Avian Influenza A Viruses: Evolution and Zoonotic Infection

Se Mi Kim; Young-Il Kim; Philippe Noriel Q. Pascua; Young Ki Choi

doi:10.1055/s-0036-1584953

Seminars in Respiratory and Critical Care Medicine, Table of Contents

Semin Respir Crit Care Med 2016; 37(04): 501-511
DOI: 10.1055/s-0036-1584953

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Avian Influenza A Viruses: Evolution and Zoonotic Infection

Se Mi Kim

¹Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea

,

Young-Il Kim

¹Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea

,

Philippe Noriel Q. Pascua

¹Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea

,

Young Ki Choi

¹Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea

› Author Affiliations

Abstract

Although efficient human-to-human transmission of avian influenza virus has yet to be seen, in the past two decades avian-to-human transmission of influenza A viruses has been reported. Influenza A/H5N1, in particular, has repeatedly caused human infections associated with high mortality, and since 1998 the virus has evolved into many clades of variants with significant antigenic diversity. In 2013, three (A/H7N9, A/H6N1, and A/H10N8) novel avian influenza viruses (AIVs) breached the animal-human host species barrier in Asia. In humans, roughly 35% of A/H7N9-infected patients succumbed to the zoonotic infection, and two of three A/H10N8 human infections were also lethal; however, neither of these viruses cause influenza-like symptoms in poultry. While most of these cases were associated with direct contact with infected poultry, some involved sustained human-to-human transmission. Thus, these events elicited concern regarding potential AIV pandemics. This article reviews the human incursions associated with AIV variants and the potential role of pigs as an intermediate host that may hasten AIV evolution. In addition, we discuss the known influenza A virus virulence and transmission factors and their evaluation in animal models. With the growing number of human AIV infections, constant vigilance for the emergence of novel viruses is of utmost importance. In addition, careful characterization and pathobiological assessment of these novel variants will help to identify strains of particular concern for future pandemics.

Keywords

avian influenza A virus - humans - pathogenicity - transmission - pandemic - influenza vaccines

