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Science 16 January 1998:
Vol. 279. no. 5349, pp. 393 - 396
DOI: 10.1126/science.279.5349.393
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Reports

Characterization of an Avian Influenza A (H5N1) Virus Isolated from a Child with a Fatal Respiratory Illness

Kanta Subbarao, * Alexander Klimov, Jacqueline Katz, Helen Regnery, Wilina Lim, Henrietta Hall, Michael Perdue, David Swayne, Catherine Bender, Jing Huang, Mark Hemphill, Thomas Rowe, Michael Shaw, Xiyan Xu, Keiji Fukuda, Nancy Cox

An avian H5N1 influenza A virus (A/Hong Kong/156/97) was isolated from a tracheal aspirate obtained from a 3-year-old child in Hong Kong with a fatal illness consistent with influenza. Serologic analysis indicated the presence of an H5 hemagglutinin. All eight RNA segments were derived from an avian influenza A virus. The hemagglutinin contained multiple basic amino acids adjacent to the cleavage site, a feature characteristic of highly pathogenic avian influenza A viruses. The virus caused 87.5 to 100 percent mortality in experimentally inoculated White Plymouth Rock and White Leghorn chickens. These results may have implications for global influenza surveillance and planning for pandemic influenza.

K. Subbarao, A. Klimov, J. Katz, H. Regnery, H. Hall, C. Bender, J. Huang, M. Hemphill, T. Rowe, M. Shaw, X. Xu, K. Fukuda, N. Cox, Influenza Branch, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
W. Lim, Government Virus Unit, Queen Mary Hospital, Hong Kong, China.
M. Perdue and D. Swayne, Southeast Poultry Research Laboratory, Agriculture Research Service, U.S. Department of Agriculture, Athens, GA 30605, USA.
*   To whom correspondence should be addressed.

The introduction and subsequent spread in the human population of influenza A viruses with a novel hemagglutinin (HA) or a novel HA and neuraminidase (NA) subtype results from a sudden and major change in virus antigenicity, which is referred to as an antigenic shift. Lack of protective immunity in the human population against the new HA and NA proteins can result in rapid global spread of the virus, leading to widespread morbidity and mortality. Pandemic strains contain new HA or NA genes derived from animal influenza A viruses. Influenza A viruses of 15 recognized HA subtypes and 9 NA subtypes are known to circulate in birds and other animals, creating a reservoir of influenza A virus genes available for genetic reassortment with circulating human strains of influenza virus. However, on the basis of seroarchaeology and virus isolation since 1933, only viruses of the H1, H2, and H3 subtypes are known to infect and cause disease in humans (1).

In general, avian influenza A viruses, including those that are highly pathogenic in birds, do not appear to replicate efficiently or cause disease in humans. The only reported natural infections of humans by avian viruses are two cases of conjunctivitis associated with avian H7 viruses, one of which was an infection with a seal virus of avian origin (2). Serosurveys of farm workers in southern China by single radial hemolysis revealed a seroprevalence ranging from 1 to 38% for avian viruses of the H4 through H13 subtypes, including 7% seroprevalence for H5 viruses (3). In contrast, there were no documented infections in U.S. poultry workers exposed to strains of avian (H5) influenza A viruses that were highly pathogenic in poultry (4).

On 9 May 1997, a previously healthy 3-year-old boy, who was a resident of Hong Kong, developed a sore throat, dry cough, and fever. He was diagnosed with pharyngitis and prescribed antibiotics and aspirin. The child continued to be symptomatic and febrile and was hospitalized on 15 May. Upon admission, he was noted to be febrile (axillary temperature above 39°C) and irritable. His laboratory tests were most remarkable for leukopenia (2000 white blood cells per cubic millimeter). His chest x-ray was within normal limits. The next day, he was transferred to another hospital, where he developed progressive respiratory distress associated with hypoxemia, consistent with acute respiratory distress syndrome. He also became increasingly unresponsive. Computerized tomography of the head was unremarkable, and examination of his cerebrospinal fluid was not suggestive of an inflammatory process. Despite mechanical ventilation and broad antibiotic coverage, the child died on 21 May with several complications, including respiratory failure, renal failure, and disseminated intravascular coagulopathy. Postmortem liver and kidney biopsies showed evidence of microvascular fatty infiltration consistent with Reye's syndrome, which is a recognized complication of influenza.

A tracheal aspirate specimen was obtained on day 10 of illness and was cultured for respiratory viruses. A cytopathic effect was noted in mammalian Madin Darby canine kidney (MDCK) cells and rhesus monkey kidney (LLC-MK2) cells 2 and 3 days after inoculation, respectively. The isolate, designated A/Hong Kong/156/97, was typed as an influenza A virus by means of monoclonal antibodies to viral nucleoprotein in an immunofluorescence test, and it did not stain with monoclonal antibodies to respiratory syncytial virus and parainfluenza viruses 1, 2, and 3 (5). Additionally, bacterial and fungal cultures of the tracheal secretions did not yield pathogenic organisms. The influenza A virus isolate was not inhibited by sheep hyperimmune antisera to H1 and H3 influenza viruses included in the World Health Organization's Influenza Reagent Kit. Confirmation of the initial identification of the isolate as influenza A was obtained by immunoperoxidase staining of infected MDCK monolayers with influenza virus-specific monoclonal antibodies (5, 6). A hemagglutination-inhibition (HI) test with a panel of antisera to different subtypes of influenza A virus gave a reaction (HI titer 1280) only with the A/Tern/South Africa/61 (H5N3) antiserum, providing an identification of the HA as H5 (7).

Because the antiviral drugs amantadine and rimantadine can be used for prophylaxis and treatment of influenza A virus infections, it was of interest to establish the antiviral sensitivity of this virus. Results of an in vitro assay revealed that the virus was sensitive to amantadine (5).

