Since the first human case of H5N1 avian influenza virus infection was reported in 1997, this highly pathogenic virus has infected hundreds of people around the world and resulted in many deaths. The ability of H5N1 to cross species boundaries, and the presence of polymorphisms that enhance virulence, present challenges to developing clear strategies to prevent the pandemic spread of this highly pathogenic avian influenza (HPAI) virus. This review summarizes the current understanding of, and recent research on, the avian influenza H5N1 virus, including transmission, virulence, pathogenesis, clinical characteristics, treatment and prevention.
Abdelwhab E M and Hafez H M. 2011. An overview of the epidemic of highly pathogenic H5N1 avian influenza virus in Egypt: epidemiology and control challenges. Epidemiol Infect, 139: 647–657.
Ayora-Talavera G, Shelton H, Scull M A, Ren J, Jones I M, Pickles R J and Barclay W S. 2009. Mutations in H5N1 influenza virus hemagglutinin that confer binding to human tracheal airway epithelium. PLoS One, 4: e7836.
Baskin C R, Bielefeldt-Ohmann H, Tumpey T M, Sabourin P J, Long J P, Garcia-Sastre A, Tolnay A E, Albrecht R, Pyles J A, Olson P H, Aicher L D, Rosenzweig E R, Murali-Krishna K, Clark E A, Kotur M S, Fornek J L, Proll S, Palermo R E, Sabourin C L and Katze M G. 2009. Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus. Proc Natl Acad Sci U S A, 106: 3455–3460.
Beigel J H, Farrar J, Han A M, Hayden F G, Hyer R, de Jong M D, Lochindarat S, Nguyen T K, Nguyen T H, Tran T H, Nicoll A, Touch S, Yuen K Y and Writing Committee of the World Health Organization Consultation on Human Influenza A H. 2005. Avian influenza A (H5N1) infection in humans. N Engl J Med, 353: 1374–1385.
Bel M, Ocana-Macchi M, Liniger M, McCullough K C, Matrosovich M and Summerfield A. 2011. Efficient sensing of avian influenza viruses by porcine plasmacytoid dendritic cells. Viruses, 3: 312–330.
Bissel S J, Giles B M, Wang G, Olevian D C, Ross T M and Wiley C A. 2012. Acute murine H5N1 influenza A encephalitis. Brain Pathol, 22: 150–158.
Budimir N, Huckriede A, Meijerhof T, Boon L, Gostick E, Price D A, Wilschut J and de Haan A. 2012. Induction of heterosubtypic cross-protection against influenza by a whole inactivated virus vaccine: the role of viral membrane fusion activity. PLoS One, 7: e30898.
Cameron M J, Ran L, Xu L, Danesh A, Bermejo-Martin J F, Cameron C M, Muller M P, Gold W L, Richardson S E, Poutanen S M, Willey B M, DeVries M E, Fang Y, Seneviratne C, Bosinger S E, Persad D, Wilkinson P, Greller L D, Somogyi R, Humar A, Keshavjee S, Louie M, Loeb M B, Brunton J, McGeer A J, Canadian S R N and Kelvin D J. 2007. Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome. J Virol, 81: 8692–8706.
Cattoli G, Monne I, Fusaro A, Joannis T M, Lombin L H, Aly M M, Arafa A S, Sturm-Ramirez K M, Couacy-Hymann E, Awuni J A, Batawui K B, Awoume K A, Aplogan G L, Sow A, Ngangnou A C, El Nasri Hamza I M, Gamatie D, Dauphin G, Domenech J M and Capua I. 2009. Highly pathogenic avian influenza virus subtype H5N1 in Africa: a comprehensive phylogenetic analysis and molecular characterization of isolates. PLoS One, 4: e4842.
Cauthen A N, Swayne D E, Schultz-Cherry S, Perdue M L and Suarez D L. 2000. Continued circulation in China of highly pathogenic avian influenza viruses encoding the hemagglutinin gene associated with the 1997 H5N1 outbreak in poultry and humans. J Virol, 74.
Centers for Disease Control and Prevention. 1997. Isolation of avian influenza A(H5N1) viruses from humans—Hong Kong, May–December 1997. MMWR Morb Mortal Wkly Rep, 46: 1204–1207.
Chan M C, Cheung C Y, Chui W H, Tsao S W, Nicholls J M, Chan Y O, Chan R W, Long H T, Poon L L, Guan Y and Peiris J S. 2005. Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res, 6: 135.
Chan R W, Yuen K M, Yu W C, Ho C C, Nicholls J M, Peiris J S and Chan M C. 2010. Influenza H5N1 and H1N1 virus replication and innate immune responses in bronchial epithelial cells are influenced by the state of differentiation. PLoS One, 5: e8713.
Chan R W, Chan M C, Wong A C, Karamanska R, Dell A, Haslam S M, Sihoe A D, Chui W H, Triana-Baltzer G, Li Q, Peiris J S, Fang F and Nicholls J M. 2009. DAS181 inhibits H5N1 influenza virus infection of human lung tissues. Antimicrob Agents Chemother, 53: 3935–3941.