Full Text

References

References
1 Palese P, Shaw ML. Orthomyxoviridae: the virus and their replication. In: Knipe DM, Howley PM, , eds. Fields virology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007. :p.1647–1690
2 Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y. Evolution and ecology of influenza A viruses. Microbiol Rev 1992; 56 (1) 152-179
3 Tong S, Zhu X, Li Y , et al. New world bats harbor diverse influenza A viruses. PLoS Pathog 2013; 9 (10) e1003657
4 Tong S, Li Y, Rivailler P , et al. A distinct lineage of influenza A virus from bats. Proc Natl Acad Sci U S A 2012; 109 (11) 4269-4274
5 Swayne DE, Radin MJ, Hoepf TM, Slemons RD. Acute renal failure as the cause of death in chickens following intravenous inoculation with avian influenza virus A/chicken/Alabama/7395/75 (H4N8). Avian Dis 1994; 38 (1) 151-157
6 World Health Organization (WHO). Cumulative number of confirmed human cases of avian influenza A(H5N1) reported to WHO, 2003–2014. Available at http://www.who.int/influenza/human_animal_interface/EN_GIP_20140124CumulativeNumberH5N1cases.pdf . Accessed on February 28, 2014.
7 Hatta M, Gao P, Halfmann P, Kawaoka Y. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 2001; 293 (5536) 1840-1842
8 Kawaoka Y, Chambers TM, Sladen WL, Webster RG. Is the gene pool of influenza viruses in shorebirds and gulls different from that in wild ducks?. Virology 1988; 163 (1) 247-250
9 Tumpey TM, Maines TR, Van Hoeven N , et al. A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science 2007; 315 (5812) 655-659
10 Matrosovich M, Suzuki T, Hirabayashi Y, Garten W, Webster RG, Klenk HD. Gangliosides are not essential for influenza virus infection. Glycoconj J 2006; 23 (1-2) 107-113
11 Rogers GN, Paulson JC, Daniels RS, Skehel JJ, Wilson IA, Wiley DC. Single amino acid substitutions in influenza haemagglutinin change receptor binding specificity. Nature 1983; 304 (5921) 76-78
12 Imai M, Watanabe T, Hatta M , et al. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 2012; 486 (7403) 420-428
13 Imai M, Kawaoka Y. The role of receptor binding specificity in interspecies transmission of influenza viruses. Curr Opin Virol 2012; 2 (2) 160-167
14 Chen W, Zhong Y, Qin Y, Sun S, Li Z. The evolutionary pattern of glycosylation sites in influenza virus (H5N1) hemagglutinin and neuraminidase. PLoS ONE 2012; 7 (11) e49224
15 Yen HL, Liang CH, Wu CY , et al. Hemagglutinin-neuraminidase balance confers respiratory-droplet transmissibility of the pandemic H1N1 influenza virus in ferrets. Proc Natl Acad Sci U S A 2011; 108 (34) 14264-14269
16 Li Z, Chen H, Jiao P , et al. Molecular basis of replication of duck H5N1 influenza viruses in a mammalian mouse model. J Virol 2005; 79 (18) 12058-12064
17 Steel J, Lowen AC, Mubareka S, Palese P. Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E/701N. PLoS Pathog 2009; 5 (1) e1000252
18 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
19 Chen LM, Davis CT, Zhou H, Cox NJ, Donis RO. Genetic compatibility and virulence of reassortants derived from contemporary avian H5N1 and human H3N2 influenza A viruses. PLoS Pathog 2008; 4 (5) e1000072
20 Belser JA, Wadford DA, Pappas C , et al. Pathogenesis of pandemic influenza A (H1N1) and triple-reassortant swine influenza A (H1) viruses in mice. J Virol 2010; 84 (9) 4194-4203
21 Medina RA, García-Sastre A. Influenza A viruses: new research developments. Nat Rev Microbiol 2011; 9 (8) 590-603
22 Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian flu: influenza virus receptors in the human airway. Nature 2006; 440 (7083) 435-436
23 Ito T, Couceiro JNS, Kelm S , et al. Molecular basis for the generation in pigs of influenza A viruses with pandemic potential. J Virol 1998; 72 (9) 7367-7373
