Adaptation of zoonotic influenza viruses towards efficient human-to-human transmissibility is a substantial public health concern. The recently emerged A/H7N9 influenza viruses in China provide an opportunity for quantitative studies of host-adaptation, as human-adaptive substitutions in the PB2 gene of the virus have been found in all sequenced human strains, while these substitutions have not been detected in any non-human A/H7N9 sequences. Given the currently available information, this observation suggests that the human-adaptive PB2 substitution might confer a fitness advantage to the virus in these human hosts that allows it to rise to proportions detectable by consensus sequencing over the course of a single human infection. We use a mathematical model of within-host virus evolution to estimate the fitness advantage required for a substitution to reach predominance in a single infection as a function of the duration of infection and the fraction of mutant present in the virus population that initially infects a human. The modeling results provide an estimate of the lower bound for the fitness advantage of this adaptive substitution in the currently sequenced A/H7N9 viruses. This framework can be more generally used to quantitatively estimate fitness advantages of adaptive substitutions based on the within-host prevalence of mutations. Such estimates are critical for models of cross-species transmission and host-adaptation of influenza virus infections.
References
[1]
Gao R, Cao B, Hu Y, Feng Z, Wang D, et al. (2013) Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med 368: 1888–1897.
[2]
Chen Y, Liang W, Yang S, Wu N, Gao H, et al.. (2013) Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet.
[3]
Bao CJ, Cui LB, Zhou MH, Hong L, Gao GF, et al. (2013) Live-animal markets and influenza A (H7N9) virus infection. N Engl J Med 368: 2337–2339.
[4]
Russell CA, Fonville JM, Brown AE, Burke DF, Smith DL, et al. (2012) The potential for respiratory droplet-transmissible A/H5N1 influenza virus to evolve in a mammalian host. Science 336: 1541–1547.
[5]
Gabriel G, Dauber B, Wolff T, Planz O, Klenk HD, et al. (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.
[6]
Munster VJ, de Wit E, van Riel D, Beyer WE, Rimmelzwaan GF, et al. (2007) The molecular basis of the pathogenicity of the Dutch highly pathogenic human influenza A H7N7 viruses. J Infect Dis 196: 258–265.
[7]
Subbarao EK, London W, Murphy BR (1993) A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol 67: 1761–1764.
[8]
de Wit E, Munster VJ, van Riel D, Beyer WE, Rimmelzwaan GF, et al. (2010) Molecular determinants of adaptation of highly pathogenic avian influenza H7N7 viruses to efficient replication in the human host. J Virol 84: 1597–1606.
[9]
Almond JW (1977) A single gene determines the host range of influenza virus. Nature 270: 617–618.
[10]
Bussey KA, Bousse TL, Desmet EA, Kim B, Takimoto T (2010) PB2 residue 271 plays a key role in enhanced polymerase activity of influenza A viruses in mammalian host cells. J Virol 84: 4395–4406.
[11]
Foeglein A, Loucaides EM, Mura M, Wise HM, Barclay WS, et al. (2011) Influence of PB2 host-range determinants on the intranuclear mobility of the influenza A virus polymerase. J Gen Virol 92: 1650–1661.
[12]
Miotto O, Heiny A, Tan TW, August JT, Brusic V (2008) Identification of human-to-human transmissibility factors in PB2 proteins of influenza A by large-scale mutual information analysis. BMC Bioinformatics 9 Suppl 1S18.
[13]
de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, et al. (2006) Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 12: 1203–1207.
[14]
Hatta M, Gao P, Halfmann P, Kawaoka Y (2001) Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293: 1840–1842.
[15]
Hatta M, Hatta Y, Kim JH, Watanabe S, Shinya K, et al. (2007) Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice. PLoS Pathog 3: 1374–1379.
[16]
Li Z, Chen H, Jiao P, Deng G, Tian G, et al. (2005) Molecular basis of replication of duck H5N1 influenza viruses in a mammalian mouse model. J Virol 79: 12058–12064.
[17]
Naffakh N, Massin P, Escriou N, Crescenzo-Chaigne B, van der Werf S (2000) Genetic analysis of the compatibility between polymerase proteins from human and avian strains of influenza A viruses. J Gen Virol 81: 1283–1291.
[18]
Shinya K, Hamm S, Hatta M, Ito H, Ito T, et al. (2004) PB2 amino acid at position 627 affects replicative efficiency, but not cell tropism, of Hong Kong H5N1 influenza A viruses in mice. Virology 320: 258–266.
[19]
Zhang Q, Shi J, Deng G, Guo J, Zeng X, et al. (2013) H7N9 influenza viruses are transmissible in ferrets by respiratory droplet. Science 341: 410–414.
[20]
Massin P, van der Werf S, Naffakh N (2001) Residue 627 of PB2 is a determinant of cold sensitivity in RNA replication of avian influenza viruses. J Virol 75: 5398–5404.
[21]
Labadie K, Dos Santos Afonso E, Rameix-Welti MA, van der Werf S, Naffakh N (2007) Host-range determinants on the PB2 protein of influenza A viruses control the interaction between the viral polymerase and nucleoprotein in human cells. Virology 362: 271–282.
