基于生物信息学的甲型H1N1流感病毒HA蛋白抗原表位进化规律研究
摘要
位于甲型流感病毒表面的HA蛋白的累积突变直接导致了流感病毒抗原性的改变,从而使其能够逃避宿主免疫系统的攻击。由于其持续的抗原性改变以及引发的多次大流行,人们越来越关注于是否可以提前预测到未来主要流行株的表位序列。因此,把握该病毒抗原性进化的轨迹并模拟其抗原性变化的过程是具有重大意义的。本课题根据19182008年间所收集到的1071条宿主为人的H1N1HA蛋白序列,依据宿主选择压力下抗原表位的突变特性构建了H1N1HA蛋白抗原表位预测模型。用1999-2008这10年的病毒序列数据对该模型的预测效果进行验证,结果表明,除极个别位点外,预测列表中前100位的表位序列可包含50%以上的真实病毒表位。接着对2009墨西哥流感随后可能出现的表位突变型做预测,发现除Sb位点外,2009/4/1-2010/9/30期间出现的其他四种真实表位,有50%以上包含在预测结果的前100个表位序列中。本法构建的H1N1HA抗原表位预测模型,也可进行跨流行周期的预测,从现有的流行株病毒抗原性较为准确的推测把握引发下一流行的病毒突变株。这可提高抗原漂变的监控水平,为大流感前的准备工作提供更多的信息。同时对于人群中传播的人感染的猪甲型H1N1流感病毒与人类季节性甲型H1N1流感病毒,分别收集了1918-2009年间17株人感染的猪甲型H1N1毒株以及21株季节性H1N1毒株,通过序列比对,氨基酸残基保守性分析以及3D结构对比等生物信息学方法来揭示造成这两者差异的原因。研究表明两者的抗原表位具有不同的进化速率。另外,受体结合位点的研究也显示这两类病毒RBS区域存在5个氨基酸水平的差异,分别为A138S,Q192K,S193T,Q196H以及A227E。这些研究结果为阐明两类甲型H1N1流感病毒性质差异提供了新的信息,并有助于进一步认识和理解流感病毒与宿主细胞作用及进化机制。
Continual mutations on HA protein of influenza A virus generate novel antigenic strains that cause new outbreaks. Since the ongoing antigenic changes and annual epidemics it caused, more attention have been paid to whether the future dominant antigenic sequences for influenza virus A can be tracked and predicted or not. Consequently, describing and simulating the antigenic evolution of influenza A is of critical importance for reasonable preparation before a new pandemic. In this article, we have analyzed more than1071human A/H1N1HA sequences from1918to2008, and combined the evolutionary information and the mutation features in antigenic sites under host selection pressure to build a prediction model for H1N1HA antigenic variations. Then the accuracy of this prediction model was evaluated with sequences collected from1999——2011, the result shows that except for few sites, more than50%of the real epitope types can be covered by the top100of the prediction list both within an epidemic circulation and across circulations. This prediction model provides a convenient way to get future antigenic mutants with the genomic sequence of current prevalent strain, and can help the early prediction for antigenic drift in the forthcoming season. This may be of great significance for preventing and preparation before the new H1N1epidemic. In addition, in order to demonstrate the different infection characteristics of human infected swine H1N1and human seasonal H1N1,17HA(hemagglutinin) sequences of human infected swine H1N1and21human seasonal H1N1HA sequences have been collected, with bioinformatical method, including sequence alignment, amino acid conservational analysis and3D structure comparison to illustrate the mechanism for their diverse. The results revealed the conservational level on HA epitope sites is different for these two kinds H1N1viruses, and5amino acid differences on receptor binding sites have been found, including A138S,Q192K,S193T,Q196H and A227E. These results provide information for illustrating the diverse between these two kinds of H1N1, and can be helpful in understanding the evolution of human H1N1influenza viruses.
Continual mutations on HA protein of influenza A virus generate novel antigenic strains that cause new outbreaks. Since the ongoing antigenic changes and annual epidemics it caused, more attention have been paid to whether the future dominant antigenic sequences for influenza virus A can be tracked and predicted or not. Consequently, describing and simulating the antigenic evolution of influenza A is of critical importance for reasonable preparation before a new pandemic. In this article, we have analyzed more than1071human A/H1N1HA sequences from1918to2008, and combined the evolutionary information and the mutation features in antigenic sites under host selection pressure to build a prediction model for H1N1HA antigenic variations. Then the accuracy of this prediction model was evaluated with sequences collected from1999——2011, the result shows that except for few sites, more than50%of the real epitope types can be covered by the top100of the prediction list both within an epidemic circulation and across circulations. This prediction model provides a convenient way to get future antigenic mutants with the genomic sequence of current prevalent strain, and can help the early prediction for antigenic drift in the forthcoming season. This may be of great significance for preventing and preparation before the new H1N1epidemic. In addition, in order to demonstrate the different infection characteristics of human infected swine H1N1and human seasonal H1N1,17HA(hemagglutinin) sequences of human infected swine H1N1and21human seasonal H1N1HA sequences have been collected, with bioinformatical method, including sequence alignment, amino acid conservational analysis and3D structure comparison to illustrate the mechanism for their diverse. The results revealed the conservational level on HA epitope sites is different for these two kinds H1N1viruses, and5amino acid differences on receptor binding sites have been found, including A138S,Q192K,S193T,Q196H and A227E. These results provide information for illustrating the diverse between these two kinds of H1N1, and can be helpful in understanding the evolution of human H1N1influenza viruses.
引文
[I]Brusic V, Petrovsky N. Immunoinformatics--the new kid in town. Novartis Found Symp 2003,254:3-13; discussion 13-22,98-101,250-102.
[2]Wang Y, Xie Y, Chen W. Immunoinformatic analysis for the epitopes on SARS virus surface protein. Beijing Da Xue Xue Bao 2003,35 Suppl:70-71.