Amplification of the HA and NA genes by polymerase chain reaction (PCR), from RNA extracted from the MDCK cell isolate, confirmed the HA subtype as H5 and identified the NA subtype as N1 (5). Nucleotide sequence analysis of the HA gene (Fig. 1) revealed multiple basic amino acids at the cleavage site between the HA1 and HA2 domains, a feature (8) that is associated with highly pathogenic H5 avian viruses and can be part of a motif (Arg-Lys-Lys-Arg) (9). In addition, there are three basic amino acids in the four-amino-acid insertion (Arg-Gln-Arg-Arg) adjacent to the cleavage site. Phylogenetic analysis (Fig. 2) shows that there are two lineages of H5 HA genes: the Eurasian and North American (10). The A/Hong Kong/156/97 virus lies in the Eurasian lineage. In addition to the sequence motif adjacent to the cleavage site, other features of the HA associated with virulence, such as glycosylation sites (11), were conserved in the A/Hong Kong/156/97 virus. The residues of the H5 receptor binding site described by Garcia et al. are conserved in the A/Hong Kong/156/97 virus as well (12).

Fig. 1. Alignment and comparison of complete HA coding sequence for the A/Hong Kong/156/97 virus isolate. Dashes under the sequence adjacent to the cleavage site indicate the positions of the insertions relative to the reference strain A/Turkey/England/91. The boxed amino acids indicate potential glycosylation sites. Underlined, bold peptides describe the location of the receptor binding site (12). The nucleotide sequence has been deposited in GenBank (accession number AF036356). [View Larger Version of this Image (32K GIF file)]

Fig. 2. Phylogenetic relationship of the HA1 domain of the hemagglutinin gene of representative avian H5 viruses and the H5 virus isolated from a human (A/Hong Kong/156/97, boxed). The tree is rooted in A/Chick/Scotland/59 (H5N1) as an outgroup. This is a neighbor-joining analysis determined by PHYLIP. [View Larger Version of this Image (23K GIF file)]

Sequence analysis of the NA gene of the A/Hong Kong/156/97 virus determined that the NA was of the N1 subtype, related most closely to the NA gene of the A/Parrot/Ulster/73 (H7N1) virus (Table 1). The stalk region, which extends from the viral membrane up to amino acid 85, had a 19-amino-acid deletion when aligned with other available N1 NA gene sequences. Large block deletions of 33 to 48 nucleotides have been described in the stalk region of N1 NA genes in several N1 subtype strains isolated between 1933 and 1957 (13). The residues corresponding to those identified by Colman et al. (14) surrounding the sialic acid binding site of the N2 NA (with the exception of 121Ile, which is seen in all N1 NA genes) are conserved in the A/Hong Kong/156/97 virus.

Table 1. Molecular analysis of the gene segments of the A/Hong Kong/156/97 virus. Nucleotide sequences were compared, and identity was determined by FASTA (Wisconsin Package, version 9.0) searches of GenBank and European Molecular Biology Laboratory (EMBL) databases as of August and June 1997, respectively. The nucleotide sequences have been deposited in GenBank (accession numbers AF036356 through AF036363).

Gene segment Region amplified Region sequenced Viruses with greatest degrees of identity Identity (%)
PB2 8-2337 61-2310 A/Budgerigar/Hokkaido/1/77 (H4N6) 90.1
PB1 10-2340 32-2291 A/Singapore/1/57 (H2N2) 90.6
PA 1-2200 31-1754 and 1974-2179 A/Duck/Hokkaido/8/80 (H3N8) 91.0
HA 1-1773 21-1743 A/Turkey/England/91 (H5N1) 93.5
NP 7-1561 21-1542 A/Mallard/Astrakhan/244/82 (H14N6) 93.6
NA 1-1400 29-1391 A/Parrot/Ulster/73 (H7N1) 91.1
M 775-1027 796-1001 A/Turkey/Minnesota/833/80 (H1N1) 98.5
NS 1-890 27-860 A/Duck/Hong Kong/717/79 (H1N3) 93.7

Nucleotide sequence and phylogenetic analysis determined that genes encoding all internal and nonstructural proteins were most closely related to known genes of avian origin (Table 1). The similarity of the A/Hong Kong/156/97 PB1 gene to the corresponding gene of human A/Singapore/1/57 (H2N2) virus can be explained by the suggestion that, in 1957, this gene was transmitted to human influenza viruses from avian species (15). The highest percent identities of the PB2, PA, NP, M, and NS genes of A/Hong Kong/156/97 to human influenza virus genes were 83.3, 83.6, 85.4, 91.2, and 89.3%, respectively, 3.1 to 9.9% lower than the percent identity with avian viruses listed in Table 1. Therefore, all gene segments of the A/Hong Kong/156/97 virus appeared to be avian in origin with no evidence of genetic reassortment with recent human influenza A virus genes.

To determine whether the A/Hong Kong/156/97 virus isolated in MDCK cells retained pathogenicity for avian species, we inoculated the virus by intravenous and intranasal routes into 16 3-week-old White Plymouth Rock chickens (Gallus domesticus) and by combined intranasal and intratracheal routes into six adult female White Leghorn chickens. The virus killed all eight chickens inoculated intravenously within 3 days; all of the chickens inoculated intranasally or by combined routes died within 9 days, except one intranasally inoculated White Plymouth Rock chicken, which survived. The chickens that died had lesions consistent with highly pathogenic avian influenza (fowl plague) and included necrosis of the combs and subcutaneous hemorrhages of the legs, thoracic wall, fat pads, proventriculus, and serosa of the heart. Most chickens had moderate to severe diffuse interstitial pneumonia with demonstration of influenza viral antigen in blood vessel and air capillary endothelium and macrophages. The virus also replicated in other tissues, as indicated by the presence of viral antigen in neurons, cardiac myocytes, and blood capillary endothelial cells. The A/Hong Kong/156/97 virus remained highly pathogenic for birds after replication in mammalian cells.

