Harvard researchers report having discovered a family of naturally occurringantiviral agents in human cells, a finding that may lead to better ways to prevent and treat influenza and other viral infections.In both human and mouse cells the flu-fighting proteinsprevented or slowed most virus particles from infecting cells at theearliest stage in the virus lifecycle. The anti-viral action happenssometime after the virus attaches itself to the cell and before itdelivers its pathogenic cargo.“We’ve uncovered the first-line defense in how our bodies fight theflu virus,” said Stephen Elledge, the Gregor Mendel professor ofgenetics and of medicine at Harvard Medical School (HMS) and a seniorgeneticist at Brigham and Women’s Hospital (BWH). “The protein isthere to stop the flu. Every cell has a constitutive immune responsethat is ready for the virus. If we get rid of that, the virus has aheyday.”“When we knocked the proteins out, we had more virus infection,” saidgeneticist Abraham Brass, an instructor in medicine at HMS and Massachusetts General Hospital (MGH), who led the study first as apostdoctoral fellow with Elledge and then in his ownlab at the Ragon Institute. “When we increased the proteins, we hadmore protection,” Brass said. The native antiviral defenders are also crucial after the cells areinfected, Brass and his co-authors found. In the cells, the proteinsaccounted for more than half of the protective effect of theinterferon immune response. Interferon orchestrates a large componentof the infection-fighting machinery.“Interferons gave the cells even more protection, but not if we tookaway the antiviral proteins,” Brass said. The study is publishedin today’s early on-line edition of the journal Cell.The potent interferon response is what makes people feel so sick whentheir bodies are fighting the flu or when receiving interferons astherapy. “If we can figure out ways to increase levels of thisprotein without interferon, we can potentially increase naturalresistance to some viruses without all the side effects of theinterferons,” Elledge said.In the study, the surprisingly versatile antiviral proteins protectedcells against several devastating human viruses-not only the currentinfluenza A strains including H1N1 and strains going back to the1930s, but also West Nile virus and dengue virus. While IFITM did notprotect against HIV or the hepatitis C virus, experiments suggestedthe protein may defend against others, including yellow fever virus.The researchers do not know how the antiviral proteins deflect thisvariety of viruses, which use different mechanisms of entry into thecell. The protein family, called interferon-inducible transmembraneproteins (IFITM), was first discovered 25 years ago as products ofone of the thousands of genes turned on by interferon. Since then,not much else has been discovered about the IFITM family. Versions ofthe IFITM genes are found in the genomes of many creatures, from fishto chickens to mice to people, suggesting the antiviral mechanism hasbeen working successfully for millions of years in protectingorganisms from viral infections.In Elledge’s lab, Brass began the study as a genetic screen to learnhow the body blocks the flu. The researchers had previously runsimilar screens with hepatitis C virus and with HIV. In the screen,the researchers used small interfering RNA to systematically knockdown one gene at a time by depleting the proteins the genes weretrying to make. Then they examined what effect each blocked gene hadon a cell’s response to influenza A virus.The screen revealed more than 120 genes with potential roles indifferent stages of infection. Four of those genes, when knockeddown, allowed for a robust increase in the infection of cells byinfluenza A virus. Of these four candidate “restriction factors,” theresearch team concentrated on the IFITM3 protein because of its knownlink to interferon and found two closely related proteins in theIFITM family with similar activity.The most distinctive property of the first-line IFITM3 defense is itspreventive action before the virus can fuse with the cell, saidco-author and virologist Michael Farzan, associate professor ofmicrobiology and molecular genetics at HMS and the New EnglandPrimate Research Center. “The virus is unable to make a protein inthe cell to counteract the IFITM proteins, because the cell isalready primed against the virus,” Farzan said. “To find somethingthat hits the flu and hits it so close to the entry stage of theviral life cycle is really interesting and unusual among viralrestriction factors.”The researchers have more questions than answers about how the IFITMrestriction factors actually work, but they are excited about therange of inquiry the discovery opens up. For example, variations inthe protein from person to person may explain differences in people’ssusceptibility to flu and other viral infections, as well as itsseverity, the researchers speculate.And if scientists can understand the mechanism of action, they may beable to design new therapies with even better antiviral actions. Theproteins themselves may be useful for defending against infections inanimals, like birds and pigs, which might prevent the emergence ofnew, potentially more dangerous influenza A strains.In another potential application, if IFITM3 has a role in the chickenembryos or canine cells used to make flu vaccines, inhibiting theproteins may speed up vaccine production, which has been an issuethis year with the manufacture of the H1N1 pandemic vaccine.The research was funded by the Howard Hughes Medical Institute, thePhillip T. and Susan M. Ragon Foundation, the National Institutes ofHealth, New England Regional Center of Excellence for Biodefense,Cancer Research UK the Wellcome Trust, and the Kay Kendall LeukaemiaFoundation. BWH and MGH have filed a U.S. patent application for thistechnology that relates to the identification and use of host factorsto modulate viral replication/growth.