[3]Rammensee HG. Immunoinformatics:bioinformatic strategies for better understanding of immune function. Introduction. Novartis Found Symp 2003,254:1-2.
[4]Blythe MJ, Doytchinova IA, Flower DR. JenPep:a database of quantitative functional peptide data for immunology. Bioinformatics 2002,18(3):434-439.
[5]Bernocchi G, Bernocchi R. DNA content and nuclear area in cerebellar histogenesis in rats. Riv Istochim Norm Patol 1975,19(1-4):121.
[6]Yan Q. Immunoinformatics and systems biology methods for personalized medicine. Methods Mol Biol 2010,662:203-220.
[7]Chen H, Smith GJ, Zhang SY, Qin K, Wang J, Li KS, Webster RG, Peiris JS, Guan Y. Avian flu:H5N1 virus outbreak in migratory waterfowl. Nature2005,436(7048):191-192.
[8]Obenauer JC, Denson J, Mehta PK, Su X, Mukatira S, Finkelstein DB, Xu X, Wang J, Ma J, Fan Y et al. Large-scale sequence analysis of avian influenza isolates. Science 2006, 311(5767):1576-1580.
[9]Kawaoka Y, Krauss S, Webster RG. Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics. J Virol 1989,63(11):4603-4608.
[10]Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y. Evolution and ecology of influenza A viruses. Microbiol Rev 1992,56(1):152-179.
[11]Fouchier RA, Munster V, Wallensten A, Bestebroer TM, Herfst S, Smith D,Rimmelzwaan GF, Olsen B, Osterhaus AD. Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls. J Virol 2005, 79(5):2814-2822.
[12]Wagner R, Matrosovich M, Klenk HD. Functional balance between haemagglutinin and neuraminidase in influenza virus infections. Rev Med Virol 2002,12(3):159-166.
[13]Rogers GN, D'Souza BL. Receptor binding properties of human and animal H1 influenza virus isolates. Virology 1989,173(1):317-322.
[14]Connor RJ, Kawaoka Y, Webster RG, Paulson JC. Receptor specificity in human, avian, and equine H2 and H3 influenza virus isolates. Virology 1994,205(1):17-23.
[15]Han T, Marasco WA. Structural basis of influenza virus neutralization. Ann N Y Acad Sci 2011,1217:178-190.
[16]Ito T, Kawaoka Y. Host-range barrier of influenza A viruses. Vet Microbiol 2000, 74(1-2):71-75.
[17]Tamura M, Yanagihara N, Tanaka H, Osajima A, Hirano T, Higashi K, Yamada KM, Nakashima Y, Hirano H. Activation of DNA synthesis and AP-1 by profilin, an actin-binding protein, via binding to a cell surface receptor in cultured rat mesangial cells. J Am Soc Nephrol 2000,11 (9):1620-1630.
[18]Couceiro JN, Paulson JC, Baum LG. Influenza virus strains selectively recognize sialyloligosaccharides on human respiratory epithelium; the role of the host cell in selection of hemagglutinin receptor specificity. Virus Res 1993,29(2):155-165.
[19]Ito T, Couceiro JN, Kelm S, Baum LG, Krauss S, Castrucci MR, Donatelli I, Kida H, Paulson JC, Webster RG et al. Molecular basis for the generation in pigs of influenza A viruses with pandemic potential. J Virol 1998,72(9):7367-7373.
[20]Subbarao K, Klimov A, Katz J, Regnery H, Lim W, Hall H, Perdue M, Swayne D, Bender C, Huang J et al. Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 1998,279(5349):393-396.
[21]Claas EC, Osterhaus AD, van Beek R, De Jong JC, Rimmelzwaan GF, Senne DA, Krauss S, Shortridge KF, Webster RG. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet 1998,351(9101):472-477.
[22]Taubenberger JK, Reid AH, Janczewski TA, Fanning TG. Integrating historical, clinical and molecular genetic data in order to explain the origin and virulence of the 1918 Spanish influenza virus. Philos Trans R Soc Lond B Biol Sci 2001, 356(1416):1829-1839.
[23]Johnson NP, Mueller J. Updating the accounts:global mortality of the 1918-1920 "Spanish" influenza pandemic. Bull Hist Med 2002,76(1):105-115.
[24]Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG. Characterization of the 1918 influenza virus polymerase genes. Nature 2005,437(7060):889-893.
[25]Antonovics J, Hood ME, Baker CH. Molecular virology:was the 1918 flu avian in origin? Nature 2006,440(7088):E9; discussion E9-10.
[26]Gibbs MJ, Gibbs AJ. Molecular virology:was the 1918 pandemic caused by a bird flu? Nature 2006,440(7088):E8; discussion E9-10.
[27]Cox NJ, Subbarao K. Global epidemiology of influenza:past and present. Annu Rev Med 2000,51:407-421.
[28]Kilbourne ED. Influenza pandemics of the 20th century. Emerg Infect Dis 2006, 12(1):9-14.
[29]Scholtissek C, Rohde W, Von Hoyningen V, Rott R. On the origin of the human influenza virus subtypes H2N2 and H3N2. Virology 1978,87(1):13-20.
[30]Bhat N, Wright JG, Broder KR, Murray EL, Greenberg ME, Glover MJ, Likos AM, Posey DL, Klimov A, Lindstrom SE et al. Influenza-associated deaths among children in the United States,2003-2004. N Engl J Med 2005,353(24):2559-2567.
[31]Ghedin E, Sengamalay NA, Shumway M, Zaborsky J, Feldblyum T, Subbu V, Spiro DJ, Sitz J, Koo H, Bolotov P et al. Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution. Nature 2005,437(7062):1162-1166.