24 Garten W, Klenk H. Cleavage activation of the influenza virus hemagglutinin and its role in pathogenesis. In: Klenk HD, Matrosovich MN, Stech J, , eds. Avian Influenza Vol.27. Basel: Karger; 2008. :p.156–167
25 Stieneke-Gröber A, Vey M, Angliker H , et al. Influenza virus hemagglutinin with multibasic cleavage site is activated by furin, a subtilisin-like endoprotease. EMBO J 1992; 11 (7) 2407-2414
26 Sonnberg S, Webby RJ, Webster RG. Natural history of highly pathogenic avian influenza H5N1. Virus Res 2013; 178 (1) 63-77
27 de Jong MD, Simmons CP, Thanh TT , et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 2006; 12 (10) 1203-1207
28 Perrone LA, Plowden JK, García-Sastre A, Katz JM, Tumpey TM. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog 2008; 4 (8) e1000115
29 Szretter KJ, Gangappa S, Lu X , et al. Role of host cytokine responses in the pathogenesis of avian H5N1 influenza viruses in mice. J Virol 2007; 81 (6) 2736-2744
30 Center for Infectious Disease Research and Policy (CIDRAP). Fatal H5N1 case in Canada is North America's first Minneapolis: CIDRAP; c2014. Available at http://www.cidrap.umn.edu/news-perspective/2014/01/fatal-h5n1-case-canada-northamericas-first . Accessed on February 28, 2014.
31 Herfst S, Schrauwen EJ, Linster M , et al. Airborne transmission of influenza A/H5N1 virus between ferrets. Science 2012; 336 (6088) 1534-1541
32 Peiris M, Yuen KY, Leung CW , et al. Human infection with influenza H9N2. Lancet 1999; 354 (9182) 916-917
33 Guan Y, Shortridge KF, Krauss S, Webster RG. 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 1999; 96 (16) 9363-9367
34 Bao Y, Bolotov P, Dernovoy D , et al. The influenza virus resource at the National Center for Biotechnology Information. J Virol 2008; 82 (2) 596-601
35 Wei L, Kao E. Hong Kong sees first case of H9N2 avian flu in four years. Hong Kong: South China Morning Post; ; c2013. 2015. . Available at http://www.scmp.com/news/hong-kong/article/1393266/86-year-old-man-infected-h9n2-avian-flu . Accessed on February 28, 2013.
36 Huang R, Wang AR, Liu ZH , et al. Seroprevalence of avian influenza H9N2 among poultry workers in Shandong Province, China. Eur J Clin Microbiol Infect Dis 2013; 32 (10) 1347-1351
37 Pawar SD, Tandale BV, Raut CG , et al. Avian influenza H9N2 seroprevalence among poultry workers in Pune, India, 2010. PLoS ONE 2012; 7 (5) e36374
38 Zhou P, Zhu W, Gu H , et al. Avian influenza H9N2 seroprevalence among swine farm residents in China. J Med Virol 2014; 86 (4) 597-600
39 Belser JA, Bridges CB, Katz JM, Tumpey TM. Past, present, and possible future human infection with influenza virus A subtype H7. Emerg Infect Dis 2009; 15 (6) 859-865
40 Kurtz J, Manvell RJ, Banks J. Avian influenza virus isolated from a woman with conjunctivitis. Lancet 1996; 348 (9031) 901-902
41 Centers for Disease Control and Prevention (CDC). Update: influenza activity—United States and worldwide, 2003-04 season, and composition of the 2004-05 influenza vaccine. MMWR Morb Mortal Wkly Rep 2004; 53 (25) 547-552 , a1
42 Ostrowsky B, Huang A, Terry W , et al. Low pathogenic avian influenza A (H7N2) virus infection in immunocompromised adult, New York, USA, 2003. Emerg Infect Dis 2012; 18 (7) 1128-1131
43 Avian influenza A/(H7N2) outbreak in the United Kingdom. Euro Surveill 2007; 12 (5) E070531.2
44 Nguyen-Van-Tam JS, Nair P, Acheson P , et al; Incident Response Team. Outbreak of low pathogenicity H7N3 avian influenza in UK, including associated case of human conjunctivitis. Euro Surveill 2006; 11 (5) E060504.2
45 Puzelli S, Di Trani L, Fabiani C , et al. Serological analysis of serum samples from humans exposed to avian H7 influenza viruses in Italy between 1999 and 2003. J Infect Dis 2005; 192 (8) 1318-1322