Chantratita W, Sukasem C, Kaewpongsri S, Srichunrusami C, Pairoj W, Thitithanyanont A, Chaichoune K, Ratanakron P, Songserm T, Damrongwatanapokin S and Landt O. 2008. Qualitative detection of avian influenza A (H5N1) viruses: a comparative evaluation of four real-time nucleic acid amplification methods. Mol Cell Probes, 22: 287–293.
Chen W, Calvo P A, Malide D, Gibbs J, Schubert U, Bacik I, Basta S, O’Neill R, Schickli J, Palese P, Henklein P, Bennink J R and Yewdell J W. 2001. A novel influenza A virus mitochondrial protein that induces cell death. Nat Med, 7: 1306–1312.
Cheung C L, Rayner J M, Smith G J, Wang P, Naipospos T S, Zhang J, Yuen K Y, Webster R G, Peiris J S, Guan Y and Chen H. 2006. Distribution of amantadine-resistant H5N1 avian influenza variants in Asia. J Infect Dis, 193: 1626–1629.
Chutinimitkul S, van Riel D, Munster V J, van den Brand J M, Rimmelzwaan G F, Kuiken T, Osterhaus A D, Fouchier R A and de Wit E. 2010. In vitro assessment of attachment pattern and replication efficiency of H5N1 influenza A viruses with altered receptor specificity. J Virol, 84: 6825–6833.
Clementi N, De Marco D, Mancini N, Solforosi L, Moreno G J, Gubareva L V, Mishin V, Di Pietro A, Vicenzi E, Siccardi A G, Clementi M and Burioni R. 2011. A human monoclonal antibody with neutralizing activity against highly divergent influenza subtypes. PLoS One, 6: e28001.
Conenello G M, Tisoncik J R, Rosenzweig E, Varga Z T, Palese P and Katze M G. 2011. A single N66S mutation in the PB1-F2 protein of influenza A virus increases virulence by inhibiting the early interferon response in vivo. J Virol, 85: 652–662.
Couch R B. 2000. Prevention and treatment of influenza. N Engl J Med, 343: 1778–1787.
Das A, Spackman E, Senne D, Pedersen J and Suarez D L. 2006. Development of an internal positive control for rapid diagnosis of avian influenza virus infections by real-time reverse transcription-PCR with lyophilized reagents. J Clin Microbiol, 44: 3065–3073.
de Jong M D and Hien T T. 2006. Avian influenza A (H5N1). J Clin Virol, 35: 2–13.
de Jong M D Bach V C, Phan T Q, Vo M H, Tran T T, Nguyen B H, Beld M, Le T P, Truong H K, Nguyen V V, Tran T H, Do Q H and Farrar J. 2005. Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma. N Engl J Med, 352: 686–691.
de Jong M D, Tran T T, Truong H K, Vo M H, Smith G J, Nguyen V C, Bach V C, Phan T Q, Do Q H, Guan Y, Peiris J S, Tran T H and Farrar J. 2005. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med, 353: 2667–2672.
de Jong M D, Simmons C P, Thanh T T, Hien V M, Smith G J, Chau T N, Hoang D M, Chau N V, Khanh T H, Dong V C, Qui P T, Cam B V, Ha do Q, Guan Y, Peiris J S, Chinh N T, Hien T T and Farrar J. 2006. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med, 12: 1203–1207.
Ding N, Chen Q, Zhang W, Ren S, Guo Y and Li Y. 2012. Structure-activity relationships of saponin derivatives: A series of entry inhibitors for highly pathogenic H5N1 influenza virus. Eur J Med Chem, 53C: 316–326.
Du N, Zhou J, Lin X, Zhang Y, Yang X, Wang Y and Shu Y. 2010. Differential activation of NK cells by influenza A pseudotype H5N1 and 1918 and 2009 pandemic H1N1 viruses. J Virol, 84: 7822–7831.
Du Q S, Wang S Q and Chou K C. 2007. Analogue inhibitors by modifying oseltamivir based on the crystal neuraminidase structure for treating drug-resistant H5N1 virus. Biochem Biophys Res Commun, 362: 525–531.
Duan L, Bahl J, Smith G J, Wang J, Vijaykrishna D, Zhang L J, Zhang J X, Li K S, Fan X H, Cheung C L, Huang K, Poon L L, Shortridge K F, Webster R G, Peiris J S, Chen H and Guan Y. 2008. The development and genetic diversity of H5N1 influenza virus in China, 1996–2006. Virology, 380: 243–254.
Fall I, Sanou A, Ngom G, Dieng M, Sankale A A and Ndoye M. 2006. Strangulated umbilical hernias in children. Pediatr Surg Int, 22: 233–235.
