Study On Mechanism Of Geldanamycin Against Lethal Influenza Virus H5N1

Countless influenza A viruses circulate globally are among the leading globalinfectious causes of the highly morbidity and mortality in mammals, including humans. Inthe20th century, three novel virus strains emerged, causing the Spanish influenza (H1N1)in1918/1919, Asian influenza (H2N2) in1957, and Hong Kong influenza (H3N2) in1968,led to millions people death, and posed a great threat to human health all around the world.The first direct avian-to-human transmission of H5N1virus was observed in1997in HongKong,18people with confirmed infection,6of which died. Recent studies have alsoshowed that the A/Indonesia/5/2005avian A/H5N1influenza virus may require as few asfive amino acid substitutions, and the A/Vietnam/1203/2004A/H5N1influenza virusrequire four amino acid substitutions and reassortments, to become transmissible betweenferrets via respiratory droplets. These findings indicated that possibility of transmission ofH5N1viruses between animals, including humans. If accidentally or intentionally released,such a virus could precipitate a historically severe influenza pandemic.Hsp90inhibitorsblock certain transcription factors that are involved in the activation of innate immunesystem, inhibit replication of influenza virus in vitro.Here male C57BL/6mice were infected with10LD50of influenza viruses, andreceived geldanamycin or oseltamivir after infection2h.Survival rates indicated that themice treated with geldanamycin were significantly protected (93.3%protection rate,P<0.01) compared with oseltamivir treatment (53.3%protection rate) or mice receivedvehicle, and lost significantly less weight compared with the mice treat withvehicle(P<0.01) or oseltamivir (24.9%,0.01<P<0.05); Compared with infectednon-treated mice or oseltamivir administration, Histopathologic analysis of lungs showedthat treatment with geldanamycin can markedly reduce tissue injury; Analysis of viral loadfrom our study showed that viral load in geldanamycin-treated mice revealed a significantreductions on days2,4or7after infection compared with vehicle-treated (P<0.05)，andhad similar effect in inhibition of virus replication in mice treated with oseltamivir on days2,4and7. However, oseltamivir administration reduced more viral load compared withgeldanamycin treated on postinfection days4and7, and had obvious difference (0.01<P<0.05) were found between mice treated with oseltamivir and geldanamycin.Analysis of inflammatory response indicated that geldanamycinadministration markedlyinhibitedthe production of proinflammatory cytokines and accumulation of T cells in lung.These findings indicated that although geldanamycin administration reduced less viral loadthan oseltamivir administration, geldanamycin administration significantly enhanced thesurvival in mice, which may tell us that excessive inflammatory response mediated byinfluenza virus may be responsible for the high mortality. Taken together, our present datasuggested the potential use of Geldanamycin as a novel, highly effective anti-influenzavirus drug.