[32]Holmes EC, Ghedin E, Miller N, Taylor J, Bao Y, St George K, Grenfell BT, Salzberg SL, Fraser CM, Lipman DJ et al. Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses. PLoS Biol 2005,3(9):e300.
[33]Cauthen AN, Swayne DE, Schultz-Cherry S, Perdue ML, Suarez DL. 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 2000,74(14):6592-6599.
[34]Guan Y, Peiris JS, Lipatov AS, Ellis TM, Dyrting KC, Krauss S, Zhang LJ, Webster RG, Shortridge KF. Emergence of multiple genotypes of H5N1 avian influenza viruses in Hong Kong SAR. Proc Natl Acad Sci U S A 2002,99(13):8950-8955.
[35]www.who.int/entity/influenza/vaccines
[36]Guan Y, Poon LL, Cheung CY, Ellis TM, Lim W, Lipatov AS, Chan KH, Sturm-Ramirez KM, Cheung CL, Leung YH et al. H5N1 influenza:a protean pandemic threat. Proc Natl Acad Sci U S A 2004,101(21):8156-8161.
[37]Drake JW. Rates of spontaneous mutation among RNA viruses. Proc Natl Acad Sci U S A1993,90(9):4171-4175.
[38]Fitch WM, Bush RM, Bender CA, Cox NJ. Long term trends in the evolution of H(3) HA1 human influenza type A. Proc Natl Acad Sci U S A 1997,94(15):7712-7718.
[39]Fitch WM, Leiter JM, Li XQ, Palese P. Positive Darwinian evolution in human influenza A viruses. Proc Natl Acad Sci U S A.1991,88(10):4270-4274.
[40]Suzuki Y. Natural selection on the influenza virus genome. Mol Biol Evol.2006, 23(10):1902-1911.
[41]Bush RM, Fitch WM, Bender CA, Cox NJ. Positive selection on the H3 hemagglutinin gene of human influenza virus A. Mol Biol Evol 1999,16(11):1457-1465.
[42]Ina Y, Gojobori T. Statistical analysis of nucleotide sequences of the hemagglutinin gene of human influenza A viruses. Proc Natl Acad Sci U S A 1994,91(18):8388-8392.
[43]Increased contribution in primary health care. Sygeplejersken 1979,79(5):19.
[44]Bean WJ, Schell M, Katz J, Kawaoka Y, Naeve C, Gorman O, Webster RG. Evolution of the H3 influenza virus hemagglutinin from human and nonhuman hosts. J Virol 1992, 66(2):1129-1138.
[45]Ferguson NM, Galvani AP, Bush RM. Ecological and immunological determinants of influenza evolution. Nature 2003,422(6930):428-433.
[46]Koelle K, Cobey S, Grenfell B, Pascual M. Epochal evolution shapes the phylodynamics of interpandemic influenza A (H3N2) in humans. Science 2006,314(5807):1898-1903.
[47]Webster RG, Laver WG, Air GM, Schild GC. Molecular mechanisms of variation in influenza viruses. Nature 1982,296(5853):115-121.
[48]Lindstrom SE, Cox NJ, Klimov A. Genetic analysis of human H2N2 and early H3N2 influenza viruses,1957-1972, evidence for genetic divergence and multiple reassortment events. Virology 2004,328(1):101-119.
[49]Nelson MI, Simonsen L, Viboud C, Miller MA, Taylor J, George KS, Griesemer SB, Ghedin E, Sengamalay NA, Spiro DJ et al. Stochastic processes are key determinants of short-term evolution in influenza a virus. PLoS Pathog 2006,2(12):e125.
[50]Barr IG, Komadina N, Hurt AC, Iannello P, Tomasov C, Shaw R, Durrant C, Sjogren H, Hampson AW. An influenza A(H3) reassortant was epidemic in Australia and New Zealand in 2003. J Med Virol 2005,76(3):391-397.
[51]Lin YP, Gregory V, Bennett M, Hay A. Recent changes among human influenza viruses. Virus Res 2004,103(1-2):47-52.
[52]Bodnar RJ, Kelly DD, Brutus M, Mansour A, Glusman M.2-Deoxy-D-glucose-induced decrements in operant and reflex pain thresholds. Pharmacol Biochem Behav 1978, 9(4):543-549.
[53]Lindstrom SE, Hiromoto Y, Nishimura H, Saito T, Nerome R, Nerome K. Comparative analysis of evolutionary mechanisms of the hemagglutinin and three internal protein genes of influenza B virus:multiple cocirculating lineages and frequent reassortment of the NP, M, and NS genes. J Virol 1999,73(5):4413-4426.
[54]Rimmelzwaan GF, Berkhoff EG, Nieuwkoop NJ, Fouchier RA, Osterhaus AD. Functional compensation of a detrimental amino acid substitution in a cytotoxic-T-lymphocyte epitope of influenza a viruses by comutations. J Virol 2004, 78(16):8946-8949.
[55]Mitnaul LJ, Matrosovich MN, Castrucci MR, Tuzikov AB, Bovin NV, Kobasa D, Kawaoka Y. Balanced hemagglutinin and neuraminidase activities are critical for efficient replication of influenza A virus. J Virol 2000,74(13):6015-6020.
[56]Voeten JT, Bestebroer TM, Nieuwkoop NJ, Fouchier RA, Osterhaus AD, Rimmelzwaan GF. Antigenic drift in the influenza A virus (H3N2) nucleoprotein and escape from recognition by cytotoxic T lymphocytes. J Virol 2000,74(15):6800-6807.
[57]Plotkin JB, Dushoff J, Levin SA. Hemagglutinin sequence clusters and the antigenic evolution of influenza A virus. Proc Natl Acad Sci U S A 2002,99(9):6263-6268.
[58]Lindberg PB, Matsson L, Klinge B, Attstrom R. A new experimental model for studies of local inflammatory reactions. Swed Dent J 1991,15(5):235-243.