Fang J, Hao Q, Liu L, Li Y, Wu J, Huo X and Zhu Y. 2011. Epigenetic Changes Mediated by MicroRNA miR29 Activate Cyclooxygenase 2 and Lambda-1 Interferon Production during Viral Infection. J Virol, 86: 1010–1020.
Gabriel G, Dauber B, Wolff T, Planz O, Klenk H D and Stech J. 2005. The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proc Natl Acad Sci U S A, 102: 18590–18595.
Gambaryan A S, Tuzikov A B, Pazynina G V, Desheva J A, Bovin N V, Matrosovich M N and Klimov A I. 2008. 6-sulfo sialyl Lewis X is the common receptor determinant recognized by H5, H6, H7 and H9 influenza viruses of terrestrial poultry. Virol J, 5: 85.
Gao P, Watanabe S, Ito T, Goto H, Wells K, McGregor M, Cooley A J and Kawaoka Y. 1999. Biological heterogeneity, including systemic replication in mice, of H5N1 influenza A virus isolates from humans in Hong Kong. J Virol, 73: 3184–3189.
Gao Y, Zhang Y, Shinya K, Deng G, Jiang Y, Li Z, Guan Y, Tian G, Li Y, Shi J, Liu L, Zeng X, Bu Z, Xia X, Kawaoka Y and Chen H. 2009. Identification of amino acids in HA and PB2 critical for the transmission of H5N1 avian influenza viruses in a mammalian host. PLoS Pathog, 5: e1000709
Gill J R, Sheng Z M, Ely S F, Guinee D G, Beasley M B, Suh J, Deshpande C, Mollura D J, Morens D M, Bray M, Travis W D and Taubenberger J K. 2010. Pulmonary pathologic findings of fatal 2009 pandemic influenza A/H1N1 viral infections. Arch Pathol Lab Med, 134: 235–243.
Guan Y, Shortridge K F, Krauss S and Webster R G. 1999. Molecular characterization of H9N2 influenza viruses: were they the donors of the “internal” genes of H5N1 viruses in Hong Kong? Proc Natl Acad Sci U S A, 96: 9363–9367.
Guan Y, Peiris J S, Lipatov A S, Ellis T M, Dyrting K C, Krauss S, Zhang L J, Webster R G and Shortridge K F. 2002. Emergence of multiple genotypes of H5N1 avian influenza viruses in Hong Kong SAR. Proc Natl Acad Sci U S A, 99: 8950–8955.
Gutierrez R A, Sorn S, Nicholls J M and Buchy P. 2011. Eurasian Tree Sparrows, risk for H5N1 virus spread and human contamination through Buddhist ritual: an experimental approach. PLoS One, 6: e28609.
Hale B G, Kerry P S, Jackson D, Precious B L, Gray A, Killip M J, Randall R E and Russell R J. 2010. Structural insights into phosphoinositide 3-kinase activation by the influenza A virus NS1 protein. Proc Natl Acad Sci U S A, 107: 1954–1959.
Harvey R, Wheeler J X, Wallis C L, Robertson J S and Engelhardt O G. 2008. Quantitation of haemagglutinin in H5N1 influenza viruses reveals low haemagglutinin content of vaccine virus NIBRG-14 (H5N1). Vaccine, 26: 6550–6554.
Haye K, Burmakina S, Moran T, Garcia-Sastre A and Fernandez-Sesma A. 2009. The NS1 protein of a human influenza virus inhibits type I interferon production and the induction of antiviral responses in primary human dendritic and respiratory epithelial cells. J Virol, 83: 6849–6862.
Hoelscher M A, Garg S, Bangari D S, Belser J A, Lu X, Stephenson I, Bright R A, Katz J M, Mittal S K and Sambhara S. 2006. Development of adenoviral-vector-based pandemic influenza vaccine against antigenically distinct human H5N1 strains in mice. Lancet, 367: 475–481.
Hoffmann E, Stech J, Leneva I, Krauss S, Scholtissek C, Chin P S, Peiris M, Shortridge K F and Webster R G. 2000. Characterization of the influenza A virus gene pool in avian species in southern China: was H6N1 a derivative or a precursor of H5N1? J Virol, 74: 6309–6315.
Hsieh S M and Chang S C. 2006. Insufficient perforin expression in CD8+ T cells in response to hemagglutinin from avian influenza (H5N1) virus. J Immunol, 176: 4530–4533.
Hui D S. 2008. Review of clinical symptoms and spectrum in humans with influenza A/H5N1 infection. Respirology, 13Suppl 1: S10–13.
Imai H, Shinya K, Takano R, Kiso M, Muramoto Y, Sakabe S, Murakami S, Ito M, Yamada S, Le M T, Nidom C A, Sakai-Tagawa Y, Takahashi K, Omori Y, Noda T, Shimojima M, Kakugawa S, Goto H, Iwatsuki-Horimoto K, Horimoto T and Kawaoka Y. 2010. The HA and NS genes of human H5N1 influenza A virus contribute to high virulence in ferrets. PLoS Pathog, 6: e1001106.