To rule out laboratory contamination as a source of the isolate, we confirmed that the H5N1 virus could be identified directly in the tracheal aspirate obtained from the patient. The MDCK cells and embryonated eggs re-inoculated with the original clinical material yielded only an H5 virus. In addition, successful PCR amplification of the HA gene from RNA extracted from the clinical material was achieved with only H5 HA-specific primers and not with H1, H3, or B HA-specific primers (Fig. 3). The nucleotide sequences of the coding regions of the HA and NA genes amplified from RNA extracted from the clinical material were identical to the sequences determined for the virus isolated in MDCK cells (5). Cells from the clinical material were stained by immunofluorescence with monoclonal antibodies against the H5 HA and influenza A NP but not with monoclonal antibody against the H3 HA and a pool of influenza B-specific monoclonal antibodies (Fig. 4). Paired sera from the patient were not available; however, a single serum specimen collected on day 10 of illness did not react with the isolate in an HI test.

Fig. 3. Amplification of influenza HA gene from RNA extracted directly from the tracheal aspirate obtained from the patient. Lanes 1 and 14 contain a DNA ladder, with fragment sizes indicated along the left edge of the gel. RNA was extracted by means of the Qiagen (Valencia, California) RNeasy kit from the clinical material (lanes labeled HK/156/97: 4, 7, 10, 13), from known H1 (lane 2), H3 (lane 5), and H5 (lane 8) influenza A viruses, influenza B virus (lane 11), and water controls (lanes labeled -: 3, 6, 9, 12); reverse transcriptase reactions were carried out using 5 µl of RNA and 25 units of avian myeloblastosis virus reverse transcriptase in a 25-µl reaction. PCR was carried out using H1 (lanes 2 to 4), H3 (lanes 5 to 7), H5 (lanes 8 to 10), and B (lanes 11 to 13) HA-specific primers (PP, primer pairs); the expected product sizes are 1104, 785, 1110, and 1104 base pairs, respectively. PCR cycling conditions included denaturation at 94°C for 7 min, annealing for 2 min at 50°C, and extension for 3 min at 72°C, followed by 29 cycles of denaturation at 94°C for 1 min, annealing for 2 min at 50°C, extension for 3 min at 72°C, and an additional extension of 7 min at 72°C. [View Larger Version of this Image (68K GIF file)]

Fig. 4. Immunofluorescence staining of cells from the tracheal aspirate obtained from the patient. Acetone-fixed cells were incubated with influenza virus-specific monoclonal antibodies followed by fluorescein isothiocyanate-conjugated goat antibodies to mouse immunoglobulin G. The influenza virus-specific monoclonal antibodies used were (A) a pool of two antibodies raised against the H5 HA of A/chicken/Pennsylvania/1370/83, (B) an antibody that is broadly cross-reactive with the HA of human H3N2 viruses, (C) a pool of two antibodies specific for the NP of influenza A viruses, and (D) antibody specific for influenza B viruses. [View Larger Version of this Image (92K GIF file)]

Although a clear epidemiologic link was not established between the infected child and infected poultry, there were three outbreaks of influenza in poultry on farms in Hong Kong between late March and early May 1997. Two viruses from one of these outbreaks were H5N1 viruses. Additionally, there were a few sick chickens at the child's preschool, but there is no evidence that the chickens were infected with avian influenza or that the child was in close contact with them.

The HA is the main determinant of the host range of influenza A viruses, a phenotype conferred by its specificity for receptor recognition and binding. All key amino acid residues believed to be associated with the specificity of receptor binding of H5 HA (12) were conserved in the A/Hong Kong/156/97 virus. Identification of the specific linkages (alpha 2,6 or alpha 2,3 Gal) that can be bound by the A/Hong Kong/156/97 virus and knowledge of the distribution of receptors bearing these linkages in the human respiratory tract may help explain why this avian H5 virus infected this child.

In addition to its role as a determinant of host range, the HA gene is important in determining the virulence of avian influenza A viruses for poultry (16). All human influenza virus HA genes characterized to date, including the 1918 viruses (17), have a single, basic Arg residue at the cleavage site between HA1 and HA2. An insertion similar to the basic amino acid insertion adjacent to the cleavage site in the HA gene of the A/Hong Kong/156/97 virus has been found in several highly pathogenic avian H5 viruses. Basic amino acids adjacent to the cleavage site allow proteases other than trypsin-like proteases to cleave the HA into HA1 and HA2 domains. This event would enable the virus to spread systemically by altering the tissue range of these viruses from the respiratory and alimentary tract to other sites, such as the brain, heart, and blood vessels (18). It has been suggested that the acquisition of a ubiquitously cleavable avian HA by a human influenza A virus could make a virus lethal (16). It remains to be shown whether gene segments other than the HA may also have contributed to the ability of the virus to infect a human.

A pandemic of influenza could begin with isolated cases, in which avian or swine influenza viruses adapt to human hosts or, over time, genetically reassort with circulating human influenza A viruses, or it could begin as a rapid and explosive spread of a pandemic virus derived from a reassortment event in an intermediate host. Increased surveillance efforts have been initiated to identify other cases of illness associated with influenza A (H5N1) viruses. In addition, serosurveys are under way in an effort to identify asymptomatic or mild clinical infections in the region and substantiate the previous report of seroprevalence to H5 viruses (3). These studies may determine whether H5 viruses similar to A/Hong Kong/156/97 are circulating in the human population and if the isolation of the A/Hong Kong/156/97 virus is the first step in the recognition of an influenza A virus with pandemic potential or whether this case is simply an isolated event.

