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Perspectives on influenza evolution and the role of research

  • Heather L. Forrest (a1) and Robert G. Webster (a1) (a2)

Influenza is a highly contagious respiratory pathogen that continues to evolve and threaten both veterinary and human public health. Influenza A viruses are continually undergoing molecular changes through mutations, reassortment, and, in rare instances, recombination. While they generally cause benign enteric infection in their natural reservoir of wild aquatic birds, they can cause catastrophic and potentially lethal disease outbreaks in humans, domestic poultry, and pigs when they cross the host species barrier. The continuing circulation of highly pathogenic (HP) H5N1 influenza viruses in domestic poultry in parts of Eurasia and the emergence and global spread of pandemic H1N1 2009 are current examples of influenza evolution. The spread of both HP H5N1 and pandemic H1N1 to multiple hosts emphasizes the potential for continued evolution. In this review, we discuss the current understanding of influenza A virus structure and strategies of variation, with a specific focus on the HP H5N1 and pandemic H1N1 influenza viruses. Additionally, we attempt to identify the gaps in our knowledge of H5N1 and pandemic H1N1 influenza viruses. These gaps include (i) an understanding of the molecular determinants of influenza virus and the host that permit efficient transmissibility and pandemic potential, (ii) the urgent need for prospective surveillance in apparently healthy swine, (iii) the molecular determinants of high pathogenicity in poultry, pigs, and people, (iv) the genetic basis of host susceptibility, (v) antigenic variability, (vi) the use of vaccine to control influenza, (vii) the role of wild birds as the reservoir of highly pathogenic avian influenza, (viii) the problems with vaccines, (ix) seasonality, (x) co-infections, and (xi) anti-influenza drug resistance. Our failure to eradicate HP H5N1 globally and to explain why H5N1 does not transmit efficiently in humans while an H1N1 pandemic virus of swine origin spread globally in months are key examples that emphasize the critical need to bridge these knowledge gaps. Future directions in influenza research that will help us resolve each of the above-mentioned knowledge gaps include complete genomic and proteomic analysis of both the virus and the host with the prospect of designing new control strategies and the development of genetically resistant hosts.

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JrAldridge JR, Moseley CE, Boltz DA, Negovetich NJ, Reynolds C, Franks J, Brown SA, Doherty PC, Webster RG and Thomas PG (2009). TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proceedings of the National Academy of Sciences U S A 106: 53065311.
Alexander DJ (2000). A review of avian influenza in different bird species. Veterinary Microbiology 74: 313.
Alexander DJ (2007). An overview of the epidemiology of avian influenza. Vaccine 25: 56375644.
Barber MRW, Aldridge JR, Webster RG and Magor KE (2010). Association of RIG-I with innate immunity of ducks to influenza. Proceedings of the National Academy of Sciences U S A 107: 59135918.
Boni MF (2008). Vaccination and antigenic drift in influenza. Vaccine 26 (suppl. 3): C8C14.
Boni MF, Zhou Y, Taubenberger JK and Holmes EC (2008). Homologous recombination is very rare or absent in human influenza A virus. Journal of Virology 82: 48074811.
Boon AC, deBeauchamp J, Hollmann A, Luke J, Kotb M, Rowe S, Finkelstein D, Neale G, Lu L, Williams RW and Webby RJ (2009). Host genetic variation affects resistance to infection with a highly pathogenic H5N1 influenza A virus in mice. Journal of Virology 83: 1041710426.
Bourmakina SV and Garcia-Sastre A (2003). Reverse genetics studies on the filamentous morphology of influenza A virus. Journal of General Virology 84: 517527.
Brookes SM, Nunez A, Choudhury B, Matrosovich M, Essen SC, Clifford D, Slomka MJ, Kuntz-Simon G, Garcon F, Nash B, Hanna A, Heegaard PM, Quéguiner S, Chiapponi C, Bublot M, Garcia JM, Gardner R, Foni E, Loeffen W, Larsen L, Van Reeth K, Banks J, Irvine RM and Brown IH (2010). Replication, pathogenesis and transmission of Pandemic (H1N1) 2009 Virus in non-immune pigs. PLoS One 5: e9068.