[59]Derek J. Smith ea. Mapping the Antigenic and Genetic Evolution of Influenza Virus.Science 2004,305:371-376.
[60]Lavenu A, Leruez-Ville M, Chaix ML, Boelle PY, Rogez S, Freymuth F, Hay A, Rouzioux C, Carrat F. Detailed analysis of the genetic evolution of influenza virus during the course of an epidemic. Epidemiol Infect 2006,134(3):514-520.
[61]de Jong JC, Beyer WE, Palache AM, Rimmelzwaan GF, Osterhaus AD. Mismatch between the 1997/1998 influenza vaccine and the major epidemic A(H3N2) virus strain as the cause of an inadequate vaccine-induced antibody response to this strain in the elderly. J Med Virol 2000,61(1):94-99.
[62]Boni MF, Gog JR, Andreasen V, Feldman MW. Epidemic dynamics and antigenic evolution in a single season of influenza A. Proc Biol Sci 2006,273(1592):1307-1316.
[63]Rambaut A. Estimating the rate of molecular evolution:incorporating non-contemporaneous sequences into maximum likelihood phylogenies. Bioinformatics 2000,16(4):395-399.
[64]Drummond AJ, Ho SY, Phillips MJ, Rambaut A. Relaxed phylogenetics and dating with confidence. PLoS Biol 2006,4(5):e88.
[65]Drummond A, Pybus OG, Rambaut A. Inference of viral evolutionary rates from molecular sequences. Adv Parasitol 2003,54:331-358.
[66]Hanada K, Suzuki Y, Gojobori T. A large variation in the rates of synonymous substitution for RNA viruses and its relationship to a diversity of viral infection and transmission modes. Mol Biol Evol 2004,21(6):1074-1080.
[67]Jenkins GM, Rambaut A, Pybus OG, Holmes EC. Rates of molecular evolution in RNA viruses:a quantitative phylogenetic analysis. J Mol Evol 2002,54(2):156-165.
[68]Chen R, Holmes EC. Avian influenza virus exhibits rapid evolutionary dynamics. Mol Biol Evol 2006,23(12):2336-2341.
[69]Ludwig S, Haustein A, Kaleta EF, Scholtissek C. Recent influenza A (H1N1) infections of pigs and turkeys in northern Europe. Virology 1994,202(1):281-286.
[70]Gorman OT, Bean WJ, Kawaoka Y, Donatelli I, Guo YJ, Webster RG. Evolution of influenza A virus nucleoprotein genes:implications for the origins of HINI human and classical swine viruses. J Virol 1991,65(7):3704-3714.
[71]Air GM, Gibbs AJ, Laver WG, Webster RG. Evolutionary changes in influenza B are not primarily governed by antibody selection. Proc Natl Acad Sci U S A 1990, 87(10):3884-3888.
[72]Suzuki Y, Nei M. Origin and evolution of influenza virus hemagglutinin genes. Mol Biol Evol 2002,19(4):501-509.
[73]Gamblin SJ, Haire LF, Russell RJ, Stevens DJ, Xiao B, Ha Y, Vasisht N, Steinhauer DA, Daniels RS, Elliot A et al. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 2004,303(5665):1838-1842.
[74]Wilson IA, Cox NJ. Structural basis of immune recognition of influenza virus hemagglutinin. Annu Rev Immunol 1990,8:737-771.
[75]Caton AJ, Brownlee GG, Yewdell JW, Gerhard W. The antigenic structure of the influenza virus A/PR/8/34 hemagglutinin (H1 subtype). Cell 1982,31(2 Pt 1):417-427.
[76]Brownlee GG, Fodor E. The predicted antigenicity of the haemagglutinin of the 1918 Spanish influenza pandemic suggests an avian origin. Philos Trans R Soc Lond B Biol Sci 2001,356(1416):1871-1876.
[77]Garten RJ, Davis CT, Russell CA, Shu B, Lindstrom S, Balish A, Sessions WM, Xu X, Skepner E, Deyde V et al. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 2009,325(5937):197-201.
[78]Igarashi M, Ito K, Yoshida R, Tomabechi D, Kida H, Takada A. Predicting the antigenic structure of the pandemic (H1N1) 2009 influenza virus hemagglutinin. PLoS One 2010, 5(l):e8553.
[79]Xu R, Ekiert DC, Krause JC, Hai R, Crowe JE, Jr., Wilson IA. Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus. Science 2010, 328(5976):357-360.
[80]Blackburne BP, Hay AJ, Goldstein RA. Changing selective pressure during antigenic changes in human influenza H3. PLoS Pathog 2008,4(5):el000058.
[81]Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W:improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 1994,22(22):4673-4680.
[82]Tamura K, Dudley J, Nei M, Kumar S. MEGA4:Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 2007,24(8):1596-1599.
[83]Fiser A, Sali A. Modeller:generation and refinement of homology-based protein structure models. Methods Enzymol 2003,374:461-491.
[84]Guex N, Peitsch MC. SWISS-MODEL and the Swiss-PdbViewer:an environment for comparative protein modeling. Electrophoresis 1997,18(15):2714-2723.
[85]Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF Chimera-a visualization system for exploratory research and analysis. J Comput Chem 2004,25(13):1605-1612.
[86]Glaser F, Pupko T, Paz I, Bell RE, Bechor-Shental D, Martz E, Ben-Tal N. ConSurf: identification of functional regions in proteins by surface-mapping of phylogenetic information. Bioinformatics 2003,19(1):163-164.
[87]Landau M, Mayrose I, Rosenberg Y, Glaser F, Martz E, Pupko T, Ben-Tal N. ConSurf 2005:the projection of evolutionary conservation scores of residues on protein structures. Nucleic Acids Res 2005,33(Web Server issue):W299-302.