Ito T, Couceiro J N, Kelm S, Baum L G, Krauss S, Castrucci M R, Donatelli I, Kida H, Paulson J C, Webster R G and Kawaoka Y. 1998. Molecular basis for the generation in pigs of influenza A viruses with pandemic potential. J Virol, 72: 7367–7373.
Jackson D, Hossain M J, Hickman D, Perez D R and Lamb R A. 2008. A new influenza virus virulence determinant: the NS1 protein four C-terminal residues modulate pathogenicity. Proc Natl Acad Sci U S A, 105: 4381–4386.
Jang H, Boltz D, Sturm-Ramirez K, Shepherd K R, Jiao Y, Webster R and Smeyne R J. 2009. Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc Natl Acad Sci U S A, 106: 14063–14068.
Jia D, Rahbar R, Chan R W, Lee S M, Chan M C, Wang B X, Baker D P, Sun B, Peiris J S, Nicholls J M and Fish E N. 2010. Influenza virus non-structural protein 1 (NS1) disrupts interferon signaling. PLoS One, 5: e13927.
Kandun I N, Tresnaningsih E, Purba W H, Lee V, Samaan G, Harun S, Soni E, Septiawati C, Setiawati T, Sariwati E and Wandra T. 2008. Factors associated with case fatality of human H5N1 virus infections in Indonesia: a case series. Lancet, 372: 744–749.
Kimble B, Nieto G R and Perez D R. 2010. Characterization of influenza virus sialic acid receptors in minor poultry species. Virol J, 7: 365.
Kongchanagul A, Suptawiwat O, Boonarkart C, Kitphati R, Puthavathana P, Uiprasertkul M and Auewarakul P. 2011. Decreased expression of surfactant protein D mRNA in human lungs in fatal cases of H5N1 avian influenza. J Med Virol, 83: 1410–1417.
Kuiken T, van den Brand J, van Riel D, Pantin-Jackwood M and Swayne D E. 2010. Comparative pathology of select agent influenza a virus infections. Vet Pathol, 47: 893–914.
Le Q M, Kiso M, Someya K, Sakai Y T, Nguyen T H, Nguyen K H, Pham N D, Ngyen H H, Yamada S, Muramoto Y, Horimoto T, Takada A, Goto H, Suzuki T, Suzuki Y and Kawaoka Y. 2005. Avian flu: isolation of drug-resistant H5N1 virus. Nature, 437: 1108.
Lee D C, Cheung C Y, Law A H, Mok C K, Peiris M and Lau A S. 2005. p38 mitogen-activated protein kinase-dependent hyperinduction of tumor necrosis factor alpha expression in response to avian influenza virus H5N1. J Virol, 79: 10147–10154.
Lee D C, Law A H, Hui K, Tam A H, Peiris J S and Lau A S. 2012. Interferon dysregulation and virus-induced cell death in avian influenza H5N1 virus infections. Hong Kong Med J, 18 Suppl 2: 12–16.
Lee S M, Gardy J L, Cheung C Y, Cheung T K, Hui K P, Ip N Y, Guan Y Hancock R E and Peiris J S. 2009. Systems-level comparison of host-responses elicited by avian H5N1 and seasonal H1N1 influenza viruses in primary human macrophages. PLoS One, 4: e8072.
Lei F and Shi W. 2011. Prospective of Genomics in Revealing Transmission, Reassortment and Evolution of Wildlife-Borne Avian Influenza A (H5N1) Viruses. Curr Genomics, 12: 466–474.
Li C, Hatta M, Nidom C A, Muramoto Y, Watanabe S, Neumann G and Kawaoka Y. 2010. Reassortment between avian H5N1 and human H3N2 influenza viruses creates hybrid viruses with substantial virulence. Proc Natl Acad Sci U S A, 107: 4687–4692.
Li K S, Guan Y and Wang J. 2004. Genesis of a highly pathogenic and potentially pandemic H5N1 Influenza virus in eastern Asia. Nature, 430: 209–213.
Li W, Wang G, Zhang H, Xin G, Zhang D, Zeng J, Chen X, Xu Y, Cui Y and Li K. 2010. Effects of NS1 variants of H5N1 influenza virus on interferon induction, TNFalpha response and p53 activity. Cell Mol Immunol, 7: 235–242.
Li W, Sun W, Liu L, Yang F, Li Y, Chen Y, Fang J, Zhang W, Wu J and Zhu Y. 2010. IL-32: a host proinflammatory factor against influenza viral replication is upregulated by aberrant epigenetic modifications during influenza A virus infection. J Immunol, 185: 5056–5065.
Li W, Yang F, Liu Y, Gong R, Liu L, Feng Y, Hu P, Sun W, Hao Q, Kang L, Wu J and Zhu Y. 2009. Negative feedback regulation of IL-32 production by iNOS activation in response to dsRNA or influenza virus infection. Eur J Immunol, 39: 1019–1024.