Note added in proof: Since the submission of this report, there have been 12 additional confirmed human cases of influenza A (H5N1) infections in Hong Kong, including three fatalities. Sequence analysis of the genes of six of the isolates revealed that all of the genes are of avian origin and are closely related to each other. The HA gene codes for a multiple basic amino acid insertion upstream of the cleavage site, associated with highly pathogenic avian influenza viruses and identical to that seen in the A/Hong Kong/156/97 virus.

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  19. We gratefully acknowledge the contributions of K. Shu-wing, J. Chan, and the doctors and nurses of Queen Elizabeth Hospital, Hong Kong; P. Lo and the doctors at the Baptist Hospital, Hong Kong; M. F. C. Chan, P. T. Saw, K. H. Mak, and T. H. Tsang of the Hong Kong Department of Health; J. S. Tam of Chinese University of Hong Kong; K. F. Shortridge of the University of Hong Kong; K. Liu of the Department of Agriculture and Fisheries, Hong Kong; D. Suarez of the Southeast Poultry Research Laboratory, Athens, GA; and H. Izurieta, C. Dentinger, T. Voss, G. Perez-Oronoz, J. Love, W. Gamble, and I. Baker of the Centers for Disease Control and Prevention, Atlanta, GA. We thank R. G. Webster of St. Jude Children's Research Hospital, Memphis, TN, for sharing oligonucleotide primers for and monoclonal antibodies against the H5 HA, and E. Claas and A. Osterhaus of Erasmus University, Rotterdam, Netherlands, for sharing primer sequences.
26 September 1997; accepted 9 December 1997