[88]Du X, Wang Z, Wu A, Song L, Cao Y, Hang H, Jiang T. Networks of genomic co-occurrence capture characteristics of human influenza A (H3N2) evolution. Genome Res 2008,18(1):178-187.
[89]Gobel U, Sander C, Schneider R, Valencia A. Correlated mutations and residue contacts in proteins. Proteins 1994,18(4):309-317.
[90]Bush RM, Bender CA, Subbarao K, Cox NJ, Fitch WM. Predicting the evolution of human influenza A. Science 1999,286(5446):1921-1925.
[91]Grenfell BT, Pybus OG, Gog JR, Wood JL, Daly JM, Mumford JA, Holmes EC. Unifying the epidemiological and evolutionary dynamics of pathogens. Science 2004, 303(5656):327-332.
[92]Jin H, Zhou H, Liu H, Chan W, Adhikary L, Mahmood K, Lee MS, Kemble G. Two residues in the hemagglutinin of A/Fujian/411/02-like influenza viruses are responsible for antigenic drift from A/Panama/2007/99. Virology 2005,336(1):113-119.
[93]Xia Z, Jin G, Zhu J, Zhou R. Using a mutual information-based site transition network to map the genetic evolution of influenza A/H3N2 virus. Bioinformatics 2009, 25(18):2309-2317.
[94]Shen J, Ma J, Wang Q. Evolutionary trends of A(H1N1) influenza virus hemagglutinin since 1918. PLoS One 2009,4(11):e7789.
[95]Smith GJ, Vijaykrishna D, Bahl J, Lycett SJ, Worobey M, Pybus OG, Ma SK, Cheung CL, Raghwani J, Bhatt S et al. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature 2009,459(7250):1122-1125.
[96]Itoh Y, Shinya K, Kiso M, Watanabe T, Sakoda Y, Hatta M, Muramoto Y, Tamura D, Sakai-Tagawa Y, Noda T et al. In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses. Nature 2009,460(7258):1021-l025.
[97]Miller MA, Viboud C, Balinska M, Simonsen L. The signature features of influenza pandemics-implications for policy. N Engl J Med 2009,360(25):2595-2598.
[98]Sugita S, Yoshioka Y, Itamura S, Kanegae Y, Oguchi K, Gojobori T, Nerome K, Oya A. Molecular evolution of hemagglutinin genes of H1N1 swine and human influenza A viruses. J Mol Evol 1991,32(1):16-23.
[99]Vines A, Wells K, Matrosovich M, Castrucci MR, Ito T, Kawaoka Y. The role of influenza A virus hemagglutinin residues 226 and 228 in receptor specificity and host range restriction. J Virol 1998,72(9):7626-7631.
[100]Pan C, Cheung B, Tan S, Li C, Li L, Liu S, Jiang S. Genomic signature and mutation trend analysis of pandemic (H1N1) 2009 influenza A virus. PLoS One 2010, 5(3):e9549.
[2]Wang Y, Xie Y, Chen W. Immunoinformatic analysis for the epitopes on SARS virus surface protein. Beijing Da Xue Xue Bao 2003,35 Suppl:70-71.
[3]Rammensee HG. Immunoinformatics:bioinformatic strategies for better understanding of immune function. Introduction. Novartis Found Symp 2003,254:1-2.
[4]Blythe MJ, Doytchinova IA, Flower DR. JenPep:a database of quantitative functional peptide data for immunology. Bioinformatics 2002,18(3):434-439.
[5]Bernocchi G, Bernocchi R. DNA content and nuclear area in cerebellar histogenesis in rats. Riv Istochim Norm Patol 1975,19(1-4):121.
[6]Yan Q. Immunoinformatics and systems biology methods for personalized medicine. Methods Mol Biol 2010,662:203-220.
[7]Chen H, Smith GJ, Zhang SY, Qin K, Wang J, Li KS, Webster RG, Peiris JS, Guan Y. Avian flu:H5N1 virus outbreak in migratory waterfowl. Nature2005,436(7048):191-192.
[8]Obenauer JC, Denson J, Mehta PK, Su X, Mukatira S, Finkelstein DB, Xu X, Wang J, Ma J, Fan Y et al. Large-scale sequence analysis of avian influenza isolates. Science 2006, 311(5767):1576-1580.
[9]Kawaoka Y, Krauss S, Webster RG. Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics. J Virol 1989,63(11):4603-4608.
[10]Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y. Evolution and ecology of influenza A viruses. Microbiol Rev 1992,56(1):152-179.
[11]Fouchier RA, Munster V, Wallensten A, Bestebroer TM, Herfst S, Smith D,Rimmelzwaan GF, Olsen B, Osterhaus AD. Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls. J Virol 2005, 79(5):2814-2822.
[12]Wagner R, Matrosovich M, Klenk HD. Functional balance between haemagglutinin and neuraminidase in influenza virus infections. Rev Med Virol 2002,12(3):159-166.
[13]Rogers GN, D'Souza BL. Receptor binding properties of human and animal H1 influenza virus isolates. Virology 1989,173(1):317-322.
[14]Connor RJ, Kawaoka Y, Webster RG, Paulson JC. Receptor specificity in human, avian, and equine H2 and H3 influenza virus isolates. Virology 1994,205(1):17-23.
[15]Han T, Marasco WA. Structural basis of influenza virus neutralization. Ann N Y Acad Sci 2011,1217:178-190.
[16]Ito T, Kawaoka Y. Host-range barrier of influenza A viruses. Vet Microbiol 2000, 74(1-2):71-75.
[17]Tamura M, Yanagihara N, Tanaka H, Osajima A, Hirano T, Higashi K, Yamada KM, Nakashima Y, Hirano H. Activation of DNA synthesis and AP-1 by profilin, an actin-binding protein, via binding to a cell surface receptor in cultured rat mesangial cells. J Am Soc Nephrol 2000,11 (9):1620-1630.
