J Gen Virol - Emergence of H5N1 avian influenza viruses with reduced sensitivity to neuraminidase inhibitors and novel reassortants in Lao People?s De

[Giuseppe]

J Gen Virol. 2009 Dec 16. [Epub ahead of print]

Emergence of H5N1 Avian Influenza Viruses with Reduced Sensitivity to Neuraminidase Inhibitors and Novel Reassortants in Lao PDR.

Boltz DA, Douangngeun B, Phommachanh P, Sinthasak S, Mondry R, Obert CA, Seiler P, Keating R, Suzuki Y, Hiramatsu H, Govorkova E, Webster RG.

St. Jude Children's Research Hospital;

Pandemic influenza viruses can emerge through continuous evolution and acquisition of specific mutations or through reassortment. We assessed the pandemic potential of H5N1 viruses isolated from poultry outbreaks occurring from July 2006 through September 2008 in the Lao People's Democratic Republic (PDR). We analyzed 29 viruses isolated from chickens and ducks and 2 from fatal human cases in 2007. Prior to 2008 all H5N1 isolates in Lao PDR were from clade 2.3.4; however, clade 2.3.2 was introduced in September 2008. Of greatest concern was the circulation of three isolates which showed decreased sensitivity to the neuraminidase (NA) inhibitor oseltamivir in an enzyme inhibition assay, each with different NA mutations: V116A, I222L and K150N, and a previously unreported N246S mutation. In addition, six isolates had an S31N mutation in the M2 protein, which confers resistance to amantadine not previously reported in clade 2.3.4 viruses. Two H5N1 reassortants were isolated whose polymerase genes, PB1 and PB2, are homologous to those of Eurasian viruses giving rise to a novel H5N1 genotype, genotype P. All H5N1 viruses retained avian-like receptor specificity, but 4 had altered affinities for alpha2,3-linked sialic acid. Our study shows that in a genetically similar population of H5N1 viruses in Lao PDR, mutants emerged with natural resistance to antivirals, altered affinities for alpha2,3-linked sialic acids and reassortants with polymerase genes homologous to Eurasian viruses. These changes may contribute to emergence of a pandemic influenza strain and are critical for devising surveillance strategies.

PMID: 20016036 [PubMed - as supplied by publisher]

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Study - Emergence of H5N1 avian influenza viruses with reduced sensitivity to neuraminidase inhibitors and novel reassortants in Lao People?s Democratic Republic

Study - Emergence of H5N1 avian influenza viruses with reduced sensitivity to neuraminidase inhibitors and novel reassortants in Lao People?s Democratic Republic

Emergence of H5N1 avian influenza viruses with
reduced sensitivity to neuraminidase inhibitors and
novel reassortants in Lao People?s Democratic
Republic
David A. Boltz,1 Bounlom Douangngeun,2 Phouvong Phommachanh,2
Settha Sinthasak,2 Ricarda Mondry,3 Caroline Obert,4 Patrick Seiler,1
Rachael Keating,5 Yasuo Suzuki,6,7 Hiroaki Hiramatsu,6,7
Elena A. Govorkova1 and Robert G. Webster1
Correspondence
Robert G. Webster
robert.webster@stjude.org
1Division of Virology, Department of Infectious Diseases, St Jude Children?s Research Hospital, Memphis, TN 38105, USA
2National Animal Health Centre, Vientiane, Lao People?s Democratic Republic
3Food and Agriculture Organization, Vientiane, Lao People?s Democratic Republic
4Hartwell Center for Bioinformatics and Biotechnology, St Jude Children?s Research Hospital, Memphis, TN 38105, USA
5Department of Immunology, St Jude Children?s Research Hospital, Memphis, TN 38105, USA
6College of Life and Health Sciences, Health Science Hills, Chubu University, Kasugai, Aichi, Japan
7Global COE Program for Innovation in Human Health Sciences, University of Shizuoka School of Pharmaceutical Sciences, Shizuoka, Japan

Received 12 October 2009
Accepted 14 December 2009

DISCUSSION
The H5N1 outbreaks in poultry in Lao PDR in 2006?2008
were controlled, but the continuing emergence and
reintroduction of H5N1 viruses emphasizes their threat
to veterinary and human public health. Previous introductions
of H5N1 viruses in Lao PDR in 2004 and early 2006
were stamped out in the local bird population, but in mid-
2006 and early 2007, outbreaks of H5N1 viruses among
domestic poultry generated mutants and reassortants.
Phylogenetic analyses suggest that they persisted in the
region for 6 months before causing outbreaks throughout
Lao PDR in 2007. H5N1 clade 2.3.4 isolates and clade 2.3.2
viruses isolated in 2008 did not cluster with H5N1 viruses from 2007, demonstrating two new introductions. Only
isolates from mid-2006 and 2007 clustered, suggesting that
isolates from 2006 persisted in the region and resurfaced in
2007, causing outbreaks in avian species in five provinces
over a 3-month period, which also resulted in the first two
human fatalities in Lao PDR. The perpetuation of these
H5N1 viruses may explain the phenotypic diversity of the
genetically similar H5N1 viruses isolated in 2007.
Segmental reassortment among influenza viruses from
different host species has caused the rapid evolution of
influenza viruses and may aid the emergence of pandemic
strains. We have isolated novel H5N1 reassortments in Lao
PDR with genes from a circulating H5N1 virus and PB1
and PB2 genes from an unknown avian influenza virus
subtype. Since its emergence, highly pathogenic H5N1 has
continued to reassort with avian viruses from aquatic birds
and undergo intra-subtype reassortment to generate novel
genotypes in Southeast Asia (Guan et al., 2002a, b; Wan
et al., 2008) and Africa (Owoade et al., 2008).

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Re: Vietnam - Research shows bird flu could become more deadly - H5N1

Re: Vietnam - Research shows bird flu could become more deadly - H5N1

from the pdf @ Post #12:

Because amantadine-resistant H5N1 strains are present in
many countries, the use of adamantanes is recommended
only in countries where H5N1 is not resistant to the drug.
Adamantanes would have been recommended before
reintroduction of H5N1 viruses in Lao PDR in 2008, but
the emergence of clade 2.3.4 viruses with the S31N
mutation in the M2 protein would limit antiviral treatment
to oseltamivir. To prepare for pandemics, stockpiles of
oseltamivir and zanamivir have been manufactured.
However, the emergence of H5N1 influenza viruses with
mutations in the NA, which alter their sensitivity to NAIs (Rameix-Welti et al., 2006), is of concern.

Although no mutation resulted in oseltamivir resistance, the presence of
multiple NA mutations accumulating during virus evolution
may ultimately confer resistance. Identification of NA
mutations in Lao H5N1 virus isolates indicates the
importance of phenotypic surveillance for antiviral drug
resistance, as it is occasionally mediated by previously
unrecognized mutations such as S246N.
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The highly pathogenic H5N1 avian influenza viruses have
continued to circulate in epicentres in Eurasia for over a
decade, resulting in the evolution of multiple clades and
subclades. Because the transmission of H5N1 among
humans is inefficient and limited, the public is becoming
complacent about the pandemic potential of H5N1 viruses
and their capacity to achieve human transmissibility.
However, our study of H5N1 viruses in Lao PDR indicates
that this notion is premature. Historically, it is not known
how long it took for the Spanish, Asian and Hong Kong
pandemics to acquire human transmissibility. Our results
support the existence of a diverse population of H5N1
influenza viruses in Lao PDR – which might be true for all
countries where H5N1 is endemic – that may mutate and
reassort to cause a human pandemic.