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J. Virol. 82, 3405-3414
   Abstract »    Full Text »    PDF »
H5N1 avian influenza re-emergence of Lake Qinghai: phylogenetic and antigenic analyses of the newly isolated viruses and roles of migratory birds in virus circulation.
G. Wang, D. Zhan, L. Li, F. Lei, B. Liu, D. Liu, H. Xiao, Y. Feng, J. Li, B. Yang, et al. (2008)
J. Gen. Virol. 89, 697-702
   Abstract »    Full Text »    PDF »
Novel Approach to the Development of Effective H5N1 Influenza A Virus Vaccines: Use of M2 Cytoplasmic Tail Mutants.
T. Watanabe, S. Watanabe, J. H. Kim, M. Hatta, and Y. Kawaoka (2008)
J. Virol. 82, 2486-2492
   Abstract »    Full Text »    PDF »
Rapid Differentiation of Influenza A Virus Subtypes and Genetic Screening for Virus Variants by High-Resolution Melting Analysis.
J.-H. Lin, C.-P. Tseng, Y.-J. Chen, C.-Y. Lin, S.-S. Chang, H.-S. Wu, and J.-C. Cheng (2008)
J. Clin. Microbiol. 46, 1090-1097
   Abstract »    Full Text »    PDF »
Antigenic Profile of Avian H5N1 Viruses in Asia from 2002 to 2007.
W. L. Wu, Y. Chen, P. Wang, W. Song, S.-Y. Lau, J. M. Rayner, G. J. D. Smith, R. G. Webster, J. S. M. Peiris, T. Lin, et al. (2008)
J. Virol. 82, 1798-1807
   Abstract »    Full Text »    PDF »
A Single-Amino-Acid Substitution in the NS1 Protein Changes the Pathogenicity of H5N1 Avian Influenza Viruses in Mice.
P. Jiao, G. Tian, Y. Li, G. Deng, Y. Jiang, C. Liu, W. Liu, Z. Bu, Y. Kawaoka, and H. Chen (2008)
J. Virol. 82, 1146-1154
   Abstract »    Full Text »    PDF »
Origin of highly pathogenic H5N1 avian influenza virus in China and genetic characterization of donor and recipient viruses.
M. M. Mukhtar, S. T. Rasool, D. Song, C. Zhu, Q. Hao, Y. Zhu, and J. Wu (2007)
J. Gen. Virol. 88, 3094-3099
   Abstract »    Full Text »    PDF »
Differential Polymerase Activity in Avian and Mammalian Cells Determines Host Range of Influenza Virus.
G. Gabriel, M. Abram, B. Keiner, R. Wagner, H.-D. Klenk, and J. Stech (2007)
J. Virol. 81, 9601-9604
   Abstract »    Full Text »    PDF »
The H5N1 Influenza Virus NS Genes Selected after 1998 Enhance Virus Replication in Mammalian Cells.
K. Y. Twu, R.-L. Kuo, J. Marklund, and R. M. Krug (2007)
J. Virol. 81, 8112-8121
   Abstract »    Full Text »    PDF »
The quail and chicken intestine have sialyl-galactose sugar chains responsible for the binding of influenza A viruses to human type receptors.
C.-T. Guo, N. Takahashi, H. Yagi, K. Kato, T. Takahashi, S.-Q. Yi, Y. Chen, T. Ito, K. Otsuki, H. Kida, et al. (2007)
Glycobiology 17, 713-724
   Abstract »    Full Text »    PDF »
Evolutionary Insights into the Ecology of Coronaviruses.
D. Vijaykrishna, G. J. D. Smith, J. X. Zhang, J. S. M. Peiris, H. Chen, and Y. Guan (2007)
J. Virol. 81, 4012-4020
   Abstract »    Full Text »    PDF »
Avian Influenza Virus (H5N1): a Threat to Human Health.
J. S. M. Peiris, M. D. de Jong, and Y. Guan (2007)
Clin. Microbiol. Rev. 20, 243-267
   Abstract »    Full Text »    PDF »
Differential onset of apoptosis in influenza A virus H5N1- and H1N1-infected human blood macrophages.
C. K. P. Mok, D. C. W. Lee, C.-Y. Cheung, M. Peiris, and A. S. Y. Lau (2007)
J. Gen. Virol. 88, 1275-1280
   Abstract »    Full Text »    PDF »
Efficacy of Oseltamivir Therapy in Ferrets Inoculated with Different Clades of H5N1 Influenza Virus.
E. A. Govorkova, N. A. Ilyushina, D. A. Boltz, A. Douglas, N. Yilmaz, and R. G. Webster (2007)
Antimicrob. Agents Chemother. 51, 1414-1424
   Abstract »    Full Text »    PDF »
Role of Host Cytokine Responses in the Pathogenesis of Avian H5N1 Influenza Viruses in Mice.
K. J. Szretter, S. Gangappa, X. Lu, C. Smith, W.-J. Shieh, S. R. Zaki, S. Sambhara, T. M. Tumpey, and J. M. Katz (2007)
J. Virol. 81, 2736-2744
   Abstract »    Full Text »    PDF »
Newcastle Disease Virus-Based Live Attenuated Vaccine Completely Protects Chickens and Mice from Lethal Challenge of Homologous and Heterologous H5N1 Avian Influenza Viruses.
J. Ge, G. Deng, Z. Wen, G. Tian, Y. Wang, J. Shi, X. Wang, Y. Li, S. Hu, Y. Jiang, et al. (2007)
J. Virol. 81, 150-158
   Abstract »    Full Text »    PDF »
From the Cover: Predicting the global spread of H5N1 avian influenza.
A. M. Kilpatrick, A. A. Chmura, D. W. Gibbons, R. C. Fleischer, P. P. Marra, and P. Daszak (2006)
PNAS 103, 19368-19373
   Abstract »    Full Text »    PDF »
The evolutionary emergence of pandemic influenza.
T. Day, J.-B. Andre, and A. Park (2006)
Proc R Soc B 273, 2945-2953
   Abstract »    Full Text »    PDF »
Recent H5N1 avian Influenza A virus increases rapidly in virulence to mice after a single passage in mice.
M. Mase, N. Tanimura, T. Imada, M. Okamatsu, K. Tsukamoto, and S. Yamaguchi (2006)
J. Gen. Virol. 87, 3655-3659
   Abstract »    Full Text »    PDF »
Acute Respiratory Distress Syndrome Induced by Avian Influenza A (H5N1) Virus in Mice.
T. Xu, J. Qiao, L. Zhao, G. Wang, G. He, K. Li, Y. Tian, M. Gao, J. Wang, H. Wang, et al. (2006)
Am. J. Respir. Crit. Care Med. 174, 1011-1017
   Abstract »    Full Text »    PDF »
Emerging Respiratory Viruses: Challenges and Vaccine Strategies.