Li W, Liu Y, Mukhtar M M, Gong R, Pan Y, Rasool S T, Gao Y, Kang L, Hao Q, Peng G, Chen Y, Chen X, Wu J and Zhu Y. 2008. Activation of interleukin-32 pro-inflammatory pathway in response to influenza A virus infection. PLoS One, 3: e1985.
Lipatov A S Andreansky S, Webby R J, Hulse D J, Rehg J E, Krauss S, Perez D R, Doherty P C, Webster R G and Sangster M Y. 2005. Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: the role of cytokines and B- and T-cell responses. J Gen Virol, 86: 1121–1130.
Liu J, Xiao H, Lei F, Zhu Q, Qin K, Zhang X W, Zhang X L, Zhao D, Wang G, Feng Y, Ma J, Liu W, Wang J and Gao G F. 2005. Highly pathogenic H5N1 influenza virus infection in migratory birds. Science, 309: 1206.
Liu L, Cao Z, Chen J, Li R, Cao Y, Zhu C, Wu K, Wu J, Liu F and Zhu Y. 2012. Influenza A virus induces interleukin-27 through cyclooxygenase-2 and protein kinase A signaling. J Biol Chem, 287: 11899–11910.
Loeffelholz M J. 2010. Avian influenza A H5N1 virus. Clin Lab Med, 30: 1–20.
Loeffelholz M J. 2011. Avian Influenza (H5N1) Update: Role of the Clinical Microbiology Laboratory. Labmedicine, 42: 291–298.
Long J X, Peng D X, Liu Y L, Wu Y T and Liu X F. 2008. Virulence of H5N1 avian influenza virus enhanced by a 15-nucleotide deletion in the viral nonstructural gene. Virus Genes, 36: 471–478.
Lowen A C, Mubareka S, Steel J and Palese P. 2007. Influenza virus transmission is dependent on relative humidity and temperature. PLoS Pathog, 3: 1470–1476.
Luke J M, Simon G G, Soderholm J, Errett J S, August J T, Gale M, Jr., Hodgson C P and Williams J A. 2011. Coexpressed RIG-I agonist enhances humoral immune response to influenza virus DNA vaccine. J Virol, 85: 1370–1383.
Malaisree M, Rungrotmongkol T, Nunthaboot N, Aruksakunwong O, Intharathep P, Decha P, Sompornpisut P and Hannongbua S. 2009. Source of oseltamivir resistance in avian influenza H5N1 virus with the H274Y mutation. Amino Acids, 37: 725–732.
Manz B, Matrosovich M, Bovin N and Schwemmle M. 2010. A polymorphism in the hemagglutinin of the human isolate of a highly pathogenic H5N1 influenza virus determines organ tropism in mice. J Virol, 84: 8316–8321.
Medina R A and Garcia-Sastre A. 2011. Influenza A viruses: new research developments. Nat Rev Microbiol, 9: 590–603.
Mok C K, Lee D C, Cheung C Y, Peiris M and Lau A S. 2007. Differential onset of apoptosis in influenza A virus H5N1- and H1N1-infected human blood macrophages. J Gen Virol, 88: 1275–1280.
Mukhtar M M, Rasool S T, Song D, Zhu C, Hao Q, Zhu Y and Wu J. 2007. Origin of highly pathogenic H5N1 avian influenza virus in China and genetic characterization of donor and recipient viruses. J Gen Virol, 88: 3094–3099.
Munir M, Zohari S, Metreveli G, Baule C, Belak S and Berg M. 2011. Alleles A and B of non-structural protein 1 of avian influenza A viruses differentially inhibit beta interferon production in human and mink lung cells. J Gen Virol, 92: 2111–2121.
Nduati R, Richardson B A, John G, Mbori-Ngacha D, Mwatha A, Ndinya-Achola J, Bwayo J, Onyango F E and Kreiss J. 2001. Effect of breastfeeding on mortality among HIV-1 infected women: a randomised trial. Lancet, 357: 1651–1655.
Ndung’u T, Sepako E, McLane M F, Chand F, Bedi K, Gaseitsiwe S, Doualla-Bell F, Peter T, Thior I, Moyo S M, Gilbert P B, Novitsky V A and Essex M. 2006. HIV-1 subtype C in vitro growth and coreceptor utilization. Virology, 347: 247–260.
Nelson M I and Holmes E C. 2007. The evolution of epidemic influenza. Nat Rev Genet, 8: 196–205.
Nicholls J M, Bourne A J, Chen H, Guan Y and Peiris J S. 2007. Sialic acid receptor detection in the human respiratory tract: evidence for widespread distribution of potential binding sites for human and avian influenza viruses. Respir Res, 8: 73.
Nicholls J M, Chan M C, Chan W Y, Wong H K, Cheung C Y, Kwong D L, Wong M P, Chui W H, Poon L L, Tsao S W, Guan Y and Peiris J S. 2007. Tropism of avian influenza A (H5N1) in the upper and lower respiratory tract. Nat Med, 13: 147–149.
