where the next pandemicmay appear.

Fortunately, the new pig strains that haveappeared in North America so far do not ap-

pear to readily infect humans. But re-searchers are sufficiently concerned thatthey are calling for increased surveillance of

both humans and pigs. Within the swine population, we now have a mammalian-

adapted virus that is extremely promiscu-

ous, says Webby, referring to the viruss proclivity to swap genes with avian andhuman flu influenza viruses. We could endup with a dangerous virus.

When pigs fly

Most genetic changes in the flu viruseshuman, pig, and birdare small and subtle

point mutations in the viruss RNA. Lesscommon but more alarming are sudden,wholesale changes that replace entire genesand are more likely to circumvent the im-mune system. This process, called geneticshift, is exactly what is now occurring in

North American pigs. Thus, the latest swineinfluenza virus is a curious hybrid: Thegenes that code for its coat proteins derivefrom classical swine influenza, but half ofits internal genes have been snatched wholefrom avian and human viruses.

The structure of the influenza virus lendsitself to such radical changes. The virus ismade of eight single-stranded segments ofRNA that together code for 10 proteins (seeillustration). If two or more different virusesinfect the same host cell, they can swap seg-

ments, creating new viral types.

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Changes on the farm may be fostering the evolution of the swine flu virusand if a dangerous new strain crossesback into humans, it could have deadly consequences

Chasing the Fickle Swine Flu

N e w s F o c u s

Crowd control. Changes in pig farming, including the rise of large farms, may be spurring theevolution of new swine flu viruses. CR

EDIT:MACDUFFEVERTON/CORBIS

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Most commonly, the virus swaps genesthat code for its two surface proteins:hemagglutinin (HA) and neuraminidase(NA). Both proteins spike off the virussouter coat, and HA initiates infection whenit binds to receptors on host cells. The im-mune system of the infected animal targetssites on these molecules. Therefore, a virus

with a novel HA can escape preexisting im-mune defenseshence the pig deaths.

Influenza viruses are named after theirHA and NA components, as in H1N1 orH3N2. Both human and swine influenzashave been historically limited to only a fewof these varieties. Birds, on the other hand,can be infected by every combination of theviruss 15 HA genes and nine NA genes,forming a vast global reservoir of virus. And

pigs have receptors for both human and birdflu virus, making them crock pots for newviral combinations.

The classical swine influenza virusdiscovered in 1931 is an H1N1 virus, relatedto the H1N1 that caused the 1918 pandemic.But in the past 5 years, a quick succession of

progeny, which now include at least threeadditional virus subtypes and four geno-types, have all but supplanted that classicalswine virus in North American pigs.

The first new virus, the one that struckthe North Carolina hogs in 1998, was anH3N2; in this case, genes had crossedfrom human viruses to pig viruses. By late1999, the novel viruses could be foundwherever there were pigs in North Americaand so were presumably spread by cross-country transport. Webby and St. Jude col-

league Robert Webster, together withOlsen and others at UW Madison, tracedthese viruses evolutions. They found bothdouble reassortant viruses, with humanand swine flu genes, and triple reassor-tants, containing genes from human,swine, and avian influenza viruses.

The avian flu genes may hold clues to theviruses evolution. They code for two of theviruss three polymerase proteins: PA andPB2. (A third polymerase, dubbed PB1,comes from either human or avian viruses,depending on the swine flu subtype.) Allthree polymerases are involved in viral repli-cation, and they tend to do a sloppy job, al-lowing countless errors to slip by.

Scientists suspect that these three import-ed polymerase genes form a viral platformthat Webby calls unnervingly adept at trig-gering change in the influenza genome. Infact, H3N2 has continued to change, acquir-ing a succession of HA genes derived fromthe human influenza viruses that circulatedseveral years previously. By 2000, Olsenslab had identified a new viral subtype, anH1N2 that is a combination of the classicalswine virus and the H3N2.

This seasons variant is an H1N1 with theinternal genes of an H3N2. Its HA gene, de-rived from the classical swine influenzavirus, appears to be rapidly mutating. Theamount of sequence divergence amongcertain 2001 isolates is as much as the dif-ference between classical H1N1 virusesisolated in the 1960s and those isolated in

the early 1990s, Webby reports. If enoughpoint mutations accumulate, that HA mole-cule could become unrecognizable to theimmune systems of both pigs and humans.

