Influenza A viruses cause pandemics at random inter-
vals. Pandemics are caused by viruses that contain a
hemagglutinin (HA) surface glycoprotein to which human
populations are immunologically naive. Such an HA can be
introduced into the human population through reassortment
between human and avian virus strains or through the
direct transfer of an avian influenza virus to humans. The
factors that determine the interspecies transmission and
pathogenicity of influenza viruses are still poorly under-
stood; however, the HA protein plays an important role in
overcoming the interspecies barrier and in virulence in
avian influenza viruses. Recently, the RNA polymerase
(PB2) protein has also been recognized as a critical factor
in host range restriction, while the nonstructural (NS1) pro-
tein affects the initial host immune responses. We summa-
rize current knowledge of viral factors that determine host
range restriction and pathogenicity of influenza A viruses.
O
f the 3 types of influenza viruses (A, B, and C), only
influenza A viruses are established in animals other
than humans. Influenza pandemics are caused by viruses
that have a hemagglutinin (HA) to which most humans
have no immune memory. The strains of the 1957 Asian
and 1968 Hong Kong pandemics had HAs derived from an
avian virus. Although little information exists about avian
influenza viruses at the time of the Spanish influenza pan-
demic, the HA of the virus responsible for that outbreak is
also thought to be of avian origin. Since avian influenza
viruses do not replicate efficiently in humans and nonhu-
man primates, they must overcome host range restriction
for the avian virus HA to be introduced into human popu-
lations. The molecular basis for host range restriction is not
well understood; however, HA plays a key role in the
restriction of interspecies transmission.
The Spanish influenza was among the most devastating
infectious diseases in history. At least 20 million people
died worldwide. Antimicrobial agents were not available
in 1918; however, existing evidence suggests that this high
death toll was due to the extreme virulence of the virus.
Although all 8 RNA segments of the Spanish influenza
virus have been sequenced, these sequences offer no
explanation for the high virulence. The Spanish influenza
exemplifies how the magnitude of a pandemic can be
determined by the pathogenicity of the virus.
In this review, we focus on 2 properties of influenza A
viruses as they relate to pandemics, host range restriction
and pathogenicity. Viral factors that affect these properties
are examined.
Viral Proteins Responsible for
Host Range Restriction
Viral Glycoproteins
The HA protein mediates virus binding to sialic acid
(SA)–containing host cell surface molecules and promotes
the release of viral ribonucleoprotein complexes through
membrane fusion. By contrast, the sialidase activity of the
neuraminidase (NA) protein removes SA to liberate newly
synthesized viruses from infected cells. Thus, efficient
virus replication requires the balanced actions of HA
receptor-binding specificity and NA sialidase activity.
HA Receptor Specificity
Influenza virus infectivity is influenced by 2 entities:
SA species (N-acetylneuraminic acid [NeuAc] and N-gly-
colylneuramic acid [NeuGc]) and the type of linkage to
galactose (sialyloligosaccharides terminated by SA linked
to galactose by an α2,6 linkage [Acα2,6Gal] or an α2,3
linkage [Acα2,3Gal]) on the host cell surface. Human
influenza viruses preferentially recognize sialyloligosac-
chrides containing SAα2,6Gal (1,2), matched by mainly
Host Range Restriction and
Pathogenicity in the Context of
Influenza Pandemic
Gabriele Neumann* and Yoshihiro Kawaoka*†‡
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 6, June 2006 881
*University of Wisconsin-Madison, Madison, USA; †University of
Tokyo, Tokyo, Japan; and ‡Japan Science and Technology
Agency, Saitama, Japan
NeuAcα2,6Gal linkages on the epithelial cells of the
human trachea (3). By contrast, avian viruses preferential-
ly recognize SAα2,3Gal sialic acids (1,2), in accordance
with the predominance of sialyoligosaccharides with
SAα2,3Gal linkages on the epithelial cells of duck intes-
tine. The epithelial cells of pig trachea contain both types
of SAs and both types of linkages (4), which likely
explains the high susceptibility of these animals to both
human and avian influenza viruses (5). Pigs may therefore
serve as a “mixing vessel” for reassortment between these
2 viruses and the source of pandemic strains, although no
evidence exists that the 1957 or 1968 pandemic viruses
originated in pigs.