Bush RM and Bender CA, Subbarao K, Cox NJ and Fitch WM (1999). Predicting the evolution of human influenza A. Science 286: 19211925.
Campitelli L, Ciccozzi M, Salemi M, Taglia F, Boros S, Donatelli I and Rezza G (2006). H5N1 influenza virus evolution: a comparison of different epidemics in birds and humans (1997–2004). Journal of General Virology 87: 955960.
Carrat F and Flahault A (2007). Influenza vaccine: the challenge of antigenic drift. Vaccine 25: 68526862.
Chen GL and Subbarao K (2009). Live attenuated vaccines for pandemic influenza. Current Topics in Microbiology and Immunology 333: 109132.
Chen H (2009). H5N1 avian influenza in China. Science in China. Series C, Life sciences 52: 419427.
Chen H, Deng G, Li Z, Tian G, Li Y, Jiao P, Zhang L, Liu Z, Webster RG and Yu K (2004). The evolution of H5N1 influenza viruses in ducks in southern China. Proceedings of the National Academy of Sciences USA 101: 1045210457.
Chen H, Smith GJ, Li KS, Wang J, Fan XH, Rayner JM, Vijaykrishna D, Zhang JX, Zhang LJ, Guo CT, Cheung CL, Xu KM, Duan L, Huang K, Qin K, Leung YH, Wu WL, Lu HR, Chen Y, Xia NS, Naipospos TS, Yuen KY, Hassan SS, Bahri S, Nguyen TD, Webster RG, Peiris JS and Guan Y (2006). Establishment of multiple sublineages of H5N1 influenza virus in Asia: implications for pandemic control. Proceedings of the National Academy of Sciences U S A 103: 28452850.
Chen W, Calvo PA, Malide D, Gibbs J, Schubert U, Bacik I, Basta S, O'Neill R, Schickli J, Palese P, Henklein P, Bennink JR and Yewdell JW (2001). A novel influenza A virus mitochondrial protein that induces cell death. Nature Medicine 7: 13061312.
Choi YK, Ozaki H, Webby RJ, Webster RG, Peiris JS, Poon L, Butt C, Leung YH and Guan Y (2004). Continuing evolution of H9N2 influenza viruses in Southeastern China. Journal of Virology 78: 86098614.
Dawood FS, Jain S, Finelli L, Shaw MW, Lindstrom S, Garten RJ, Gubareva LV, Xu X, Bridges CB and Uyeki TM (2009). Emergence of a novel swine-origin influenza A (H1N1) virus in humans. New England Journal of Medicine 360: 26052615.
de Jong JC, van Nieuwstadt AP, Kimman TG, Loeffen WL, Bestebroer TM, Bijlsma K, Verweij C, Osterhaus AD and Class EC (1999). Antigenic drift in swine influenza H3 haemagglutinins with implications for vaccination policy. Vaccine 17: 13211328.
Desselberger U, Racaniello VR, Zazra JJ and Palese P (1980). The 3′ and 5′-terminal sequences of influenza A, B and C virus RNA segments are highly conserved and show partial inverted complementarity. Gene 8: 315328.
Domenech J, Dauphin G, Rushton J, McGrane J, Lubroth J, Tripodi A, Gilbert J and Sims LD (2009). Experiences with vaccination in countries endemically infected with highly pathogenic avian influenza: the Food and Agriculture Organization perspective. Revue scientifique et technique (International Office of Epizootics) 28: 293305.
Dominguez-Cherit G, Lapinsky SE, Macias AE, Pinto R, Espinosa-Perez L, de la Torre A, Poblano-Morales M, Baltazar-Torres JA, Bautista E, Martinez A, Martinez MA, Rivero E, Valdez R, Ruiz-Palacios G, Hernández M, Stewart TE and Fowler RA (2009). Critically Ill patients with 2009 influenza A(H1N1) in Mexico. Journal of the American Medical Association 302: 18801887.
Duan L, Bahl J, Smith GJ, Wang J, Vijaykrishna D, Zhang LJ, Zhang JX, Li KS, Fan XH, Cheung CL, Huang K, Poon LL, Shortridge KF, Webster RG, Peiris JS, Chen H and Guan Y (2008). The development and genetic diversity of H5N1 influenza virus in China, 1996–2006. Virology 380: 243254.
