Highly pathogenic H5N1 avian influenza virus has spread through at least 45 countries in three continents. Despite the ability to infect and cause severe disease in humans, the virus cannot transmit efficiently from human to human. The lack of efficient transmission indicates the incompletion of the adaptation of the avian virus to the new host species. The required mutations for the complete adaptation and the emergence of a potential pandemic virus are likely to originate and be selected within infected human tissues. Differential receptor preference plays an important role in the species-tropism of avian influenza. We have analysed quasispecies of sequences covering the receptor-binding domain of the haemagglutinin gene of H5N1 viruses derived from fatal human cases. We employed a likelihood ratio test to identify positive-selection sites within the quasispecies. Nine of seventeen positive-selection sites identified in our analyses were found to be located within or flanking the receptor-binding domain. Some of these mutations are known to alter receptor-binding specificity. This suggests that our approach could be used to screen for mutations with significant functional impact. Our data provide new candidate mutations for the viral adaptation to a human host, and a new approach to search for new genetic markers of potential pandemic viruses.
GambaryanA.,
TuzikovA.,
PazyninaG.,
BovinN.,
BalishA.,
KlimovA.2006; Evolution of the receptor binding phenotype of influenza A (H5) viruses. Virology 344:432–438[CrossRef]
HaY.,
StevensD. J.,
SkehelJ. J.,
WileyD. C.2001; X-ray structures of H5 avian and H9 swine influenza virus hemagglutinins bound to avian and human receptor analogs. Proc Natl Acad Sci U S A 98:11181–11186[CrossRef]
KaverinN. V.,
RudnevaI. A.,
IlyushinaN. A.,
VarichN. L.,
LipatovA. S.,
SmirnovY. A.,
GovorkovaE. A.,
GitelmanA. K.,
LvovD. K.,
WebsterR. G.2002; Structure of antigenic sites on the haemagglutinin molecule of H5 avian influenza virus and phenotypic variation of escape mutants. J Gen Virol 83:2497–2505
KaverinN. V.,
RudnevaI. A.,
GovorkovaE. A.,
TimofeevaT. A.,
ShilovA. A.,
Kochergin-NikitskyK. S.,
KrylovP. S.,
WebsterR. G.2007; Epitope mapping of the hemagglutinin molecule of a highly pathogenic H5N1 influenza virus by using monoclonal antibodies. J Virol 81:12911–12917[CrossRef]
NielsenR.,
YangZ.1998; Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene. Genetics 148:929–936
RogersG. N.,
PaulsonJ. C.1983; Receptor determinants of human and animal influenza virus isolates: differences in receptor specificity of the H3 hemagglutinin based on species of origin. Virology 127:361–373[CrossRef]
ShinyaK.,
HattaM.,
YamadaS.,
TakadaA.,
WatanabeS.,
HalfmannP.,
HorimotoT.,
NeumannG.,
KimJ. H.other authors2005; Characterization of a human H5N1 influenza A virus isolated in 2003. J Virol 79:9926–9932[CrossRef]
StevensJ.,
BlixtO.,
TumpeyT. M.,
TaubenbergerJ. K.,
PaulsonJ. C.,
WilsonI. A.2006; Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 312:404–410[CrossRef]
SubbaraoK.,
KlimovA.,
KatzJ.,
RegneryH.,
LimW.,
HallH.,
PerdueM.,
SwayneD.,
BenderC.other authors1998; Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 279:393–396[CrossRef]
TranT. H.,
NguyenT. L.,
NguyenT. D.,
LuongT. S.,
PhamP. M.,
NguyenV. C.,
PhamT. S.,
VoC. D.,
LeT. Q.other authors2004; Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med 350:1179–1188[CrossRef]
YamadaS.,
SuzukiY.,
SuzukiT.,
LeM. Q.,
NidomC. A.,
Sakai-TagawaY.,
MuramotoY.,
ItoM.,
KisoM.other authors2006; Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature 444:378–382[CrossRef]