[18]Couceiro JN, Paulson JC, Baum LG. Influenza virus strains selectively recognize sialyloligosaccharides on human respiratory epithelium; the role of the host cell in selection of hemagglutinin receptor specificity. Virus Res 1993,29(2):155-165.
[19]Ito T, Couceiro JN, Kelm S, Baum LG, Krauss S, Castrucci MR, Donatelli I, Kida H, Paulson JC, Webster RG et al. Molecular basis for the generation in pigs of influenza A viruses with pandemic potential. J Virol 1998,72(9):7367-7373.
[20]Subbarao K, Klimov A, Katz J, Regnery H, Lim W, Hall H, Perdue M, Swayne D, Bender C, Huang J et al. Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 1998,279(5349):393-396.
[21]Claas EC, Osterhaus AD, van Beek R, De Jong JC, Rimmelzwaan GF, Senne DA, Krauss S, Shortridge KF, Webster RG. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet 1998,351(9101):472-477.
[22]Taubenberger JK, Reid AH, Janczewski TA, Fanning TG. Integrating historical, clinical and molecular genetic data in order to explain the origin and virulence of the 1918 Spanish influenza virus. Philos Trans R Soc Lond B Biol Sci 2001, 356(1416):1829-1839.
[23]Johnson NP, Mueller J. Updating the accounts:global mortality of the 1918-1920 "Spanish" influenza pandemic. Bull Hist Med 2002,76(1):105-115.
[24]Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG. Characterization of the 1918 influenza virus polymerase genes. Nature 2005,437(7060):889-893.
[25]Antonovics J, Hood ME, Baker CH. Molecular virology:was the 1918 flu avian in origin? Nature 2006,440(7088):E9; discussion E9-10.
[26]Gibbs MJ, Gibbs AJ. Molecular virology:was the 1918 pandemic caused by a bird flu? Nature 2006,440(7088):E8; discussion E9-10.
[27]Cox NJ, Subbarao K. Global epidemiology of influenza:past and present. Annu Rev Med 2000,51:407-421.
[28]Kilbourne ED. Influenza pandemics of the 20th century. Emerg Infect Dis 2006, 12(1):9-14.
[29]Scholtissek C, Rohde W, Von Hoyningen V, Rott R. On the origin of the human influenza virus subtypes H2N2 and H3N2. Virology 1978,87(1):13-20.
[30]Bhat N, Wright JG, Broder KR, Murray EL, Greenberg ME, Glover MJ, Likos AM, Posey DL, Klimov A, Lindstrom SE et al. Influenza-associated deaths among children in the United States,2003-2004. N Engl J Med 2005,353(24):2559-2567.
[31]Ghedin E, Sengamalay NA, Shumway M, Zaborsky J, Feldblyum T, Subbu V, Spiro DJ, Sitz J, Koo H, Bolotov P et al. Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution. Nature 2005,437(7062):1162-1166.
[32]Holmes EC, Ghedin E, Miller N, Taylor J, Bao Y, St George K, Grenfell BT, Salzberg SL, Fraser CM, Lipman DJ et al. Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses. PLoS Biol 2005,3(9):e300.
[33]Cauthen AN, Swayne DE, Schultz-Cherry S, Perdue ML, Suarez DL. 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 2000,74(14):6592-6599.
[34]Guan Y, Peiris JS, Lipatov AS, Ellis TM, Dyrting KC, Krauss S, Zhang LJ, Webster RG, Shortridge KF. Emergence of multiple genotypes of H5N1 avian influenza viruses in Hong Kong SAR. Proc Natl Acad Sci U S A 2002,99(13):8950-8955.
[35]www.who.int/entity/influenza/vaccines
[36]Guan Y, Poon LL, Cheung CY, Ellis TM, Lim W, Lipatov AS, Chan KH, Sturm-Ramirez KM, Cheung CL, Leung YH et al. H5N1 influenza:a protean pandemic threat. Proc Natl Acad Sci U S A 2004,101(21):8156-8161.
[37]Drake JW. Rates of spontaneous mutation among RNA viruses. Proc Natl Acad Sci U S A1993,90(9):4171-4175.
[38]Fitch WM, Bush RM, Bender CA, Cox NJ. Long term trends in the evolution of H(3) HA1 human influenza type A. Proc Natl Acad Sci U S A 1997,94(15):7712-7718.
[39]Fitch WM, Leiter JM, Li XQ, Palese P. Positive Darwinian evolution in human influenza A viruses. Proc Natl Acad Sci U S A.1991,88(10):4270-4274.
[40]Suzuki Y. Natural selection on the influenza virus genome. Mol Biol Evol.2006, 23(10):1902-1911.
[41]Bush RM, Fitch WM, Bender CA, Cox NJ. Positive selection on the H3 hemagglutinin gene of human influenza virus A. Mol Biol Evol 1999,16(11):1457-1465.
[42]Ina Y, Gojobori T. Statistical analysis of nucleotide sequences of the hemagglutinin gene of human influenza A viruses. Proc Natl Acad Sci U S A 1994,91(18):8388-8392.
[43]Increased contribution in primary health care. Sygeplejersken 1979,79(5):19.
[44]Bean WJ, Schell M, Katz J, Kawaoka Y, Naeve C, Gorman O, Webster RG. Evolution of the H3 influenza virus hemagglutinin from human and nonhuman hosts. J Virol 1992, 66(2):1129-1138.
[45]Ferguson NM, Galvani AP, Bush RM. Ecological and immunological determinants of influenza evolution. Nature 2003,422(6930):428-433.
[46]Koelle K, Cobey S, Grenfell B, Pascual M. Epochal evolution shapes the phylodynamics of interpandemic influenza A (H3N2) in humans. Science 2006,314(5807):1898-1903.