Ellis TM, Bousfield RB, Bissett LA, Dyrting KC, Luk GS, Tsim ST, Sturm-Ramirez K, Webster RG, Guan Y and Malik Peiris JS (2004). Investigation of outbreaks of highly pathogenic H5N1 avian influenza in waterfowl and wild birds in Hong Kong in late 2002. Avian Pathology 33: 492505.
Ferguson NM, Galvani AP and Bush RM (2003). Ecological and immunological determinants of influenza evolution. Nature 422: 428433.
Fouchier RA, Osterhaus AD and Brown IH (2003). Animal influenza virus surveillance. Vaccine 21: 17541757.
Gack MU, Albrecht RA, Urano T, Inn KS, Huang IC, Carnero E, Farzan M, Inoue S, Jung JU and García-Sastre A (2009). Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe 5: 439449.
Garcia-Sastre A, Egorov A, Matassov D, Brandt S, Levy DE, Durbin JE, Palese P and Muster T (1998). Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 252: 324330.
Garman E and Laver G (2005). The Structure, Function, and Inhibition of Influenza Virus Neuraminidase. In: Fischer WB (ed.) Viral Membrane Proteins: Structure, Function, and Drug Design. New York: Plenum, pp. 247267.
Garten RJ, Davis CT, Russell CA, Shu B, Lindstrom S, Balish A, Sessions WM, Xu X, Skepner E, Deyde V, Okomo-Adhiambo M, Gubareva L, Barnes J, Smith CB, Emery SL, Hillman MJ, Rivailler P, Smagala J, de Graaf M, Burke DF, Fouchier RA, Pappas C, Alpuche-Aranda CM, López-Gatell H, Olivera H, López I, Myers CA, Faix D, Blair PJ, Yu C, Keene KM, JrDotson PD, Boxrud D, Sambol AR, Abid SH, St George K, Bannerman T, Moore AL, Stringer DJ, Blevins P, Demmler-Harrison GJ, Ginsberg M, Kriner P, Waterman S, Smole S, Guevara HF, Belongia EA, Clark PA, Beatrice ST, Donis R, Katz J, Finelli L, Bridges CB, Shaw M, Jernigan DB, Uyeki TM, Smith DJ, Klimov AI and Cox NJ (2009). Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 325: 197201.
Ghendon Y (1994). Introduction to pandemic influenza through history. European Journal of Epidemiology 10: 451453.
Gibbs JS, Malide D, Hornung F, Bennink JR and Yewdell JW (2003). The influenza A virus PB1-F2 protein targets the inner mitochondrial membrane via a predicted basic amphipathic helix that disrupts mitochondrial function. Journal of Virology 77: 72147224.
Gorman OT, Bean WJ and Webster RG (1992). Evolutionary processes in influenza viruses: divergence, rapid evolution, and stasis. Current Topics in Microbiology and Immunology 176: 7597.
Guan Y, Smith GJ, Webby R and Webster RG (2009). Molecular epidemiology of H5N1 avian influenza. Revue scientifique et technique (International Office of Epizootics) 28: 3947.
Guo YJ, Jin FG, Wang P, Wang M and Zhu JM (1983). Isolation of influenza C virus from pigs and experimental infection of pigs with influenza C virus. Journal of General Virology 64: 177182.
Harder TC and Vahlenkamp TW (2010). Influenza virus infections in dogs and cats. Veterinary Immunology and Immunopathology 134: 5460.
Hay AJ, Gregory V, Douglas AR and Lin YP (2001). The evolution of human influenza viruses. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 356: 18611870.
He CQ, Han GZ, Douglas AR and Lin YP (2008). Homologous recombination evidence in human and swine influenza A viruses. Virology 380: 1220.
He CQ, Xie ZX, Han GZ, Dong JB, Wang D, Liu JB, Ma LY, Tang XF, Liu XP, Pang YS and Li GR (2009). Homologous recombination as an evolutionary force in the avian influenza A virus. Molecular Biology and Evolution 26: 177187.
Hoffmann E, Stech J, Guan Y, Webster RG and Perez DR (2001). Universal primer set for the full-length amplification of all influenza A viruses. Archives of Virology 146: 22752289.