46 Tweed SA, Skowronski DM, David ST , et al. Human illness from avian influenza H7N3, British Columbia. Emerg Infect Dis 2004; 10 (12) 2196-2199
47 Centers for Disease Control and Prevention (CDC). Notes from the field: highly pathogenic avian influenza A (H7N3) virus infection in two poultry workers—Jalisco, Mexico, July 2012. MMWR Morb Mortal Wkly Rep 2012; 61 (36) 726-727
48 Fouchier RA, Schneeberger PM, Rozendaal FW , et al. 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 2004; 101 (5) 1356-1361
49 Gao R, Cao B, Hu Y , et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med 2013; 368 (20) 1888-1897
50 World Health Organization(WHO). Human Infection with Avian Influenza A(H7N9). Available at http://www.wpro.who.int/outbreaks_emergencies/H7N9/en/ . Accessed on March 10, 2015.
51 Zhang Q, Shi J, Deng G , et al. H7N9 influenza viruses are transmissible in ferrets by respiratory droplet. Science 2013; 341 (6144) 410-414
52 Watanabe T, Kiso M, Fukuyama S , et al. Characterization of H7N9 influenza A viruses isolated from humans. Nature 2013; 501 (7468) 551-555
53 Liu D, Shi W, Shi Y , et al. Origin and diversity of novel avian influenza A H7N9 viruses causing human infection: phylogenetic, structural, and coalescent analyses. Lancet 2013; 381 (9881) 1926-1932
54 Rudge JW, Coker R. Human to human transmission of H7N9. BMJ 2013; 347: f4730
55 Yi L, Guan D, Kang M , et al. Family clusters of avian influenza A H7N9 virus infection in Guangdong Province, China. J Clin Microbiol 2015; 53 (1) 22-28
56 World Health Organization(WHO). WHO risk assessment of human infections with avian influenza A(H7N9) virus. Available at http://www.who.int/influenza/human_animal_interface/influenza_h7n9/RiskAssessment_H7N9_23Feb20115.pdf . Accessed on February 23, 2015.
57 Centers for Disease Control and Prevention. H7N9 case detected in Malaysia. Available at http://www.cdc.gov/flu/news/h7n9-case-malaysia.htm . Accessed on February 13, 2014.
58 Yuan J, Zhang L, Kan X , et al. Origin and molecular characteristics of a novel 2013 avian influenza A(H6N1) virus causing human infection in Taiwan. Clin Infect Dis 2013; 57 (9) 1367-1368
59 Pan American Health Organization (PAHO). (2014) Avian influenza virus A (H10N7) circulating among humans in Egypt. c2007. Available at http://www1.paho.org/hq/dmdocuments/2010/Avian_Influenza_Egypt_070503.pdf . Accessed on February 28, 2014.
60 Arzey GG, Kirkland PD, Arzey KE , et al. Influenza virus A (H10N7) in chickens and poultry abattoir workers, Australia. Emerg Infect Dis 2012; 18 (5) 814-816
61 Chen H, Yuan H, Gao R , et al. Clinical and epidemiological characteristics of a fatal case of avian influenza A H10N8 virus infection: a descriptive study. Lancet 2014; 383 (9918) 714-721
62 Health and Family Planning Commision of Jiangxi Province. Jiangxi 1 new confirmed cases of human infection with avian influenza H10N8. Available at http://www.jxwst.gov.cn/gzdt/201402/t20140213_308109.htm . Accessed on February 28, 2014.
63 Castrucci MR, Donatelli I, Sidoli L, Barigazzi G, Kawaoka Y, Webster RG. Genetic reassortment between avian and human influenza A viruses in Italian pigs. Virology 1993; 193 (1) 503-506
64 Ma W, Kahn RE, Richt JA. The pig as a mixing vessel for influenza viruses: Human and veterinary implications. J Mol Genet Med 2008; 3 (1) 158-166
65 Lipatov AS, Kwon YK, Sarmento LV , et al. Domestic pigs have low susceptibility to H5N1 highly pathogenic avian influenza viruses. PLoS Pathog 2008; 4 (7) e1000102
66 He L, Zhao G, Zhong L , et al. Isolation and characterization of two H5N1 influenza viruses from swine in Jiangsu Province of China. Arch Virol 2013; 158 (12) 2531-2541