Despite these differences in receptor specificity, avian
viruses can infect humans and have caused lethal infec-
tions (6–8). This fact may be explained by the recent find-
ing that in differentiated cultures of human tracheo-
bronchial epithelium, α2,3-linked SAs were found on cili-
ated cells, whereas α2,6-linked SAs were present on non-
ciliated cells (9). The prevalence of cells that possess α2,6
and/or α2,3-linked SAs in the lower respiratory tract
remains unknown; however, ciliated cells support avian
virus infection. Despite the presence of α2,6-linked SA-
bearing cells in differentiated human tracheobronchial
epithelium, viruses with avian-type receptor specificity
can infect humans, since the index 1997 H5N1 virus iso-
lated from a human preferentially recognized an avian
receptor (10). Nevertheless, for efficient human-to-human
transmission, HA derived from an avian virus must prefer-
entially recognize the human receptor. This notion is sup-
ported by the finding that the earliest isolates in the 1918
(11,12), 1957, and 1968 pandemics preferentially recog-
nized NeuAcα2,6Gal–containing sialyloligosaccharides
(13), even though their HAs were derived from avian
viruses. Conversion of receptor specificity from
SAα2,3Gal to SAα2,6Gal may therefore be critical for
generating pandemic influenza viruses.
Sequence comparison, receptor specificity assays, and
crystallographic analysis have identified amino acid
residues that determine receptor specificity: Gln-226
(found in avian viruses) determines specificity for
SAα2,3Gal, whereas Leu-226 correlates with SAα2,6Gal
specificity in human H2 and H3, but not H1, viruses
(2,13). In all human viruses (with the few exceptions of
early isolates from the Asian influenza outbreak [13]),
Leu-226 is associated with Ser-228, while Gln-226 is asso-
ciated with Gly-228 in avian viruses. For H1 viruses, Asp-
190 (found in human and swine virus isolates) or Glu-190
(found in avian virus isolates) determines preferential
binding to α2,6 or α2,3 linkages, respectively (11–14).
Land-based poultry are thought to play a critical role in
the emergence of pandemic influenza viruses. Compared
to H5N1 viruses isolated from aquatic birds, those isolated
from chickens have significantly lower affinity for
NeuAcα2,3Gal (10), similar to human virus isolates; how-
ever, H5N1 chicken isolates have not acquired preferential
specificity for NeuAcα2,6Gal. H5N1 chicken isolates with
reduced avian receptor specificity share 2 characteristic
features of human viruses, namely, an additional glycosy-
lation site in the globular head region of HA and a deletion
in the NA stalk (see below). Similarly, the receptor speci-
ficity of H9N2 viruses isolated from land-based poultry,
but not of those isolated from aquatic birds, is similar to
that of human isolates (15). Hence, land-based poultry may
serve as an intermediate host that facilitates the conversion
of avian to human-type receptors. Avian viruses in land-
based poultry may, therefore, pose a greater threat to
humans than previously thought.
NA Properties
Since efficient release of virus from infected cells
requires the removal of SA by NA, the receptor-binding
and receptor-destroying properties of HA and NA, respec-
tively, must be balanced. When an avian virus with an N2
NA was introduced into the human population, its SAα2,6
cleavage activity increased (16,17), which suggests it had
adapted to the SAα2,6 receptor specificity of human HAs.
The NA stalk, which separates the head region with the
enzymatic center from the transmembrane and cytoplas-
mic domains, varies in sequence and length, depending on
the virus (18). Typically, shortened stalks result in less effi-
cient virus release since the active site in the head region
cannot efficiently access its substrate (19,20). However,
naturally occurring avian viruses with shortened stalks are
virulent in poultry, and the 1997 H5N1 viruses isolated
from patients in Hong Kong (which are believed to have
been transmitted to humans from poultry) are character-
ized by a deletion in the NA stalk (10). Moreover, most
recent highly pathogenic H5N1 viruses isolated from ter-
restrial poultry possess short NA stalks (21).
In avian species, the intestinal tract is the primary site
of replication, whereas in humans, influenza virus replica-
tion is typically restricted to the respiratory tract. The NA
activity of avian H1N1 viruses is more resistant to the low
pH environment in the upper digestive tract than is its
human or swine-derived counterpart (22). In line with this
finding, highly pathogenic H5N1 viruses can replicate in
the human intestine, causing gastrointestinal symptoms
(23), and are shed in large amounts in stool.