[47]Webster RG, Laver WG, Air GM, Schild GC. Molecular mechanisms of variation in influenza viruses. Nature 1982,296(5853):115-121.
[48]Lindstrom SE, Cox NJ, Klimov A. Genetic analysis of human H2N2 and early H3N2 influenza viruses,1957-1972, evidence for genetic divergence and multiple reassortment events. Virology 2004,328(1):101-119.
[49]Nelson MI, Simonsen L, Viboud C, Miller MA, Taylor J, George KS, Griesemer SB, Ghedin E, Sengamalay NA, Spiro DJ et al. Stochastic processes are key determinants of short-term evolution in influenza a virus. PLoS Pathog 2006,2(12):e125.
[50]Barr IG, Komadina N, Hurt AC, Iannello P, Tomasov C, Shaw R, Durrant C, Sjogren H, Hampson AW. An influenza A(H3) reassortant was epidemic in Australia and New Zealand in 2003. J Med Virol 2005,76(3):391-397.
[51]Lin YP, Gregory V, Bennett M, Hay A. Recent changes among human influenza viruses. Virus Res 2004,103(1-2):47-52.
[52]Bodnar RJ, Kelly DD, Brutus M, Mansour A, Glusman M.2-Deoxy-D-glucose-induced decrements in operant and reflex pain thresholds. Pharmacol Biochem Behav 1978, 9(4):543-549.
[53]Lindstrom SE, Hiromoto Y, Nishimura H, Saito T, Nerome R, Nerome K. Comparative analysis of evolutionary mechanisms of the hemagglutinin and three internal protein genes of influenza B virus:multiple cocirculating lineages and frequent reassortment of the NP, M, and NS genes. J Virol 1999,73(5):4413-4426.
[54]Rimmelzwaan GF, Berkhoff EG, Nieuwkoop NJ, Fouchier RA, Osterhaus AD. Functional compensation of a detrimental amino acid substitution in a cytotoxic-T-lymphocyte epitope of influenza a viruses by comutations. J Virol 2004, 78(16):8946-8949.
[55]Mitnaul LJ, Matrosovich MN, Castrucci MR, Tuzikov AB, Bovin NV, Kobasa D, Kawaoka Y. Balanced hemagglutinin and neuraminidase activities are critical for efficient replication of influenza A virus. J Virol 2000,74(13):6015-6020.
[56]Voeten JT, Bestebroer TM, Nieuwkoop NJ, Fouchier RA, Osterhaus AD, Rimmelzwaan GF. Antigenic drift in the influenza A virus (H3N2) nucleoprotein and escape from recognition by cytotoxic T lymphocytes. J Virol 2000,74(15):6800-6807.
[57]Plotkin JB, Dushoff J, Levin SA. Hemagglutinin sequence clusters and the antigenic evolution of influenza A virus. Proc Natl Acad Sci U S A 2002,99(9):6263-6268.
[58]Lindberg PB, Matsson L, Klinge B, Attstrom R. A new experimental model for studies of local inflammatory reactions. Swed Dent J 1991,15(5):235-243.
[59]Derek J. Smith ea. Mapping the Antigenic and Genetic Evolution of Influenza Virus.Science 2004,305:371-376.
[60]Lavenu A, Leruez-Ville M, Chaix ML, Boelle PY, Rogez S, Freymuth F, Hay A, Rouzioux C, Carrat F. Detailed analysis of the genetic evolution of influenza virus during the course of an epidemic. Epidemiol Infect 2006,134(3):514-520.
[61]de Jong JC, Beyer WE, Palache AM, Rimmelzwaan GF, Osterhaus AD. Mismatch between the 1997/1998 influenza vaccine and the major epidemic A(H3N2) virus strain as the cause of an inadequate vaccine-induced antibody response to this strain in the elderly. J Med Virol 2000,61(1):94-99.
[62]Boni MF, Gog JR, Andreasen V, Feldman MW. Epidemic dynamics and antigenic evolution in a single season of influenza A. Proc Biol Sci 2006,273(1592):1307-1316.
[63]Rambaut A. Estimating the rate of molecular evolution:incorporating non-contemporaneous sequences into maximum likelihood phylogenies. Bioinformatics 2000,16(4):395-399.
[64]Drummond AJ, Ho SY, Phillips MJ, Rambaut A. Relaxed phylogenetics and dating with confidence. PLoS Biol 2006,4(5):e88.
[65]Drummond A, Pybus OG, Rambaut A. Inference of viral evolutionary rates from molecular sequences. Adv Parasitol 2003,54:331-358.
[66]Hanada K, Suzuki Y, Gojobori T. A large variation in the rates of synonymous substitution for RNA viruses and its relationship to a diversity of viral infection and transmission modes. Mol Biol Evol 2004,21(6):1074-1080.
[67]Jenkins GM, Rambaut A, Pybus OG, Holmes EC. Rates of molecular evolution in RNA viruses:a quantitative phylogenetic analysis. J Mol Evol 2002,54(2):156-165.
[68]Chen R, Holmes EC. Avian influenza virus exhibits rapid evolutionary dynamics. Mol Biol Evol 2006,23(12):2336-2341.
[69]Ludwig S, Haustein A, Kaleta EF, Scholtissek C. Recent influenza A (H1N1) infections of pigs and turkeys in northern Europe. Virology 1994,202(1):281-286.
[70]Gorman OT, Bean WJ, Kawaoka Y, Donatelli I, Guo YJ, Webster RG. Evolution of influenza A virus nucleoprotein genes:implications for the origins of HINI human and classical swine viruses. J Virol 1991,65(7):3704-3714.
[71]Air GM, Gibbs AJ, Laver WG, Webster RG. Evolutionary changes in influenza B are not primarily governed by antibody selection. Proc Natl Acad Sci U S A 1990, 87(10):3884-3888.