Noah D L, Hill H, Hines D, White E L and Wolff M C. 2009. Qualification of the hemagglutination inhibition assay in support of pandemic influenza vaccine licensure. Clin Vaccine Immunol, 16: 558–566.
Noda T, Sagara H, Yen A, Takada A, Kida H, Cheng R H and Kawaoka Y. 2006. Architecture of ribonucleoprotein complexes in influenza A virus particles. Nature, 439: 490–492.
Nolan T, Richmond P C, Formica N T, Hoschler K, Skeljo M V, Stoney T, McVernon J, Hartel G, Sawlwin D C, Bennet J, Ryan D, Basser R L and Zambon M C. 2008. Safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in infants and children. Vaccine, 26: 6383–6391.
Ohnishi K, Takahashi Y, Kono N, Nakajima N, Mizukoshi F, Misawa S, Yamamoto T, Mitsuki Y Y, Fu S, Hirayama N, Ohshima M, Ato M, Kageyama T, Odagiri T, Tashiro M, Kobayashi K, Itamura S and Tsunetsugu-Yokota Y. 2012. Newly established monoclonal antibodies for immunological detection of H5N1 influenza virus. Jpn J Infect Dis, 65: 19–27.
Park A W and Glass K. 2007. Dynamic patterns of avian and human influenza in east and southeast Asia. Lancet Infect Dis, 7: 543–548.
Peiris J S, de Jong M D and Guan Y. 2007. Avian influenza virus (H5N1): a threat to human health. Clin Microbiol Rev, 20: 243–267.
Peiris J S, Hui K P and Yen H L. 2010. Host response to influenza virus: protection versus immunopathology. Curr Opin Immunol, 22: 475–481.
Peiris J S, Cheung C Y, Leung C Y and Nicholls J M. 2009. Innate immune responses to influenza A H5N1: friend or foe? Trends Immunol, 30: 574–584.
Peiris M. 2006. Pathogenesis of avian flu H5N1 and SARS. Novartis Found Symp, 279: 56–60; discussion 60–55, 216–219.
Pfeiffer D U, Otte M J, Roland-Holst D, Inui K, Nguyen T and Zilberman D. 2011. Implications of global and regional patterns of highly pathogenic avian influenza virus H5N1 clades for risk management. Vet J, 190: 309–316.
Qin G, Mao H, Zheng J, Sia S F, Liu Y, Chan P L, Lam K T, Peiris J S, Lau Y L and Tu W. 2009. Phosphoantigen-expanded human gammadelta T cells display potent cytotoxicity against monocyte-derived macrophages infected with human and avian influenza viruses. J Infect Dis, 200: 858–865.
Qin G, Liu Y, Zheng J, Ng I H, Xiang Z, Lam K T, Mao H, Li H, Peiris J S, Lau Y L and Tu W. 2011. Type 1 responses of human Vgamma9Vdelta2 T cells to influenza A viruses. J Virol, 85: 10109–10116.
Ramos I, Bernal-Rubio D, Durham N, Belicha-Villanueva A, Lowen A C, Steel J and Fernandez-Sesma A. 2011. Effects of receptor binding specificity of avian influenza virus on the human innate immune response. J Virol, 85: 4421–4431.
Reperant L A, van de Bildt M W, van Amerongen G, Buehler D M, Osterhaus A D, Jenni-Eiermann S, Piersma T and Kuiken T. 2011. Highly pathogenic avian influenza virus H5N1 infection in a long-distance migrant shorebird under migratory and non-migratory states. PLoS One, 6: e27814.
Rimmelzwaan G F, Kuiken T, van Amerongen G, Bestebroer T M, Fouchier R A and Osterhaus A D. 2001. Pathogenesis of influenza A (H5N1) virus infection in a primate model. J Virol, 75: 6687–6691.
Robb N C and Fodor E. 2012. The accumulation of influenza A virus segment 7 spliced mRNAs is regulated by the NS1 protein. J Gen Virol, 93: 113–118.
Rockman S and Brown L. 2010. Pre-pandemic and pandemic influenza vaccines. Hum Vaccin, 6: 792–801.
Sambhara S and Poland G A. 2010. H5N1 Avian influenza: preventive and therapeutic strategies against a pandemic. Annu Rev Med, 61: 187–198.
Sandbulte M R, Boon A C, Webby R J and Riberdy J M. 2008. Analysis of cytokine secretion from human plasmacytoid dendritic cells infected with H5N1 or low-pathogenicity influenza viruses. Virology, 381: 22–28.
Seo S H, Hoffmann E and Webster R G. 2002. Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nat Med, 8: 950–954.
Shaw M, Arden N H and Maassab H F. 1992. New Aspect of Influenza Viruses. Clin Microbiol Rev, 5: 74–92.
Shu Y, Yu H and Li D. 2006. Lethal avian influenza A (H5N1) infection in a pregnant woman in Anhui Province, China. N Engl J Med, 354: 1421–1422.