67 Li H, Yu K, Yang H , et al. Isolation and characterization of H5N1 and H9N2 influenza viruses from pigs in China. Chin J Prev Vet Med 2003; 26: 1-6
68 Shi WF, Gibbs MJ, Zhang YZ , et al. Genetic analysis of four porcine avian influenza viruses isolated from Shandong, China. Arch Virol 2008; 153 (1) 211-217
69 Zhu Q, Yang H, Chen W , et al. A naturally occurring deletion in its NS gene contributes to the attenuation of an H5N1 swine influenza virus in chickens. J Virol 2008; 82 (1) 220-228
70 Takano R, Nidom CA, Kiso M , et al. A comparison of the pathogenicity of avian and swine H5N1 influenza viruses in Indonesia. Arch Virol 2009; 154 (4) 677-681
71 Nidom CA, Takano R, Yamada S , et al. Influenza A (H5N1) viruses from pigs, Indonesia. Emerg Infect Dis 2010; 16 (10) 1515-1523
72 Choi YK, Nguyen TD, Ozaki H , et al. Studies of H5N1 influenza virus infection of pigs by using viruses isolated in Vietnam and Thailand in 2004. J Virol 2005; 79 (16) 10821-10825
73 Peiris JSM, Guan Y, Markwell D, Ghose P, Webster RG, Shortridge KF. Cocirculation of avian H9N2 and contemporary “human” H3N2 influenza A viruses in pigs in southeastern China: potential for genetic reassortment?. J Virol 2001; 75 (20) 9679-9686
74 Cong YL, Pu J, Liu QF , et al. Antigenic and genetic characterization of H9N2 swine influenza viruses in China. J Gen Virol 2007; 88 (Pt 7): 2035-2041
75 Yu H, Zhou YJ, Li GX , et al. Genetic diversity of H9N2 influenza viruses from pigs in China: a potential threat to human health?. Vet Microbiol 2011; 149 (1–2) 254-261
76 Nichol KL, Treanor JJ. Vaccines for seasonal and pandemic influenza. J Infect Dis 2006; 194 (Suppl. 02) S111-S118
77 O'Donnell CD, Subbarao K. The contribution of animal models to the understanding of the host range and virulence of influenza A viruses. Microbes Infect 2011; 13 (5) 502-515
78 Neumann G, Noda T, Kawaoka Y. Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 2009; 459 (7249) 931-939
79 Chen H, Bright RA, Subbarao K , et al. Polygenic virulence factors involved in pathogenesis of 1997 Hong Kong H5N1 influenza viruses in mice. Virus Res 2007; 128 (1-2) 159-163
80 Seo SH, Hoffmann E, Webster RG. Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nat Med 2002; 8 (9) 950-954
81 Subbarao EK, London W, Murphy BR. A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol 1993; 67 (4) 1761-1764
82 Conenello GM, Zamarin D, Perrone LA, Tumpey T, Palese P. A single mutation in the PB1-F2 of H5N1 (HK/97) and 1918 influenza A viruses contributes to increased virulence. PLoS Pathog 2007; 3 (10) 1414-1421
83 Zamarin D, García-Sastre A, Xiao X, Wang R, Palese P. Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog 2005; 1 (1) e4
84 Sidwell RW, Huffman JH, Gilbert J , et al. Utilization of pulse oximetry for the study of the inhibitory effects of antiviral agents on influenza virus in mice. Antimicrob Agents Chemother 1992; 36 (2) 473-476
85 Schulman JL, Kilbourne ED. Experimental transmission of influenza virus infection in mice. i. the period of transmissibility. J Exp Med 1963; 118: 257-266
86 Lowen AC, Mubareka S, Tumpey TM, García-Sastre A, Palese P. The guinea pig as a transmission model for human influenza viruses. Proc Natl Acad Sci U S A 2006; 103 (26) 9988-9992
87 Van Hoeven N, Belser JA, Szretter KJ , et al. Pathogenesis of 1918 pandemic and H5N1 influenza virus infections in a guinea pig model: antiviral potential of exogenous alpha interferon to reduce virus shedding. J Virol 2009; 83 (7) 2851-2861
88 Eichelberger MC. The cotton rat as a model to study influenza pathogenesis and immunity. Viral Immunol 2007; 20 (2) 243-249