Internal Proteins
Classical coinfection experiments, or reverse genetics
experiments that tested multiple gene combinations of 2
parental viruses, suggest that the genes encoding the
“internal proteins”—namely, RNApolymerase (PB2, PB1,
PA), nucleoprotein (NP), matrix protein (M1, M2), and
PERSPECTIVE
882 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 6, June 2006
nonstructural protein (NS1, NS2/NEP)—also contribute to
host range. The contribution of individual proteins to host
range restriction, however, likely varies, depending on the
test system and the virus strains under investigation.
PB2
PB2 is a component of the viral polymerase complex
and, as such, is essential for viral replication. The 1997
H5N1 human virus isolates in Hong Kong have been
divided into 2 groups on the basis of their pathogenicity in
mice; this classification also generally corresponds to dis-
ease severity in humans (24,25). Reverse genetics studies
have shown that Lys at position 627 of PB2 (found in all
human isolates) determines high pathogenicity in mice,
while Glu at this position (found in all avian isolates)
determines low pathogenicity (26). However, the nature of
the amino acid at position 627 of PB2 does not affect the
cell tropism of the virus but rather its replicative ability in
mice and probably in humans.
Several other findings underline the importance of
residue 627 of PB2: 1) an H7N7 virus isolated from a
patient with fatal pneumonia in the Netherlands in 2003
contained Lys at this position, in contrast to viruses isolat-
ed from nonfatal cases and from chickens (27); 2) some of
the H5N1 viruses isolated from patients in Vietnam are
characterized by Lys-627 in PB2 (28); 3) a single reassor-
tant virus bearing an avian virus PB2 gene against a human
virus background replicated efficiently in avian but not
human cells, a feature that could be traced to the nature of
the amino acid at position 627 of PB2 (29); and 4) ribonu-
cleoprotein complexes reconstituted from human or avian
polymerase and NP proteins identified residue 627 of PB2
as the major determinant of replication efficiency in mam-
malian cells (30). Collectively, these findings suggest that
a Glu-to-Lys mutation at position 627 of the PB2 protein
allows avian viruses to efficiently grow in humans and
implicates Lys at this position as an important host range
determinant.
Other Components of the Replication Complex
In addition to PB2, the remaining 2 polymerase pro-
teins (PB1 and PA) and the nucleoprotein NP may also
contribute to host range. In a minireplicon system, replica-
tion in mammalian cells was more efficient with avian than
with human virus PB1 proteins (30), which suggests that
avian PB1 may have greater activity that could provide a
replicative advantage in mammalian systems. This sce-
nario is especially appealing in light of the finding that
both the 1957 and 1968 pandemic viruses possessed avian
PB1 genes, in addition to avian HA, NA, or both genes
(31,32). In one study, however, an avian PB1 gene severe-
ly restricted replication of a human virus in mammalian
cells and squirrel monkeys (33). These findings seem to
contradict a role of avian PB1 in replication in mammalian
cells. PAand NP proteins have also been implicated in host
range restriction; for example, an avian virus NP segment
against a background of a human virus resulted in attenua-
tion in squirrel monkeys (33). However, because of the
limited data available, whether these findings indicate a
contribution of these gene products to host range restric-
tion or simply reflect incompatibility among the viral gene
segments is unclear.
M Segment
Segment 7 of influenza A viruses encodes the M1
matrix and the M2 ion channel proteins. In coinfection
experiments that selected for reassortants containing a
human virus M gene and an avian virus HA gene, the M
segment of an early human virus (A/PR/8/34, H1N1)
cooperated efficiently with avian virus HAs, whereas M
segments derived from more recent isolates have gradual-
ly lost this ability (34). This finding may suggest that cur-
rently circulating human viruses are less likely to reassort
with avian viruses than their predecessors. If this is the
case, the risk for a global pandemic caused by reassortants
possessing avian HA, NA, or both segments against a
human virus background would be reduced.