Snelgrove R J, Godlee A and Hussell T. 2011. Airway immune homeostasis and implications for influenza-induced inflammation. Trends Immunol, 32: 328–334.
Stelzer-Braid S, Wong B, Robertson P, Lynch G W, Laurie K, Shaw R, Barr I, Selleck P W, Baleriola C, Escott R, Katsoulotos G and Rawlinson W D. 2008. A commercial ELISA detects high levels of human H5 antibody but cross-reacts with influenza A antibodies. J Clin Virol, 43: 241–243.
Stevens J, Blixt O, Tumpey T M, Taubenberger J K, Paulson J C and Wilson I A. 2006. Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science, 312: 404–410.
Stewart C R, Karpala A J, Lowther S, Lowenthal J W and Bean A G. 2011. Immunostimulatory motifs enhance antiviral siRNAs targeting highly pathogenic avian influenza H5N1. PLoS One, 6: 7.
Suarez D L. 2010. Avian influenza: our current understanding. Anim Health Res Rev, 11: 19–33.
Suarez D L and Schultz-Cherry S. 2000. Immunology of avian influenza virus: a review. Dev Comp Immunol, 24: 269–283.
Subbarao E K, London W and Murphy B R. 1993. A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol, 67: 1761–1764.
Subbarao K, Klimov A, Katz J, Regnery H, Lim W, Hall H, Perdue M, Swayne D, Bender C, Huang J, Hemphill M, Rowe T, Shaw M, Xu X, Fukuda K and Cox N. 1998. Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science, 279: 393–396.
Suksatu A, Sangsawad W, Thitithanyanont A, Smittipat N, Fukuda M M and Ubol S. 2009. Characteristics of stork feces-derived H5N1 viruses that are preferentially transmitted to primary human airway epithelial cells. Microbiol Immunol, 53: 675–684.
Sun Y, Li C, Shu Y, Ju X, Zou Z, Wang H, Rao S, Guo F, Liu H, Nan W, Zhao Y, Yan Y, Tang J, Zhao C, Yang P, Liu K, Wang S, Lu H, Li X, Tan L, Gao R, Song J, Gao X, Tian X, Qin Y, Xu K F, Li D, Jin N and Jiang C. 2012. Inhibition of autophagy ameliorates acute lung injury caused by avian influenza A H5N1 infection. Sci Signal, 5: ra16.
Szretter K J, Gangappa S, Lu X, Smith C, Shieh W J, Zaki S R, Sambhara S, Tumpey T M and Katz J M. 2007. Role of host cytokine responses in the pathogenesis of avian H5N1 influenza viruses in mice. J Virol, 81: 2736–2744.
Szretter K J, Gangappa S, Belser J A, Zeng H, Chen H, Matsuoka Y, Sambhara S, Swayne D E, Tumpey T M and Katz J M. 2009. Early control of H5N1 influenza virus replication by the type I interferon response in mice. J Virol, 83: 5825–5834.
Tafforeau L, Chantier T, Pradezynski F, Pellet J, Mangeot P E, Vidalain P O, Andre P, Rabourdin-Combe C and Lotteau V. 2011. Generation and comprehensive analysis of an influenza virus polymerase cellular interaction network. J Virol, 85: 13010–13018.
Thanh T T, van Doorn H R and de Jong M D. 2008. Human H5N1 influenza: current insight into pathogenesis. Int J Biochem Cell Biol, 40: 2671–2674.
Thiry E, Zicola A, Addie D, Egberink H, Hartmann K, Lutz H, Poulet H and Horzinek M C. 2007. Highly pathogenic avian influenza H5N1 virus in cats and other carnivores. Vet Microbiol, 122: 25–31.
Tolnay A E, Baskin C R, Tumpey T M, Sabourin P J, Sabourin C L, Long J P, Pyles J A, Albrecht R A, Garcia-Sastre A, Katze M G and Bielefeldt-Ohmann H. 2010. Extrapulmonary tissue responses in cynomolgus macaques (Macaca fascicularis) infected with highly pathogenic avian influenza A (H5N1) virus. Arch Virol, 155: 905–914.
Tu W, Zheng J, Liu Y, Sia S F, Liu M, Qin G, Ng I H, Xiang Z, Lam K T, Peiris J S and Lau Y L. 2011. The aminobisphosphonate pamidronate controls influenza pathogenesis by expanding a gammadelta T cell population in humanized mice. J Exp Med, 208: 1511–1522.
Ungchusak K, Auewarakul P, Dowell S F, Kitphati R, Auwanit W, Puthavathana P, Uiprasertkul M, Boonnak K, Pittayawonganon C, Cox N J, Zaki S R, Thawatsupha P, Chittaganpitch M, Khontong R, Simmerman J M and Chunsutthiwat S. 2005. Probable person-to-person transmission of avian influenza A (H5N1). N Engl J Med, 352: 333–340.