L. Gillim-Ross and K. Subbarao (2006)
Clin. Microbiol. Rev. 19, 614-636
   Abstract »    Full Text »    PDF »
Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model.
T. R. Maines, L.-M. Chen, Y. Matsuoka, H. Chen, T. Rowe, J. Ortin, A. Falcon, N. T. Hien, L. Q. Mai, E. R. Sedyaningsih, et al. (2006)
PNAS 103, 12121-12126
   Abstract »    Full Text »    PDF »
Infection of human airway epithelium by human and avian strains of influenza a virus..
C. I. Thompson, W. S. Barclay, M. C. Zambon, and R. J. Pickles (2006)
J. Virol. 80, 8060-8068
   Abstract »    Full Text »    PDF »
DETECTION AND ISOLATION OF HIGHLY PATHOGENIC H5N1 AVIAN INFLUENZA A VIRUSES FROM BLOW FLIES COLLECTED IN THE VICINITY OF AN INFECTED POULTRY FARM IN KYOTO, JAPAN, 2004..
K. SAWABE, K. HOSHINO, H. ISAWA, T. SASAKI, T. HAYASHI, Y. TSUDA, H. KURAHASHI, K. TANABAYASHI, A. HOTTA, T. SAITO, et al. (2006)
Am J Trop Med Hyg 75, 327-332
   Abstract »    Full Text »    PDF »
Characterization of a highly pathogenic H5N1 influenza virus derived from bar-headed geese in China.
J.-Y. Zhou, H.-G. Shen, H.-X. Chen, G.-Z. Tong, M. Liao, H.-C. Yang, and J.-X. Liu (2006)
J. Gen. Virol. 87, 1823-1833
   Abstract »    Full Text »    PDF »
Properties and Dissemination of H5N1 Viruses Isolated during an Influenza Outbreak in Migratory Waterfowl in Western China..
H. Chen, Y. Li, Z. Li, J. Shi, K. Shinya, G. Deng, Q. Qi, G. Tian, S. Fan, H. Zhao, et al. (2006)
J. Virol. 80, 5976-5983
   Abstract »    Full Text »    PDF »
Establishment of multiple sublineages of H5N1 influenza virus in Asia: Implications for pandemic control.
H. Chen, G. J. D. Smith, K. S. Li, J. Wang, X. H. Fan, J. M. Rayner, D. Vijaykrishna, J. X. Zhang, L. J. Zhang, C. T. Guo, et al. (2006)
PNAS 103, 2845-2850
   Abstract »    Full Text »    PDF »
Influenza A Virus (H5N1) Infection in Cats Causes Systemic Disease with Potential Novel Routes of Virus Spread within and between Hosts.
G. F. Rimmelzwaan, D. van Riel, M. Baars, T. M. Bestebroer, G. van Amerongen, R. A.M. Fouchier, A. D.M.E. Osterhaus, and T. Kuiken (2006)
Am. J. Pathol. 168, 176-183
   Abstract »    Full Text »    PDF »
The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host.
G. Gabriel, B. Dauber, T. Wolff, O. Planz, H.-D. Klenk, and J. Stech (2005)
PNAS 102, 18590-18595
   Abstract »    Full Text »    PDF »
An improved reverse genetics system for influenza A virus generation and its implications for vaccine production.
G. Neumann, K. Fujii, Y. Kino, and Y. Kawaoka (2005)
PNAS 102, 16825-16829
   Abstract »    Full Text »    PDF »
Transmission of Equine Influenza Virus to Dogs.
P. C. Crawford, E. J. Dubovi, W. L. Castleman, I. Stephenson, E. P. J. Gibbs, L. Chen, C. Smith, R. C. Hill, P. Ferro, J. Pompey, et al. (2005)
Science 310, 482-485
   Abstract »    Full Text »    PDF »
Avian Influenza (H5N1) Viruses Isolated from Humans in Asia in 2004 Exhibit Increased Virulence in Mammals.
T. R. Maines, X. H. Lu, S. M. Erb, L. Edwards, J. Guarner, P. W. Greer, D. C. Nguyen, K. J. Szretter, L.-M. Chen, P. Thawatsupha, et al. (2005)
J. Virol. 79, 11788-11800
   Abstract »    Full Text »    PDF »
Molecular Basis of Replication of Duck H5N1 Influenza Viruses in a Mammalian Mouse Model.
Z. Li, H. Chen, P. Jiao, G. Deng, G. Tian, Y. Li, E. Hoffmann, R. G. Webster, Y. Matsuoka, and K. Yu (2005)
J. Virol. 79, 12058-12064
   Abstract »    Full Text »    PDF »
Are Ducks Contributing to the Endemicity of Highly Pathogenic H5N1 Influenza Virus in Asia?.
K. M. Sturm-Ramirez, D. J. Hulse-Post, E. A. Govorkova, J. Humberd, P. Seiler, P. Puthavathana, C. Buranathai, T. D. Nguyen, A. Chaisingh, H. T. Long, et al. (2005)
J. Virol. 79, 11269-11279
   Abstract »    Full Text »    PDF »
Highly Pathogenic H5N1 Influenza Virus Infection in Migratory Birds.
J. Liu, H. Xiao, F. Lei, Q. Zhu, K. Qin, X.-w. Zhang, X.-l. Zhang, D. Zhao, G. Wang, Y. Feng, et al. (2005)
Science 309, 1206
   Abstract »    Full Text »    PDF »
p38 Mitogen-Activated Protein Kinase-Dependent Hyperinduction of Tumor Necrosis Factor Alpha Expression in Response to Avian Influenza Virus H5N1.
D. C. W. Lee, C.-Y. Cheung, A. H. Y. Law, C. K. P. Mok, M. Peiris, and A. S. Y. Lau (2005)
J. Virol. 79, 10147-10154
   Abstract »    Full Text »    PDF »
Functional Chimeras of Human Immunodeficiency Virus Type 1 gp120 and Influenza A Virus (H3) Hemagglutinin.
K. M. Copeland, A. J. Elliot, and R. S. Daniels (2005)
J. Virol. 79, 6459-6471
   Abstract »    Full Text »    PDF »
Isolation and Characterization of Avian Influenza Viruses, Including Highly Pathogenic H5N1, from Poultry in Live Bird Markets in Hanoi, Vietnam, in 2001.
D. C. Nguyen, T. M. Uyeki, S. Jadhao, T. Maines, M. Shaw, Y. Matsuoka, C. Smith, T. Rowe, X. Lu, H. Hall, et al. (2005)
J. Virol. 79, 4201-4212
   Abstract »    Full Text »    PDF »
Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: the role of cytokines and B- and T-cell responses.
A. S. Lipatov, S. Andreansky, R. J. Webby, D. J. Hulse, J. E. Rehg, S. Krauss, D. R. Perez, P. C. Doherty, R. G. Webster, and M. Y. Sangster (2005)
J. Gen. Virol. 86, 1121-1130