Horimoto T and Kawaoka Y (2001). Pandemic threat posed by avian influenza A viruses. Clinical Microbiology Reviews 14: 129149.
Iamnikova SS, Gambarian AS, Aristova VA, L'vov DK, Lomakina NF, Munster V, Lexmond P and Foucher RA (2009). A/H13 and A/H16 influenza viruses: different lines of one precursors. Voprosy Virusologii 54: 1018.
Kash JC, Tumpey TM, Proll SC, Carter V, Perwitasari O, Thomas MJ, Basler CF, Palese P, Taubenberger JK, García-Sastre A, Swayne DE and Katze MG (2006). Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature 443: 578581.
Kendal AP, Noble GR, Skehel JJ and Dowdle WR (1978). Antigenic similarity of influenza A (H1N1) viruses from epidemics in 1977–1978 to “Scandinavian” strains isolated in epidemics of 1950–1951. Virology 89: 632636.
Khatchikian D, Orlich M and Roitt R (1989). Increased viral pathogenicity after insertion of a 28S ribosomal RNA sequence into the haemagglutinin gene of an influenza virus. Nature 340: 156157.
Kim YH, Kim HS, Cho SH and Seo SH (2009). Influenza B virus causes milder pathogenesis and weaker inflammatory responses in ferrets than influenza A virus. Viral Immunology 22: 423430.
Kishida N, Sakoda Y, Eto M, Sunaga Y and Kida H (2004). Co-infection of Staphylococcus aureus or Haemophilus paragallinarum exacerbates H9N2 influenza A virus infection in chickens. Archives of Virology 149: 20952104.
Kobasa D, Jones SM, Shinya K, Kash JC, Copps J, Ebihara H, Hatta Y, Kim JH, Halfmann P, Hatta M, Feldmann F, Alimonti JB, Fernando L, Li Y, Katze MG, Feldmann H and Kawaoka Y (2007). Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445: 319323.
Lamb RA (1989). Genes and proteins of the influenza viruses. In: Krug RM, Fraenkel-Conrat H and Wagner RR (eds) The Influenza Viruses. New York: Plenum Press, pp. 188.
Lee JH, Pascua PN, Song MS, Baek YH, Kim CJ, Choi HW, Sung MH, Webby RJ, Webster RG, Poo H and Choi YK (2009). Isolation and genetic characterization of H5N2 influenza viruses from pigs in Korea. Journal of Virology 83: 42054215.
Li C, Yu K, Tian G, Yu D, Liu L, Jing B, Ping J and Chen H (2005). Evolution of H9N2 influenza viruses from domestic poultry in Mainland China. Virology 340: 7083.
Li KS, Xu KM, Peiris JS, Poon LL, Yu KZ, Yuen KY, Shortridge KF, Webster RG and Guan Y (2003). Characterization of H9 subtype influenza viruses from the ducks of southern China: a candidate for the next influenza pandemic in humans? Journal of Virology 77: 69886994.
Lipsitch M and Viboud C (2009). Influenza seasonality: lifting the fog. Proceedings of the National Academy of Sciences U S A 106: 36453646.
Makarova NV, Ozaki H, Kida H, Webster RG and Perez DR (2003). Replication and transmission of influenza viruses in Japanese quail. Virology 310: 815.
Peiris JS (2009). Avian influenza viruses in humans. Revue scientifique et technique (International Office of Epizootics) 28: 161173.
Manuguerra JC and Hannoun C (1992). Natural infection of dogs by influenza C virus. Research in Virology 143: 199204.
Manuguerra JC, Zientara S, Sailleau C, Rousseaux C, Gicquel B, Rijks I and van der Werf S (2000). Evidence for evolutionary stasis and genetic drift by genetic analysis of two equine influenza H3 viruses isolated in France. Veterinary Microbiology 74: 5970.
Matrosovich M, Stech J and Klenk HD (2009). Influenza receptors, polymerase and host range. Revue scientifique et technique (International Office of Epizootics) 28: 203217.
Matsuzaki Y, Katsushima N, Nagai Y, Shoji M, Itagaki T, Sakamoto M, Kitaoka S, Mizuta K and Nishimura H (2006). Clinical features of influenza C virus infection in children. Journal of Infectious Diseases 193: 12291235.