[72]Suzuki Y, Nei M. Origin and evolution of influenza virus hemagglutinin genes. Mol Biol Evol 2002,19(4):501-509.
[73]Gamblin SJ, Haire LF, Russell RJ, Stevens DJ, Xiao B, Ha Y, Vasisht N, Steinhauer DA, Daniels RS, Elliot A et al. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 2004,303(5665):1838-1842.
[74]Wilson IA, Cox NJ. Structural basis of immune recognition of influenza virus hemagglutinin. Annu Rev Immunol 1990,8:737-771.
[75]Caton AJ, Brownlee GG, Yewdell JW, Gerhard W. The antigenic structure of the influenza virus A/PR/8/34 hemagglutinin (H1 subtype). Cell 1982,31(2 Pt 1):417-427.
[76]Brownlee GG, Fodor E. The predicted antigenicity of the haemagglutinin of the 1918 Spanish influenza pandemic suggests an avian origin. Philos Trans R Soc Lond B Biol Sci 2001,356(1416):1871-1876.
[77]Garten RJ, Davis CT, Russell CA, Shu B, Lindstrom S, Balish A, Sessions WM, Xu X, Skepner E, Deyde V et al. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 2009,325(5937):197-201.
[78]Igarashi M, Ito K, Yoshida R, Tomabechi D, Kida H, Takada A. Predicting the antigenic structure of the pandemic (H1N1) 2009 influenza virus hemagglutinin. PLoS One 2010, 5(l):e8553.
[79]Xu R, Ekiert DC, Krause JC, Hai R, Crowe JE, Jr., Wilson IA. Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus. Science 2010, 328(5976):357-360.
[80]Blackburne BP, Hay AJ, Goldstein RA. Changing selective pressure during antigenic changes in human influenza H3. PLoS Pathog 2008,4(5):el000058.
[81]Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W:improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 1994,22(22):4673-4680.
[82]Tamura K, Dudley J, Nei M, Kumar S. MEGA4:Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 2007,24(8):1596-1599.
[83]Fiser A, Sali A. Modeller:generation and refinement of homology-based protein structure models. Methods Enzymol 2003,374:461-491.
[84]Guex N, Peitsch MC. SWISS-MODEL and the Swiss-PdbViewer:an environment for comparative protein modeling. Electrophoresis 1997,18(15):2714-2723.
[85]Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF Chimera-a visualization system for exploratory research and analysis. J Comput Chem 2004,25(13):1605-1612.
[86]Glaser F, Pupko T, Paz I, Bell RE, Bechor-Shental D, Martz E, Ben-Tal N. ConSurf: identification of functional regions in proteins by surface-mapping of phylogenetic information. Bioinformatics 2003,19(1):163-164.
[87]Landau M, Mayrose I, Rosenberg Y, Glaser F, Martz E, Pupko T, Ben-Tal N. ConSurf 2005:the projection of evolutionary conservation scores of residues on protein structures. Nucleic Acids Res 2005,33(Web Server issue):W299-302.
[88]Du X, Wang Z, Wu A, Song L, Cao Y, Hang H, Jiang T. Networks of genomic co-occurrence capture characteristics of human influenza A (H3N2) evolution. Genome Res 2008,18(1):178-187.
[89]Gobel U, Sander C, Schneider R, Valencia A. Correlated mutations and residue contacts in proteins. Proteins 1994,18(4):309-317.
[90]Bush RM, Bender CA, Subbarao K, Cox NJ, Fitch WM. Predicting the evolution of human influenza A. Science 1999,286(5446):1921-1925.
[91]Grenfell BT, Pybus OG, Gog JR, Wood JL, Daly JM, Mumford JA, Holmes EC. Unifying the epidemiological and evolutionary dynamics of pathogens. Science 2004, 303(5656):327-332.
[92]Jin H, Zhou H, Liu H, Chan W, Adhikary L, Mahmood K, Lee MS, Kemble G. Two residues in the hemagglutinin of A/Fujian/411/02-like influenza viruses are responsible for antigenic drift from A/Panama/2007/99. Virology 2005,336(1):113-119.
[93]Xia Z, Jin G, Zhu J, Zhou R. Using a mutual information-based site transition network to map the genetic evolution of influenza A/H3N2 virus. Bioinformatics 2009, 25(18):2309-2317.
[94]Shen J, Ma J, Wang Q. Evolutionary trends of A(H1N1) influenza virus hemagglutinin since 1918. PLoS One 2009,4(11):e7789.
[95]Smith GJ, Vijaykrishna D, Bahl J, Lycett SJ, Worobey M, Pybus OG, Ma SK, Cheung CL, Raghwani J, Bhatt S et al. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature 2009,459(7250):1122-1125.
[96]Itoh Y, Shinya K, Kiso M, Watanabe T, Sakoda Y, Hatta M, Muramoto Y, Tamura D, Sakai-Tagawa Y, Noda T et al. In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses. Nature 2009,460(7258):1021-l025.
[97]Miller MA, Viboud C, Balinska M, Simonsen L. The signature features of influenza pandemics-implications for policy. N Engl J Med 2009,360(25):2595-2598.
[98]Sugita S, Yoshioka Y, Itamura S, Kanegae Y, Oguchi K, Gojobori T, Nerome K, Oya A. Molecular evolution of hemagglutinin genes of H1N1 swine and human influenza A viruses. J Mol Evol 1991,32(1):16-23.
[99]Vines A, Wells K, Matrosovich M, Castrucci MR, Ito T, Kawaoka Y. The role of influenza A virus hemagglutinin residues 226 and 228 in receptor specificity and host range restriction. J Virol 1998,72(9):7626-7631.
[100]Pan C, Cheung B, Tan S, Li C, Li L, Liu S, Jiang S. Genomic signature and mutation trend analysis of pandemic (H1N1) 2009 influenza A virus. PLoS One 2010, 5(3):e9549.