Van Kerkhove M D, Mumford E, Mounts A W, Bresee J, Ly S, Bridges C B and Otte J. 2011. Highly pathogenic avian influenza (H5N1): pathways of exposure at the animal-human interface, a systematic review. PLoS One, 6: e14582.
van Riel D, Munster V J, de Wit E, Rimmelzwaan G F, Fouchier R A, Osterhaus A D and Kuiken T. 2006. H5N1 Virus Attachment to Lower Respiratory Tract. Science, 312: 399.
van Riel D, Munster V J, de Wit E, Rimmelzwaan G F, Fouchier R A, Osterhaus A D and Kuiken T. 2007. Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals. Am J Pathol, 171: 1215–1223.
Vandegrift K J, Sokolow S H, Daszak P and Kilpatrick A M. 2010. Ecology of avian influenza viruses in a changing world. Ann N Y Acad Sci, 1195: 113–128.
Wan H and Perez D R. 2006. Quail carry sialic acid receptors compatible with binding of avian and human influenza viruses. Virology, 346: 278–286.
Wang H and Jiang C. 2009. Avian influenza H5N1 an update on molecular pathogensis. Sci China C Life Sci, 52: 459–463.
Wang J, Oberley-Deegan R, Wang S, Nikrad M, Funk C J, Hartshorn K L and Mason R J. 2009. Differentiated human alveolar type II cells secrete antiviral IL-29 (IFN-lambda 1) in response to influenza A infection. J Immunol, 182: 1296–1304.
Wang S, Hackett A, Jia N, Zhang C, Zhang L, Parker C, Zhou A, Li J, Cao W C, Huang Z, Li Y and Lu S. 2011. Polyvalent DNA vaccines expressing HA antigens of H5N1 influenza viruses with an optimized leader sequence elicit cross-protective antibody responses. PLoS One, 6: e28757.
Wasilenko J L, Lee C W, Sarmento L, Spackman E, Kapczynski D R, Suarez D L and Pantin-Jackwood M J. 2008. NP, PB1 and PB2 viral genes contribute to altered replication of H5N1 avian influenza viruses in chickens. J Virol, 82: 4544–4553.
Watanabe Y, Ibrahim M S, Suzuki Y and Ikuta K. 2012. The changing nature of avian influenza A virus (H5N1). Trends Microbiol, 20: 11–20.
Webster R G, Bean W J, Gorman O T, Chambers T M and Kawaoka Y. 1992. Evolution and ecology of influenza A viruses. Microbiol Rev, 56: 152–179.
Wise H M, Foeglein A, Sun J, Dalton R M, Patel S, Howard W, Anderson E C, Barclay W S and Digard P. 2009. A complicated message: Identification of a novel PB1-related protein translated from influenza A virus segment 2 mRNA. J Virol, 83: 8021–8031.
Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) V. 2008. Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med, 358: 261–273.
Yu W C, Chan R W, Wang J, Travanty E A, Nicholls J M, Peiris J S, Mason R J and Chan M C. 2011. Viral replication and innate host responses in primary human alveolar epithelial cells and alveolar macrophages infected with influenza H5N1 and H1N1 viruses. J Virol, 85: 6844–6855.
Yuen K Y, Chan P K, Peiris M, Tsang D N, Que T L, Shortridge K F, Cheung P T, To W K, Ho E T, Sung R and Cheng A F. 1998. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet, 351: 467–471.
Zamarin D, Ortigoza M B and Palese P. 2006. Influenza A virus PB1-F2 protein contributes to viral pathogenesis in mice. J Virol, 80: 7976–7983.
Zamarin D, Garcia-Sastre A, Xiao X, Wang R and Palese P. 2005. Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog, 1: e4.
Zeng H, Goldsmith C, Thawatsupha P, Chittaganpitch M, Waicharoen S, Zaki S, Tumpey T M and Katz J M. 2007. Highly pathogenic avian influenza H5N1 viruses elicit an attenuated type i interferon response in polarized human bronchial epithelial cells. J Virol, 81: 12439–12449.
Zheng B J, Chan K W, Lin Y P, Zhao G Y, Chan C, Zhang H J, Chen H L, Wong S S, Lau S K, Woo P C, Chan K H, Jin D Y and Yuen K Y. 2008. Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus. Proc Natl Acad Sci U S A, 105: 8091–8096.
Zhu Q, Yang H, Chen W, Cao W, Zhong G, Jiao P, Deng G, Yu K, Yang C, Bu Z, Kawaoka Y and Chen H. 2008. A naturally occurring deletion in its NS gene contributes to the attenuation of an H5N1 swine influenza virus in chickens. J Virol, 82: 220–228.
Foundation items: National Natural Science Foundation of China (30979144 and 81271821).
Rights and permissions
About this article
Cite this article
Yin, J., Liu, S. & Zhu, Y. An overview of the highly pathogenic H5N1 influenza virus. Virol. Sin. 28, 3–15 (2013). https://doi.org/10.1007/s12250-013-3294-9
- Avian influenza