Molecular Basis of Pathogenicity
HA Cleavability
The HA protein is synthesized as a precursor protein
that is cleaved into 2 subunits (HA1 and HA2) by host cell
proteases. HA cleavage is a prerequisite for fusion of the
viral and endosomal membranes and, therefore, for viral
infectivity (35). Low pathogenic avian influenza viruses
possess a single Arg residue at the cleavage site, recog-
nized by extracellular, trypsinlike proteases. These pro-
teases are thought to be secreted only by cells of the
respiratory and intestinal tract and consequently limit
infections to these organs. By contrast, highly pathogenic
avian viruses possess multiple basic amino acids at the
cleavage that are recognized by ubiquitous, intracellular,
subtilisin-like proteases that thus trigger systemic infec-
tion. In addition, HAcleavability is affected by the absence
or presence of a carbohydrate side chain near the cleavage
site that may interfere with the accessibility of host pro-
teases to the cleavage site (36). The acquisition of a high-
ly cleavable HA converted an avirulent strain to virulence
in Pennsylvania in 1983 (H5N2), Mexico in 1994 (H5N2),
Italy in 1997 (H7N1), Chile in 2002 (H7N3), and Canada
in 2004 (H7N3) (Table). HA cleavability is, therefore, con-
sidered the major determinant of tissue tropism of avian
influenza viruses (41). This correlation seems to extend to
humans, since all avian viruses that have killed humans
possess a highly cleavable HA (6,7,27), and an H5N1
Host Range and Pathogenicity in Influenza Pandemic
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 6, June 2006 883
mutant virus whose HA cleavage site had been changed to
an avirulent type was attenuated in mice (26).
Role of NS1 in Antagonizing Cellular
Immune Responses
Pathogenesis depends partly on the ability of a virus to
evade or suppress the host immune response. The NS1 pro-
tein, encoded by segment 8, plays a central role in this
process by counteracting the cellular interferon (IFN)
response in a 2-pronged approach: 1) by binding to double-
stranded RNA, thereby suppressing the activation of dou-
ble-stranded RNA-activated protein kinase, a known
stimulator of type I IFN, and 2) by preventing the activa-
tion of transcription factors such as ATF-2/c-Jun, NFkB,
and IRF-3/5/7, all of which stimulate IFN production
(42,43). The NS gene of the 1918 Spanish flu blocked the
expression of IFN-regulated genes in human cells more
efficiently than did the NS gene of the A/PR/8/34 (H1N1)
virus (44), which suggests that the NS genes of highly
pathogenic viruses may be more proficient in counteract-
ing the host immune response than those of less pathogen-
ic viruses.
Viruses containing the NS gene of the 1997 H5N1 virus
are potent inducers of proinflammatory cytokine genes,
particularly tumor necrosis factor-α (TNF-α) and IFN-β in
human primary monocyte-derived macrophages (45).
Similarly, 2003 human H5N1 isolates induce high levels of
proinflammatory cytokines in primary human macro-
phages (46). These in vitro findings are substantiated by
reports of unusually high serum concentrations of
chemokines in patients infected with H5N1 influenza
viruses. High levels of macrophage-derived chemokines
and cytokines were also induced by a recombinant virus
containing a gene segment of the 1918 Spanish flu; in this
case, however, the HA segment stimulated the increased
levels of chemokines and cytokines (14,47). This upregu-
lation of cytokine function at later phases of infection may
account for the unusual clinical signs and symptoms and
the degree of disease severity associated with human infec-
tions of highly pathogenic influenza viruses.
Highly pathogenic H5N1 viruses not only trigger the
overproduction of proinflammatory cytokines but also are
resistant to the antiviral effects of IFN and TNF-α.
Pretreatment of porcine lung epithelial cells with IFN-α,
IFN-γ, or TNF-α has no effect on the replication of a
recombinant human H1N1 virus possessing the NS gene of
the 1997 H5N1 virus but abolishes replication of the
parental human H1N1 virus (48,49). Resistance to the
antiviral effects of IFN and TNF-α is associated with glu-
tamic acid at position 92 of the NS1 protein, as demon-
strated by reverse genetics studies. These in vitro data
extend to in vivo findings, since pigs infected with a virus
containing Glu-92 in NS1 experience higher virus titers
and body temperatures than those infected with a control
virus (48,49). Collectively, these findings indicate that
NS1 induces a cytokine imbalance that likely contributes
to the extreme pathogenicity of avian influenza viruses in
humans.