Pig pressures

As they seek to under-stand what upset thestatus quo in NorthAmerican swine, re-searchers have turnedto the environment.For North American

pigs, the environmenthas recently changeddramatically in twoways: herd size andvaccination practices.

In the past decade, big swine producershave gotten bigger,and many small pro-ducers have gone outof business. The per-centage of farms with5000 or more animalssurged from 18% in1993 to 53% in 2002,according to Rodger

Ott, an agriculturalstatistician at the National AgriculturalStatistics Service in Washington, D.C.Having more pigs under one roof makes itmore likely that a rogue virus can take hold.With a group of 5000 animals, if a novelvirus shows up, it will have more opportuni-ty to replicate and potentially spread than ina group of 100 pigs on a small farm,Rossow says. On the other hand, pigs in out-side pens, as is common on small farms, can

be exposed to the droppings of migratorywaterfowl, which may contain infectiousviruses; large-scale confinement agriculturemay prevent such exposure, points out LizWagstrom, director of veterinary science atthe National Pork Board in Clive, Iowa.

Another crucial change has been the re-cent wide-scale vaccination for swine in-fluenza. In less than a decade, vaccinationhas become the norm for breeding sows,which in turn pass their maternal antibod-ies on to their progeny. In 1995, swine fluvaccination was so new that the NationalSwine Survey conducted by the UnitedStates Department of Agriculture didnt

bother to assess its extent. In 2000, the

same survey showed that 44.1% of breed-ing females received a vaccine. Today,more than half of all sows are vaccinatedagainst both H1N1 and H3N2 viruses, saysRobyn Fleck, a veterinarian at Schering-Plough, one of the nations three producersof swine influenza vaccine. But the vac-cine is not protecting against all new

strains. Were seeing clinical disease invaccinated pigs, says Rossow. Flu is alsoshowing up in piglets thought to be pro-tected by maternal antibodies passed on

from vaccinated sows, such as those on theMinnesota farm.

Widespread vaccination may actuallybe selecting for new viral types. If vacci-nation develops populations with uniformimmunity to certain virus genotypes, sayH1N1 and H3N2, then other viral mutantswould be favored. Webby suggests thatthe combination of avian polymerasegenes generating errors in the genetic se-quence and immunologic pressure fromvaccination may be selecting for uniquevariants. However, he adds that the bene-fits of vaccination far outweigh this sideeffect. From a human perspective, reduc-ing the overall viral burden in pigsthrough vaccination is a plus. If you candecrease the amount of virus, you can re-duce the chances of interspecies transmis-sion, he says.

Schering-Plough veterinarian TerriWasmoen acknowledges that vaccinesmay be pressuring change. But she alsonotes that larger hog confinement opera-tions and more shipping from state to statemay play a role. We need epidemiological

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ILLUSTRATION:CARIN

CAIN

1 PB2

PB1

PA

HA

NP

NA

NA

(Helpsinitiateinfection)

(Binds toreceptorson host cells)

M

NS

2

3

4

5

6

7

8

Avianpolymerase

Avian or humanpolymerase

Avianpolymerase

Human orswineorigin

Swineorigin

Human orswine origin

Swine origin

HA

M2

New flus. The influenza viruses now found in North American pigs havegenes from both human and bird viruses.

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work to understand these issues,and there is no funding now,she says.

Breaking the species barrier

Although scientists know thatinfluenza viruses can jump thespecies barrier directly, such anevent has been seen as a rarity.

A review of the literature yieldsonly 18 cases of pure swine in-fluenza directly crossing into

people, says Olsen. But his worksuggests that many cases oftransmission may occur, thenfizzle out. Olsen tested 74 swinefarm owners, employees, theirfamily members, and veterinari-ans in rural Wisconsin for anti-

bodies to swine influenza andcompared the results to those for114 city folk in a study published last sum-mer in Emerging Infectious Disease .Seventeen of those routinely exposed to

pigs tested positive for the antibodies,whereas only one urban dweller did so.