McCullers JA (2006). Insights into the interaction between influenza virus and pneumococcus. Clinical Microbiology Reviews 19: 571582.
McHardy AC and Adams B (2009). The role of genomics in tracking the evolution of influenza A virus. PLoS Pathogens 5: e1000566.
Mehle A and Doudna JA (2009). Adaptive strategies of the influenza virus polymerase for replication in humans. Proceedings of the National Academy of Sciences USA 106: 2131221316.
Monto AS (2003). The role of antivirals in the control of influenza. Vaccine 21: 17961800.
Monto AS (2008). Epidemiology of influenza. Vaccine 26 (suppl. 4): D45D48.
Morens DM, Taubenberger JK and Fauci AS (2009). The persistent legacy of the 1918 influenza virus. New England Journal of Medicine 361: 225229.
Munster VJ and Fouchier RA (2009). Avian influenza virus: of virus and bird ecology. Vaccine 27: 6340–5344.
Myers KP, Olsen CW and Gray GC (2007). Cases of swine influenza in humans: a review of the literature. Clinical Infectious Diseases 44: 10841088.
Nelson MI and Holmes EC (2007). The evolution of epidemic influenza. Nature Reviews Genetics 8: 196205.
Neumann G, Noda T and Kawaoka Y (2009). Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 459: 931939.
Nielsen O, Clavijo A and Broughen JA (2001). Serologic evidence of influenza A infection in marine mammals of arctic Canada. Journal of Wildlife Diseases 37: 820825.
Nobusawa E, Aoyama T, Kato H, Suzuki Y, Tateno Y and Nakajima K (1991). Comparison of complete amino acid sequences and receptor-binding properties among 13 serotypes of hemagglutinins of influenza A viruses. Virology 182: 475485.
O'Neill RE, Talon J and Palese P (1998). The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins. EMBO Journal 17: 288296.
Olsen SJ, Ungchusak K, Sovann L, Uyeki TM, Dowell SF, Cox NJ, Aldis W and Chunsuttiwat S (2005). Family clustering of avian influenza A (H5N1). Emerging Infectious Diseases 11: 17991801.
Orlich M, Gottwald H and Rott R (1994). Nonhomologous recombination between the hemagglutinin gene and the nucleoprotein gene of an influenza virus. Virology 204: 462465.
Osterhaus AD, Rimmelzwaan GF, Martina BE, Bestebroer TM and Fouchier RA (2000). Influenza B virus in seals. Science 288: 10511053.
Palese P and Young JF (1982). Variation of influenza A, B, and C viruses. Science 215: 14681474.
Peiris JS, Cheung CY, Leung CY and Nicholls JM (2009). Innate immune responses to influenza A H5N1: friend or foe? Trends in Immunology 30: 574584.
Peiris JS, de Jong MD and Guan Y (2007). Avian influenza virus (H5N1): a threat to human health. Clinical Microbiology Reviews 20: 243267.
Perez-Padilla R, de la Rosa-Zamboni D, Ponce de Leon S, Hernandez M, Quiñones-Falconi F, Bautista E, Ramirez-Venegas A, Rojas-Serrano J, Ormsby CE, Corrales A, Higuera A, Mondragon E, Cordova-Villalobos JA; INER Working Group on Influenza (2009). Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico. New England Journal of Medicine 361: 680689.
Portela A and Digard P (2002). The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication. Journal of General Virology 83: 723734.
Rappuoli R, Medini D, Siena E, Budroni S, Dormitzer PR and Del Giudice G (2010). Building an insurance against modern pandemics. Current Opinion in Investigational Drugs 11: 126130.
Reed C, Angulo FJ, Swerdlow DL, Lipsitch M, Meltzer MI, Jernigan D and Finelli L (2009). Estimates of the prevalence of pandemic (H1N1) 2009, United States, April-July 2009. Emerging Infectious Diseases 15: 20042007.
Reid AH and Taubenberger JK (2003). The origin of the 1918 pandemic influenza virus: a continuing enigma. Journal of General Virology 84: 22852292.
Reperant LA, Rimmelzwaan GF and Kuiken T (2009). Avian influenza viruses in mammals. Revue scientifique et technique (International Office of Epizootics) 28: 137159.