Conclusions
One might speculate that the next pandemic may be
caused by highly pathogenic H5N1 viruses that acquire the
ability to be efficiently transmitted among humans, or by
H9N2 viruses, which are as prevalent as H5N1 viruses in
Asia and in some cases already recognize human recep-
tors. Further investigation of the molecular basis of host
range restriction is therefore important. In addition, a bet-
ter understanding of the mechanisms and consequences of
PERSPECTIVE
884 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 6, June 2006
chemokine/cytokine imbalance caused by highly patho-
genic avian viruses is essential, as is a greater appreciation
for the contributions of other viral properties, such as
replicative ability, to pathogenesis.
Dr Neumann is a research associate professor at the
University of Wisconsin-Madison, Madison, Wisconsin. Her
research interests are the pathogenicity of influenza and Ebola
viruses and the development of reverse genetics techniques for
negative-strand RNA viruses.
Dr Kawaoka is a professor at the University of Wisconsin-
Madison and at the University of Tokyo, Tokyo, Japan. His
research focuses on the molecular biology and pathogenesis of
influenza and Ebola viruses.
References
1. Rogers GN, Paulson JC. Receptor determinants of human and animal
influenza virus isolates: differences in receptor specificity of the H3
hemagglutinin based on species of origin. Virology. 1983;127:
361–73.
2. 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;304:76–8.
3. Couceiro JN, Paulson JC, Baum LG. Influenza virus strains selective-
ly recognize sialyloligosaccharides on human respiratory epithelium;
the role of the host cell in selection of hemagglutinin receptor speci-
ficity. Virus Res. 1993;29:155–65.
4. Ito T, Couceiro JN, Kelm S, Baum LG, Krauss S, Castrucci MR, et al.
Molecular basis for the generation in pigs of influenza A viruses with
pandemic potential. J Virol. 1998;72:7367–73.
5. Kida H, Ito T, Yasuda J, Shimizu Y, Itakura C, Shortridge KF, et al.
Potential for transmission of avian influenza viruses to pigs. J Gen
Virol. 1994;75:2183–8.
6. Claas EC, Osterhaus AD, Van Beek R, de Jong JC, Rimmelzwaan GF,
Senne DA, et al. Human influenza A H5N1 virus related to a highly
pathogenic avian influenza virus. Lancet. 1998;351:472–7.
7. Subbarao K, Klimov A, Katz J, Regnery H, Lim W, Hall H, et al.
Characterization of an avian influenza A (H5N1) virus isolated from
a child with a fatal respiratory illness. Science. 1998;279:393–6.
8. Fouchier RA, Schneeberger PM, Rozendaal FW, Broekman JM,
Kemink SA, Munster V, et al. Avian influenza A virus (H7N7) asso-
ciated with human conjunctivitis and a fatal case of acute respiratory
distress syndrome. Proc Natl Acad Sci U S A. 2004;101:1356–61.
9. Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk HD.
Human and avian influenza viruses target different cell types in cul-
tures of human airway epithelium. Proc Natl Acad Sci U S A.
2004;101:4620–4.
10. Matrosovich M, Zhou N, Kawaoka Y, Webster R. The surface glyco-
proteins of H5 influenza viruses isolated from humans, chickens, and
wild aquatic birds have distinguishable properties. J Virol.
1999;73:1146–55.
11. Gamblin SJ, Haire LF, Russell RJ, Stevens DJ, Xiao B, Ha Y, et al.
The structure and receptor-binding properties of the 1918 influenza
hemagglutinin. Science. 2004;303:1838–42.
12. Stevens J, Corper AL, Basler CF, Taubenberger JK, Palese P, Wilson
IA. Structure of the uncleaved human h1 hemagglutinin from the
extinct 1918 influenza virus. Science. 2004;303:1866–70.
13. Matrosovich M, Tuzikov A, Bovin N, Gambaryan A, Klimov A,
Castrucci MR, et al. Early alterations of the receptor-binding proper-
ties of H1, H2, and H3 avian influenza virus hemagglutinins after
their introduction into mammals. J Virol. 2000;74:8502–12.