[22]
Steel J, Lowen AC, Mubareka S, Palese P (2009) Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E/701N. PLoS Pathog 5: e1000252.
[23]
Yamada S, Hatta M, Staker BL, Watanabe S, Imai M, et al. (2010) Biological and structural characterization of a host-adapting amino acid in influenza virus. PLoS Pathog 6: e1001034.
[24]
Mehle A, Doudna JA (2009) Adaptive strategies of the influenza virus polymerase for replication in humans. Proc Natl Acad Sci U S A 106: 21312–21316.
[25]
Mok CK, Yen HL, Yu MY, Yuen KM, Sia SF, et al. (2011) Amino acid residues 253 and 591 of the PB2 protein of avian influenza virus A H9N2 contribute to mammalian pathogenesis. J Virol 85: 9641–9645.
[26]
Jonges M, Meijer A, Fouchier R, Koch G, Li J, et al.. (2013) Guiding outbreak management by the use of influenza A(H7Nx) virus sequence analysis. Euro Surveill 18.
[27]
Kageyama T, Fujisaki S, Takashita E, Xu H, Yamada S, et al.. (2013) Genetic analysis of novel avian A(H7N9) influenza viruses isolated from patients in China, February to April 2013. Euro Surveill 18.
[28]
Li J, Yu X, Pu X, Xie L, Sun Y, et al.. (2013) Environmental connections of novel avian-origin H7N9 influenza virus infection and virus adaptation to the human. Sci China Life Sci.
[29]
Liu Q, Lu L, Sun Z, Chen GW, Wen Y, et al.. (2013) Genomic signature and protein sequence analysis of a novel influenza A (H7N9) virus that causes an outbreak in humans in China. Microbes Infect.
[30]
Zhu H, Wang D, Kelvin DJ, Li L, Zheng Z, et al.. (2013) Infectivity, Transmission, and Pathology of Human H7N9 Influenza in Ferrets and Pigs. Science.
[31]
Watanabe T, Kiso M, Fukuyama S, Nakajima N, Imai M, et al.. (2013) Characterization of H7N9 influenza A viruses isolated from humans. Nature.
[32]
Richard M, Schrauwen EJ, de Graaf M, Bestebroer TM, Spronken MI, et al.. (2013) Limited airborne transmission of H7N9 influenza A virus between ferrets. Nature.
[33]
Li Q, Zhou L, Zhou M, Chen Z, Li F, et al.. (2013) Preliminary Report: Epidemiology of the Avian Influenza A (H7N9) Outbreak in China. N Engl J Med.
[34]
Qi X, Qian YH, Bao CJ, Guo XL, Cui LB, et al. (2013) Probable person to person transmission of novel avian influenza A (H7N9) virus in Eastern China, 2013: epidemiological investigation. BMJ 347: f4752.
[35]
Liu D, Shi W, Shi Y, Wang D, Xiao H, et al.. (2013) Origin and diversity of novel avian influenza A H7N9 viruses causing human infection: phylogenetic, structural, and coalescent analyses. Lancet.
[36]
Ribeiro RM, Bonhoeffer S (2000) Production of resistant HIV mutants during antiretroviral therapy. Proc Natl Acad Sci U S A 97: 7681–7686.
[37]
Chen GW, Chang SC, Mok CK, Lo YL, Kung YN, et al. (2006) Genomic signatures of human versus avian influenza A viruses. Emerg Infect Dis 12: 1353–1360.
[38]
Fouchier RA, Schneeberger PM, Rozendaal FW, Broekman JM, Kemink SA, et al. (2004) Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci U S A 101: 1356–1361.
[39]
Jonges M, Bataille A, Enserink R, Meijer A, Fouchier RA, et al. (2011) Comparative analysis of avian influenza virus diversity in poultry and humans during a highly pathogenic avian influenza A (H7N7) virus outbreak. J Virol 85: 10598–10604.
[40]
Chang SY, Lin PH, Tsai JC, Hung CC, Chang SC (2013) The first case of H7N9 influenza in Taiwan. Lancet 381: 1621.
[41]
Gao HN, Lu HZ, Cao B, Du B, Shang H, et al. (2013) Clinical findings in 111 cases of influenza A (H7N9) virus infection. N Engl J Med 368: 2277–2285.
[42]
Ip DK, Liao Q, Wu P, Gao Z, Cao B, et al. (2013) Detection of mild to moderate influenza A/H7N9 infection by China's national sentinel surveillance system for influenza-like illness: case series. BMJ 346: f3693.
[43]
Ribeiro RM, Bonhoeffer S (1999) A stochastic model for primary HIV infection: optimal timing of therapy. Aids 13: 351–357.
[44]
Park M, Loverdo C, Schreiber SJ, Lloyd-Smith JO (2013) Multiple scales of selection influence the evolutionary emergence of novel pathogens. Philos Trans R Soc Lond B Biol Sci 368: 20120333.
[45]
Gillespie JH (1984) The status of the neutral theory: the neutral theory of molecular evolution. Science 224: 732–733.
[46]
Perelson AS, Rong L, Hayden FG (2012) Combination antiviral therapy for influenza: predictions from modeling of human infections. J Infect Dis 205: 1642–1645.