89 Sadowski W, Semkow R, Wilczyński J, Kruś S, Kańtoch M. The cotton rat (Sigmodon hispidus) as an experimental model for studying viruses in human respiratory tract infections. I. Para-influenza virus type 1, 2 and 3, adenovirus type 5 and RS virus [article in Polish].. Med Dosw Mikrobiol 1987; 39 (1) 33-42
90 Kobasa D, Jones SM, Shinya K , et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 2007; 445 (7125) 319-323
91 Rimmelzwaan GF, Kuiken T, van Amerongen G, Bestebroer TM, Fouchier RA, Osterhaus AD. A primate model to study the pathogenesis of influenza A (H5N1) virus infection. Avian Dis 2003; 47 (3, Suppl): 931-933
92 Belser JA, Szretter KJ, Katz JM, Tumpey TM. Use of animal models to understand the pandemic potential of highly pathogenic avian influenza viruses. Adv Virus Res 2009; 73: 55-97
93 Sweet C, Bird RA, Cavanagh D, Toms GL, Collie MH, Smith H. The local origin of the febrile response induced in ferrets during respiratory infection with a virulent influenza virus. Br J Exp Pathol 1979; 60 (3) 300-308
94 Zitzow LA, Rowe T, Morken T, Shieh WJ, Zaki S, Katz JM. Pathogenesis of avian influenza A (H5N1) viruses in ferrets. J Virol 2002; 76 (9) 4420-4429
95 Maines TR, Chen LM, Matsuoka Y , et al. Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model. Proc Natl Acad Sci U S A 2006; 103 (32) 12121-12126
96 Herlocher ML, Elias S, Truscon R , et al. Ferrets as a transmission model for influenza: sequence changes in HA1 of type A (H3N2) virus. J Infect Dis 2001; 184 (5) 542-546
97 Yen HL, Lipatov AS, Ilyushina NA , et al. Inefficient transmission of H5N1 influenza viruses in a ferret contact model. J Virol 2007; 81 (13) 6890-6898
98 Meng Z, Han R, Hu Y , et al. Possible pandemic threat from new reassortment of influenza A(H7N9) virus in China. Euro Surveill 2014; 19 (6) pii 20699
99 Ma C, Lam TT-Y, Chai Y , et al. Emergence and evolution of H10 subtype influenza viruses in poultry in China. J Virol 2015; 89 (7) 3534-3541
100 Zhao K, Gu M, Zhong L , et al. Characterization of three H5N5 and one H5N8 highly pathogenic avian influenza viruses in China. Vet Microbiol 2013; 163 (3–4) 351-357
101 Qi X, Cui L, Yu H, Ge Y, Tang F. Whole-genome sequence of a reassortant H5N6 avian influenza virus isolated from a live poultry market in China, 2013. Genome Announc 2014; 2 (5) 706-714
102 Lam TT-Y, Zhou B, Wang J , et al. Dissemination, divergence and establishment of H7N9 influenza viruses in China. Nature 2015; 522 (7554) 102-105
103 Yamada S, Hatta M, Staker BL , et al. Biological and structural characterization of a host-adapting amino acid in influenza virus. PLoS Pathog 2010; 6 (8) e1001034
104 Gabriel G, Herwig A, Klenk HD. Interaction of polymerase subunit PB2 and NP with importin alpha1 is a determinant of host range of influenza A virus. PLoS Pathog 2008; 4 (2) e11
105 Song MS, Pascua PN, Lee JH , et al. The polymerase acidic protein gene of influenza a virus contributes to pathogenicity in a mouse model. J Virol 2009; 83 (23) 12325-12335
106 Kawaoka Y, Webster RG. Sequence requirements for cleavage activation of influenza virus hemagglutinin expressed in mammalian cells. Proc Natl Acad Sci U S A 1988; 85 (2) 324-328
107 Yen HL, Peiris JS. Mapping antibody epitopes of the avian H5N1 influenza virus. PLoS Med 2009; 6 (4) e1000064
108 LeGoff J, Rousset D, Abou-Jaoudé G , et al. I223R mutation in influenza A(H1N1)pdm09 neuraminidase confers reduced susceptibility to oseltamivir and zanamivir and enhanced resistance with H275Y. PLoS ONE 2012; 7 (8) e37095
109 de Vries E, de Vries RP, Wienholts MJ , et al. Influenza A virus entry into cells lacking sialylated N-glycans. Proc Natl Acad Sci U S A 2012; 109 (19) 7457-7462