14. Kobasa D, Takada A, Shinya K, Hatta M, Halfmann P, Theriault S, et
al. Enhanced virulence of influenza A viruses with the haemagglu-
tinin of the 1918 pandemic virus. Nature. 2004;431:703–7.
15. Matrosovich MN, Krauss S, Webster RG. H9N2 influenza A viruses
from poultry in Asia have human virus-like receptor specificity.
Virology. 2001;281:156–62.
16. Baum LG, Paulson JC. The N2 neuraminidase of human influenza
virus has acquired a substrate specificity complementary to the
hemagglutinin receptor specificity. Virology. 1991;180:10–5.
17. Kobasa D, Kodihalli S, Luo M, Castrucci MR, Donatelli I, Suzuki Y,
et al. Amino acid residues contributing to the substrate specificity of
the influenza A virus neuraminidase. J Virol. 1999;73:6743–51.
18. Blok J, Air GM. Variation in the membrane-insertion and “stalk”
sequences in eight subtypes of influenza type A virus neuraminidase.
Biochemistry. 1982;21:4001–7.
19. Els MC, Air GM, Murti KG, Webster RG, Laver WG. An 18-amino
acid deletion in an influenza neuraminidase. Virology.
1985;142:241–7.
20. Luo G, Chung J, Palese P. Alterations of the stalk of the influenza
virus neuraminidase: deletions and insertions. Virus Res. 1993;29:
141–53.
21. Li KS, Guan Y, Wang J, Smith GJ, Xu KM, Duan L, et al. Genesis of
a highly pathogenic and potentially pandemic H5N1 influenza virus
in eastern Asia. Nature. 2004;430:209–13.
22. Takahashi T, Suzuki Y, Nishinaka D, Kawase N, Kobayashi Y, Hidari
KI, et al. Duck and human pandemic influenza A viruses retain siali-
dase activity under low pH conditions. J Biochem (Tokyo).
2001;130:279–83.
23. de Jong, Bach VC, Phan TQ, Vo MH, Tran TT, Nguyen BH, et al.
Fatal avian influenza A (H5N1) in a child presenting with diarrhea
followed by coma. N Engl J Med. 2005;352:686–91.
24. Gao P, Watanabe S, Ito T, Goto H, Wells K, McGregor M, et al.
Biological heterogeneity, including systemic replication in mice, of
H5N1 influenza A virus isolates from humans in Hong Kong. J Virol.
1999;73:3184–9.
25. Lu X, Tumpey TM, Morken T, Zaki SR, Cox NJ, Katz JM. A mouse
model for the evaluation of pathogenesis and immunity to influenza
A (H5N1) viruses isolated from humans. J Virol. 1999;73:5903–11.
26. Hatta M, Gao P, Halfmann P, Kawaoka Y. Molecular basis for high
virulence of Hong Kong H5N1 influenza A viruses. Science.
2001;293:1840–2.
27. Fouchier RA, Schneeberger PM, Rozendaal FW, Broekman JM,
Kemink SA, Munster V, et al. Avian influenza A virus (H7N7) asso-
ciated with human conjunctivitis and a fatal case of acute respiratory
distress syndrome. Proc Natl Acad Sci U S A. 2004;101:1356–61.
28. Puthavathana P, Auewarakul P, Charoenying PC, Sangsiriwut K,
Pooruk P, Boonnak K, et al. Molecular characterization of the com-
plete genome of human influenza H5N1 virus isolates from Thailand.
J Gen Virol. 2005;86:423–33.
29. 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;67:1761–4.
30. Naffakh N, Massin P, Escriou N, Crescenzo-Chaigne B, van der Werf
S. Genetic analysis of the compatibility between polymerase proteins
from human and avian strains of influenza A viruses. J Gen Virol.
2000;81 (Part 5):1283–91.
31. Scholtissek C, Rohde W, Von Hoyningen V, Rott R. On the origin of
the human influenza virus subtypes H2N2 and H3N2. Virology.
1978;87:13–20.
Host Range and Pathogenicity in Influenza Pandemic
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 6, June 2006 885
32. 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;63:4603–8.
33. Snyder MH, Buckler-White AJ, London WT, Tierney EL, Murphy
BR. The avian influenza virus nucleoprotein gene and a specific con-
stellation of avian and human virus polymerase genes each specify
attenuation of avian-human influenza A/Pintail/79 reassortant viruses
for monkeys. J Virol. 1987;61:2857–63.