   Abstract »    Full Text »    PDF »
Characterization of Highly Pathogenic H5N1 Avian Influenza A Viruses Isolated from South Korea.
C.-W. Lee, D. L. Suarez, T. M. Tumpey, H.-W. Sung, Y.-K. Kwon, Y.-J. Lee, J.-G. Choi, S.-J. Joh, M.-C. Kim, E.-K. Lee, et al. (2005)
J. Virol. 79, 3692-3702
   Abstract »    Full Text »    PDF »
Lethality to Ferrets of H5N1 Influenza Viruses Isolated from Humans and Poultry in 2004.
E. A. Govorkova, J. E. Rehg, S. Krauss, H.-L. Yen, Y. Guan, M. Peiris, T. D. Nguyen, T. H. Hanh, P. Puthavathana, H. T. Long, et al. (2005)
J. Virol. 79, 2191-2198
   Abstract »    Full Text »    PDF »
Molecular characterization of the complete genome of human influenza H5N1 virus isolates from Thailand.
P. Puthavathana, P. Auewarakul, P. C. Charoenying, K. Sangsiriwut, P. Pooruk, K. Boonnak, R. Khanyok, P. Thawachsupa, R. Kijphati, and P. Sawanpanyalert (2005)
J. Gen. Virol. 86, 423-433
   Abstract »    Full Text »    PDF »
Characterization of Avian H3N3 and H1N1 Influenza A Viruses Isolated from Pigs in Canada.
A. I. Karasin, K. West, S. Carman, and C. W. Olsen (2004)
J. Clin. Microbiol. 42, 4349-4354
   Abstract »    Full Text »    PDF »
Influenza: Emergence and Control.
A. S. Lipatov, E. A. Govorkova, R. J. Webby, H. Ozaki, M. Peiris, Y. Guan, L. Poon, and R. G. Webster (2004)
J. Virol. 78, 8951-8959
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Global Host Immune Response: Pathogenesis and Transcriptional Profiling of Type A Influenza Viruses Expressing the Hemagglutinin and Neuraminidase Genes from the 1918 Pandemic Virus.
J. C. Kash, C. F. Basler, A. Garcia-Sastre, V. Carter, R. Billharz, D. E. Swayne, R. M. Przygodzki, J. K. Taubenberger, M. G. Katze, and T. M. Tumpey (2004)
J. Virol. 78, 9499-9511
   Abstract »    Full Text »    PDF »
Continuing Evolution of H9N2 Influenza Viruses in Southeastern China.
Y. K. Choi, H. Ozaki, R. J. Webby, R. G. Webster, J. S. Peiris, L. Poon, C. Butt, Y. H. C. Leung, and Y. Guan (2004)
J. Virol. 78, 8609-8614
   Abstract »    Full Text »    PDF »
Matrix Gene of Influenza A Viruses Isolated from Wild Aquatic Birds: Ecology and Emergence of Influenza A Viruses.
L. Widjaja, S. L. Krauss, R. J. Webby, T. Xie, and R. G. Webster (2004)
J. Virol. 78, 8771-8779
   Abstract »    Full Text »    PDF »
Influenza A viruses in feral Canadian ducks: extensive reassortment in nature.
T. F. Hatchette, D. Walker, C. Johnson, A. Baker, S. P. Pryor, and R. G. Webster (2004)
J. Gen. Virol. 85, 2327-2337
   Abstract »    Full Text »    PDF »
The evolution of H5N1 influenza viruses in ducks in southern China.
H. Chen, G. Deng, Z. Li, G. Tian, Y. Li, P. Jiao, L. Zhang, Z. Liu, R. G. Webster, and K. Yu (2004)
PNAS 101, 10452-10457
   Abstract »    Full Text »    PDF »
Protection against lethal influenza virus challenge by RNA interference in vivo.
S. M. Tompkins, C.-Y. Lo, T. M. Tumpey, and S. L. Epstein (2004)
PNAS 101, 8682-8686
   Abstract »    Full Text »    PDF »
H5N1 influenza: A protean pandemic threat.
Y. Guan, L. L. M. Poon, C. Y. Cheung, T. M. Ellis, W. Lim, A. S. Lipatov, K. H. Chan, K. M. Sturm-Ramirez, C. L. Cheung, Y. H. C. Leung, et al. (2004)
PNAS 101, 8156-8161
   Abstract »    Full Text »    PDF »
Use of the DNA Flow-Thru Chip, a Three-Dimensional Biochip, for Typing and Subtyping of Influenza Viruses.
N. Kessler, O. Ferraris, K. Palmer, W. Marsh, and A. Steel (2004)
J. Clin. Microbiol. 42, 2173-2185
   Abstract »    Full Text »    PDF »
Reemerging H5N1 Influenza Viruses in Hong Kong in 2002 Are Highly Pathogenic to Ducks.
K. M. Sturm-Ramirez, T. Ellis, B. Bousfield, L. Bissett, K. Dyrting, J. E. Rehg, L. Poon, Y. Guan, M. Peiris, and R. G. Webster (2004)
J. Virol. 78, 4892-4901
   Abstract »    Full Text »    PDF »
The index influenza A virus subtype H5N1 isolated from a human in 1997 differs in its receptor-binding properties from a virulent avian influenza virus.
K. Iwatsuki-Horimoto, R. Kanazawa, S. Sugii, Y. Kawaoka, and T. Horimoto (2004)
J. Gen. Virol. 85, 1001-1005
   Abstract »    Full Text »    PDF »
Structure of the Uncleaved Human H1 Hemagglutinin from the Extinct 1918 Influenza Virus.
J. Stevens, A. L. Corper, C. F. Basler, J. K. Taubenberger, P. Palese, and I. A. Wilson (2004)
Science 303, 1866-1870
   Abstract »    Full Text »    PDF »
Alterations of pr-M Cleavage and Virus Export in pr-M Junction Chimeric Dengue Viruses.
P. Keelapang, R. Sriburi, S. Supasa, N. Panyadee, A. Songjaeng, A. Jairungsri, C. Puttikhunt, W. Kasinrerk, P. Malasit, and N. Sittisombut (2004)
J. Virol. 78, 2367-2381
   Abstract »    Full Text »    PDF »
Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome.
R. A. M. Fouchier, P. M. Schneeberger, F. W. Rozendaal, J. M. Broekman, S. A. G. Kemink, V. Munster, T. Kuiken, G. F. Rimmelzwaan, M. Schutten, G. J. J. van Doornum, et al. (2004)
PNAS 101, 1356-1361
   Abstract »    Full Text »    PDF »
Phenotypic Drug Susceptibility Assay for Influenza Virus Neuraminidase Inhibitors.
J. J. McSharry, A. C. McDonough, B. A. Olson, and G. L. Drusano (2004)
Clin. Vaccine Immunol. 11, 21-28
   Abstract »    Full Text »    PDF »