Olsen and his colleagues have alsofound evidence that a novel H4N6 swinevirus isolated in pigs in Ontariowhich

probably came from local duckshas al-ready acquired genetic mutations thatgive it the potential to bind to human cellreceptors. Such an event could be cata-strophic, as humans have no immunity toH4 viruses. But getting into humans is

just the first step. To have pandemic po-tential, a new influenza virus must also beable to move easily from one person to

the next. No new virus from swine or birds, nor any hybrid created in pigs, hasbeen able to accomplish this since the1968 pandemic.

Even so, experts in both animal and hu-man health are beginning to call for in-creased surveillance to stop a new pan-demic before it starts. The World HealthOrganization (WHO) constantly scans theglobe for new strains of human influenza,which are used to make annual recommen-dations for next years vaccines. But thereis no systematic monitoring of [human]

populations where there may be inter-species transmission between humans,

birds, and pigs, says Carolyn BuxtonBridges, an epidemiologist at the U.S.Centers for Disease Control andPrevention in Atlanta.

In addition, we dont have any officialsurveillance system for swine influenza,says Sabrina Swenson, head of bovine and

porcine viruses at the National VeterinaryServices Laboratories in Ames, Iowa. Wehave to bring the human-health peopletogether with the veterinary-health people

because of concern that the viruses can

move to people. It would be nice to havesomething better defined, but its dependent

on funding, she says.Webster, who heads the WHO collabo-rating laboratory on animal influenza inMemphis, Tennessee, calls for the devel-opment of reagents to recognize every

possible influenza subtype and for a global

network for monitoring of ani-mal influenzas at the human-animal interface. If some-thing strange pops up inGeorgia or Washington state,do we have the reagents in

place to move quickly fromidentification to making a hu-man vaccine? he asks.

Last month, at a WHOmeeting to determine nextyears vaccine constituents,Webster presented his data onanimal influenza and urgedthe development of vaccinesfor every HA subtype, to beused as a first defense shouldan unusual virus appear in thehuman population. WHOagreed and is developing a

prioritized list of viral sub-types that it will send to all vaccine manu-facturers, urging preparedness for the next

pandemic. It wouldnt provide total pro-tection, but it could keep the virus fromkilling you, Webster says.

BERNICE WUETHRICH

Bernice Wuethrich is a science writer in theWashington, D.C., area.

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CREDIT:SETH

DIXONA

NDLAURAHAJA

BOSTON , MASSACHUSETTSMove over,Darwins finches. As examples of evolu-tion in action, few organisms are betterthan the AIDS virus. Researchers haveknown for nearly 20 years that the virusgains a huge evolutionary advantage bytargeting immune system cells that the

body sends out to defeat it. But thats justits most obvious trait. New studies present-ed here last month during the largest an-nual U.S. AIDS conference*provide freshinsights into how the virus has deftlyadapted to humans, hijacking, mimicking,and dodging defenses that otherwise mightkeep it at bay.

Few of these new findings capturedheadlines from the meeting, and some im-mediately kicked up controversies. But they

prompted a buzz among AIDS researchershere, many of whom have been trying totake the measure of this virus for 2 decades.Every new piece of evidence seems to pro-

duce new respect for HIVs Darwinianprowess. And some of these new insightsmay also uncover weaknesses in the virusshighly evolved modus operandi. Someyears from now, people will look back andsay These are the breakthroughs, pre-dicts David Ho, the chair of the meeting,who heads the Aaron Diamond AIDSResearch Center in New York City.

Evading innate immunity

HIV apparently has picked up clever tricksto get around an arm of the immune systemknown as innate immunity. Unlike themore refined adaptive immunity, which re-lies on white blood cells that learn to rec-ognize foreigners and then attack themwith exquisite precision, innate immunityuses natural killer cells, biochemicals,and cellular proteins that behave with more

brawn than brain. They take out wholeclasses of invaders with little discrimina-tion and no memory of what theyve done.

At the meeting, Paul Bieniasz, a virolo-gist who works at Aaron Diamond, report-

Escape Artist Par ExcellenceRecent findings are giving researchers new respect for HIVs Darwinian prowess in

evading the bodys immune defenses

Rapid response. Robert Webster (left) and Richard Webby work to tracethe dramatic evolution of swine flu in North America.

N E W S F O C U S

*10th Conference on Retroviruses andOpportunistic Infections, 10 to 14 February.

HIV