34. Scholtissek C, Stech J, Krauss S, Webster RG. Cooperation between
the hemagglutinin of avian viruses and the matrix protein of human
influenza A viruses. J Virol. 2002;76:1781–6.
35. Garten W, Klenk HD. Understanding influenza virus pathogenicity.
Trends Microbiol. 1999;7:99–100.
36. Kawaoka Y, Naeve CW, Webster RG. Is virulence of H5N2 influenza
viruses in chickens associated with loss of carbohydrate from the
hemagglutinin? Virology. 1984;139:303–16.
37. Garcia M, Crawford JM, Latimer JW, Rivera-Cruz E, Perdue ML.
Heterogeneity in the haemagglutinin gene and emergence of the high-
ly pathogenic phenotype among recent H5N2 avian influenza viruses
from Mexico. J Gen Virol. 1996;77:1493–504.
38. Banks J, Speidel ES, Moore E, Plowright L, Piccirillo A, Capua I, et
al. Changes in the haemagglutinin and the neuraminidase genes prior
to the emergence of highly pathogenic H7N1 avian influenza viruses
in Italy. Arch Virol. 2001;146:963–73.
39. Suarez DL, Senne DA, Banks J, Brown IH, Essen SC, Lee CW, et al.
Recombination resulting in virulence shift in avian influenza out-
break, Chile. Emerg Infect Dis. 2004;10:693–9.
40. Pasick J, Handel K, Robinson J, Copps J, Ridd D, Hills K, et al.
Intersegmental recombination between the haemagglutinin and
matrix genes was responsible for the emergence of a highly pathogen-
ic H7N3 avian influenza virus in British Columbia. J Gen Virol.
2005;86:727–31.
41. Horimoto T, Kawaoka Y. Reverse genetics provides direct evidence
for a correlation of hemagglutinin cleavability and virulence of an
avian influenza A virus. J Virol. 1994;68:3120–8.
42. Garcia-Sastre A. Identification and characterization of viral antago-
nists of type I interferon in negative-strand RNA viruses. Curr Top
Microbiol Immunol. 2004;283:249–80.
43. Krug RM, Yuan W, Noah DL, Latham AG. Intracellular warfare
between human influenza viruses and human cells: the roles of the
viral NS1 protein. Virology. 2003;309:181–9.
44. Geiss GK, Salvatore M, Tumpey TM, Carter VS, Wang X, Basler CF,
et al. Cellular transcriptional profiling in influenza A virus-infected
lung epithelial cells: the role of the nonstructural NS1 protein in the
evasion of the host innate defense and its potential contribution to
pandemic influenza. Proc Natl Acad Sci U S A. 2002;99:10736–41.
45. Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, et al.
Induction of proinflammatory cytokines in human macrophages by
influenza A (H5N1) viruses: a mechanism for the unusual severity of
human disease? Lancet. 2002;360:1831–7.
46. Guan Y, Poon LL, Cheung CY, Ellis TM, Lim W, Lipatov AS, et al.
H5N1 influenza: a protean pandemic threat. Proc Natl Acad Sci
U S A. 2004;101:8156–61.
47. Kash JC, Basler CF, Garcia-Sastre A, Carter V, Billharz R, Swayne
DE, et al. Global host immune response: pathogenesis and transcrip-
tional profiling of type A influenza viruses expressing the hemagglu-
tinin and neuraminidase genes from the 1918 pandemic virus. J Virol.
2004;78:9499–511.
48. Seo SH, Hoffmann E, Webster RG. Lethal H5N1 influenza viruses
escape host anti-viral cytokine responses. Nat Med. 2002;8:950–4.
49. Seo SH, Hoffmann E, Webster RG. The NS1 gene of H5N1 influenza
viruses circumvents the host anti-viral cytokine responses. Virus Res.
2004;103:107–13.
Address for correspondence: Yoshihiro Kawaoka, Department of
Pathobiological Sciences, School of Veterinary Medicine, University of
Wisconsin-Madison, 2015 Linden Dr, Madison, WI 53706, USA; email:
kawaokay@svm.vetmed.wisc.edu
PERSPECTIVE
886 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 6, June 2006
Search
past issues