Russell RJ, Kerry PS, Stevens DJ, Steinhauer DA, Martin SR, Gamblin SJ and Skehel JJ (2008). Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion. Proceedings of the National Academy of Sciences USA 105: 1773617741.
Salomon R, Staeheli P, Kochs G, Yen HL, Franks J, Rehg JE, Webster RG and Hoffmann E (2007). Mx1 gene protects mice against the highly lethal human H5N1 influenza virus. Cell Cycle 6: 24172421.
Salzberg SL, Kingsford C, Cattoli G, Spiro DJ, Janies DA, Aly MM, Brown IH, Couacy-Hymann E, De Mia GM, Dung do H, Guercio A, Joannis T, Maken Ali AS, Osmani A, Padalino I, Saad MD, Savić V, Sengamalay NA, Yingst S, Zaborsky J, Zorman-Rojs O, Ghedin E and Capua I (2007). Genome analysis linking recent European and African influenza (H5N1) viruses. Emerging Infectious Diseases 13: 713718.
Scholtissek C (1979). The genes coding for the surface glycoproteins of influenza A viruses contain a small conserved and a large variable region. Virology 93: 594597.
Scholtissek C (1990). Pigs as ‘mixing vessels’ for the creation of new pandemic influenza A viruses. Medical Principles and Practice 2: 6571.
Smith DJ, Lapedes AS, de Jong JC, Bestebroer TM, Rimmelzwaan GF, Osterhaus AD and Fouchier RA (2004). Mapping the antigenic and genetic evolution of influenza virus. Science 305: 371376.
Smith FI and Palese P (1989). Variation in influenza virus genes. In: Krug RM (ed.) The Influenza Viruses. New York: Plenum Press, pp. 319359.
Smith GJ, Bahl J, Vijaykrishna D, Zhang J, Poon LL, Chen H, Webster RG, Peiris JS and Guan Y (2009a). Dating the emergence of pandemic influenza viruses. Proceedings of the National Academy of Sciences USA 106: 1170911712.
Smith GJ, Vijaykrishna D, Bahl J, Lycett SJ, Worobey M, Pybus OG, Ma SK, Cheung CL, Raghwani J, Bhatt S, Peiris JS, Guan Y and Rambaut A (2009b). Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature 459: 11221125.
Sponseller BA, Strait E, Jergens A, Trujillo J, Harmon K, Koster L, Jenkins-Moore M, Killian M, Swenson S, Bender H, Waller K, Miles K, Pearce T, Yoon KJ and Nara P (2010). Influenza A pandemic (H1N1) 2009 virus infection in domestic cat. Emerging Infectious Diseases 16: 534537.
Suarez DL, Senne DA, Banks J, Brown IH, Essen SC, Lee CW, Manvell RJ, Mathieu-Benson C, Moreno V, Pedersen JC, Panigrahy B, Rojas H, Spackman E and Alexander DJ (2004). Recombination resulting in virulence shift in avian influenza outbreak, Chile. Emerging Infectious Diseases 10: 693699.
Swayne DE and Kapczynski DR (2008). Vaccines, vaccination, and immunology for avian influenza viruses in poultry. In: Swayne DE (ed.) Avian influenza. Ames: Blackwell Publishing, pp. 407451.
Swayne DE and Pantin-Jackwood M (2008). Pathobiology of avian influenza virus infections in birds and mammals. In: Swayne DE (ed.) Avian Influenza. Ames: Blackwell Publishing, pp. 87122.
Swayne DE and Suarez DL (2000). Highly pathogenic avian influenza. Revue scientifique et technique (International Office of Epizootics) 19: 463482.
Taubenberger JK, Hultin JV and Morins DM (2007). Discovery and characterization of the 1918 pandemic influenza virus in historical context. Antiviral Therapy 12 (4 Pt B): 581591.
Taubenberger JK and Morens DM (2006). 1918 Influenza: the mother of all pandemics. Emerging Infectious Diseases 12: 1522.
Taubenberger JK, Reid AH, Krafft AE, Bijwaard KE and Fanning TG (1997). Initial genetic characterization of the 1918 “Spanish” influenza virus. Science 275: 17931796.
Treanor J (2004). Influenza vaccine–outmaneuvering antigenic shift and drift. New England Journal of Medicine 350: 218220.