Restrictions to the Adaptation of Influenza A Virus H5 Hemagglutinin to the Human Host.
R. Harvey, A. C. R. Martin, M. Zambon, and W. S. Barclay (2004)
J. Virol. 78, 502-507
   Abstract »    Full Text »    PDF »
Severe Acute Respiratory Syndrome and Influenza: Virus Incursions from Southern China.
K. F. Shortridge (2003)
Am. J. Respir. Crit. Care Med. 168, 1416-1420
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The origin of the 1918 pandemic influenza virus: a continuing enigma.
A. H. Reid and J. K. Taubenberger (2003)
J. Gen. Virol. 84, 2285-2292
   Abstract »    Full Text »    PDF »
Characterization of H9 Subtype Influenza Viruses from the Ducks of Southern China: a Candidate for the Next Influenza Pandemic in Humans?.
K. S. Li, K. M. Xu, J. S. M. Peiris, L. L. M. Poon, K. Z. Yu, K. Y. Yuen, K. F. Shortridge, R. G. Webster, and Y. Guan (2003)
J. Virol. 77, 6988-6994
   Abstract »    Full Text »    PDF »
Pathology of Human Influenza A (H5N1) Virus Infection in Cynomolgus Macaques (Macaca fascicularis).
T. Kuiken, G. F. Rimmelzwaan, G. Van Amerongen, and A. D. M. E. Osterhaus (2003)
Vet. Pathol. 40, 304-310
   Abstract »    Full Text »    PDF »
Neurovirulence in Mice of H5N1 Influenza Virus Genotypes Isolated from Hong Kong Poultry in 2001.
A. S. Lipatov, S. Krauss, Y. Guan, M. Peiris, J. E. Rehg, D. R. Perez, and R. G. Webster (2003)
J. Virol. 77, 3816-3823
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Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus.
T. M. Tumpey, A. Garcia-Sastre, A. Mikulasova, J. K. Taubenberger, D. E. Swayne, P. Palese, and C. F. Basler (2002)
PNAS 99, 13849-13854
   Abstract »    Full Text »    PDF »
Emergence of multiple genotypes of H5N1 avian influenza viruses in Hong Kong SAR.
Y. Guan, J. S. M. Peiris, A. S. Lipatov, T. M. Ellis, K. C. Dyrting, S. Krauss, L. J. Zhang, R. G. Webster, and K. F. Shortridge (2002)
PNAS 99, 8950-8955
   Abstract »    Full Text »    PDF »
Evaluation of the Subtype Specificity of Monoclonal Antibodies Raised against H1 and H3 Subtypes of Human Influenza A Virus Hemagglutinins.
E. Vareckova, N. Cox, and A. Klimov (2002)
J. Clin. Microbiol. 40, 2220-2223
   Abstract »    Full Text »    PDF »
Characterization of a Highly Pathogenic H5N1 Avian Influenza A Virus Isolated from Duck Meat.
T. M. Tumpey, D. L. Suarez, L. E. L. Perkins, D. A. Senne, J.-g. Lee, Y.-J. Lee, I.-P. Mo, H.-W. Sung, and D. E. Swayne (2002)
J. Virol. 76, 6344-6355
   Abstract »    Full Text »    PDF »
Pathogenesis of Avian Influenza A (H5N1) Viruses in Ferrets.
L. A. Zitzow, T. Rowe, T. Morken, W.-J. Shieh, S. Zaki, and J. M. Katz (2002)
J. Virol. 76, 4420-4429
   Abstract »    Full Text »    PDF »
H3N2 influenza viruses from domestic chickens in Italy: an increasing role for chickens in the ecology of influenza?.
L. Campitelli, C. Fabiani, S. Puzelli, A. Fioretti, E. Foni, A. De Marco, S. Krauss, R. G. Webster, and I. Donatelli (2002)
J. Gen. Virol. 83, 413-420
   Abstract »    Full Text »    PDF »
Molecular Evolution of H6 Influenza Viruses from Poultry in Southeastern China: Prevalence of H6N1 Influenza Viruses Possessing Seven A/Hong Kong/156/97 (H5N1)-Like Genes in Poultry.
P. S. Chin, E. Hoffmann, R. Webby, R. G. Webster, Y. Guan, M. Peiris, and K. F. Shortridge (2002)
J. Virol. 76, 507-516
   Abstract »    Full Text »    PDF »
Characterization of H5N1 Influenza Viruses That Continue To Circulate in Geese in Southeastern China.
R. G. Webster, Y. Guan, M. Peiris, D. Walker, S. Krauss, N. N. Zhou, E. A. Govorkova, T. M. Ellis, K. C. Dyrting, T. Sit, et al. (2002)
J. Virol. 76, 118-126
   Abstract »    Full Text »    PDF »
Combined PCR-Heteroduplex Mobility Assay for Detection and Differentiation of Influenza A Viruses from Different Animal Species.
J. S. Ellis and M. C. Zambon (2001)
J. Clin. Microbiol. 39, 4097-4102
   Abstract »    Full Text »    PDF »
Cocirculation of Avian H9N2 and Contemporary ""Human"" H3N2 Influenza A Viruses in Pigs in Southeastern China: Potential for Genetic Reassortment?.
J. S. M. Peiris, Y. Guan, D. Markwell, P. Ghose, R. G. Webster, and K. F. Shortridge (2001)
J. Virol. 75, 9679-9686
   Abstract »    Full Text »    PDF »
Comparison of Efficacies of RWJ-270201, Zanamivir, and Oseltamivir against H5N1, H9N2, and Other Avian Influenza Viruses.
E. A. Govorkova, I. A. Leneva, O. G. Goloubeva, K. Bush, and R. G. Webster (2001)
Antimicrob. Agents Chemother. 45, 2723-2732
   Abstract »    Full Text »
X-ray structures of H5 avian and H9 swine influenza virus hemagglutinins bound to avian and human receptor analogs.
Y. Ha, D. J. Stevens, J. J. Skehel, and D. C. Wiley (2001)
PNAS
   Abstract »    Full Text »    PDF »
Molecular Basis for High Virulence of Hong Kong H5N1 Influenza A Viruses.
M. Hatta, P. Gao, P. Halfmann, and Y. Kawaoka (2001)
Science 293, 1840-1842
   Abstract »    Full Text »    PDF »
Recombination in the Hemagglutinin Gene of the 1918 ""Spanish Flu"".
M. J. Gibbs, J. S. Armstrong, and A. J. Gibbs (2001)
Science 293, 1842-1845
   Abstract »    Full Text »    PDF »


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