Tumpey TM, Basler CF, Van Hoeven N, Katz JM, Kochs G, Haller O, García-Sastre A and Staeheli P (2005). Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 310: 7780.
Tumpey TM, Szretter KJ, Van Hoeven N, Katz JM, Kochs G, Haller O, García-Sastre A and Staeheli P (2007). The Mx1 gene protects mice against the pandemic 1918 and highly lethal human H5N1 influenza viruses. Journal of Virology 81: 1081810821.
Van Reeth K (2007). Avian and swine influenza viruses: our current understanding of the zoonotic risk. Veterinary Research 38: 243260.
Vijaykrishna D, Bahl J, Riley S, Duan L, Zhang JX, Chen H, Peiris JS, Smith GJ and Guan Y (2008). Evolutionary dynamics and emergence of panzootic H5N1 influenza viruses. PLoS Pathogens 4: e1000161.
Wan H, Sorrell EM, Song H, Hossain MJ, Ramirez-Nieto G, Monne I, Stevens J, Cattoli G, Capua I, Chen LM, Donis RO, Busch J, Paulson JC, Brockwell C, Webby R, Blanco J, Al-Natour MQ and Perez DR (2008). Replication and transmission of H9N2 influenza viruses in ferrets: evaluation of pandemic potential. PLoS One 3: e2923.
Webster RG (2004). Wet markets – a continuing source of severe acute respiratory syndrome and influenza? Lancet 363: 234236.
Webster RG, Bean WJ, Gorman OT, Chambers TM and Kawaoka Y (1992). Evolution and ecology of influenza A viruses. Microbiological Reviews 56: 152179.
Webster RG and Hulse DJ (2004). Microbial adaptation and change: avian influenza. Revue scientifique et technique (International Office of Epizootics) 23: 453465.
Webster RG, Peiris M, Chen H and Guan Y (2006). H5N1 outbreaks and enzootic influenza. Emerging Infectious Diseases 12: 38.
White NJ, Webster RG, Govorkova EA and Uyeki TM (2009). What is the optimal therapy for patients with H5N1 influenza? PLoS Medicine 6: e1000091.
WHO (2009). Continuing progress towards a unified nomenclature system for the highly pathogenic H5N1 avian influenza viruses. Available online at
WHO (2010a). Recommendations for Influenza Vaccines. Available online at
WHO (2010b). Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO. Available online at
WHO/OIE/FAO (2008). Toward a unified nomenclature system for highly pathogenic avian influenza virus (H5N1). Emerging Infectious Diseases 14: e1.
Wimmer E, Mueller S, Tumpey TM and Taubenberger JK (2009). Synthetic viruses: a new opportunity to understand and prevent viral disease. Nature Biotechnology 27: 11631172.
Wolf YI, Viboud C, Holmes EC, Koonin EV and Lipman DJ (2006). Long intervals of stasis punctuated by bursts of positive selection in the seasonal evolution of influenza A virus. Biology Direct 1: 34.
Wuethrich B (2003). Infectious disease. An avian flu jumps to people. Science 299: 1504.
Xu KM, Li KS, Smith GJ, Li JW, Tai H, Zhang JX, Webster RG, Peiris JS, Chen H and Guan Y (2007). Evolution and molecular epidemiology of H9N2 influenza A viruses from quail in southern China, 2000 to 2005. Journal of Virology 81: 26352645.
Yen HL, Guan Y, Peiris M and Webster RG (2008). H5N1 in Asia. In: Klenk HD, Matrosovich MN and Stech J (eds) Monographs in Virology: Avian Influenza. Switzerland: S. Karger AG, pp. 1126.
Yen HL and Webster RG (2009). Pandemic influenza as a current threat. Current Topics in Microbiology and Immunology 333: 324.
Zhou NN, Senne DA, Landgraf JS, Swenson SL, Erickson G, Rossow K, Liu L, Yoon K, Krauss S and Webster RG (1999). Genetic reassortment of avian, swine, and human influenza A viruses in American pigs. Journal of Virology 73: 88518856.
Zimmer SM and Burke DS (2009). Historical perspective – Emergence of influenza A (H1N1) viruses. New England Journal of Medicine 361: 279285.
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