Molecular distribution of amino acid substitutions on neuraminidase from the 2009 (H1N1) human influenza pandemic virus
Identifieur interne : 000964 ( Pmc/Corpus ); précédent : 000963; suivant : 000965Molecular distribution of amino acid substitutions on neuraminidase from the 2009 (H1N1) human influenza pandemic virus
Auteurs : Miguelmiguel Quiliano ; Hugo Valdivia-Olarte ; Carlos Olivares ; David Requena ; Andrés H. Gutiérrez ; Paola Reyes-Loyola ; Luis E. Tolentino-Lopez ; Patricia Sheen ; Ver Nica Briz ; Maria A. Mu Oz-Fernández ; José Correa-Basurto ; Mirko ZimicSource :
- Bioinformation [ 0973-8894 ] ; 2013.
Abstract
The pandemic influenza AH1N1 (2009) caused an outbreak of human infection that spread to the world. Neuraminidase (NA) is an antigenic surface glycoprotein, which is essential to the influenza infection process, and is the target of anti-flu drugs oseltamivir and zanamivir. Currently, NA inhibitors are the pillar pharmacological strategy against seasonal and global influenza. Although mutations observed after NA-inhibitor treatment are characterized by changes in conserved amino acids of the enzyme catalytic site, it is possible that specific amino acid substitutions (AASs) distant from the active site such as H274Y, could confer oseltamivir or zanamivir resistance. To better understand the molecular distribution pattern of NA AASs, we analyzed NA AASs from all available reported pandemic AH1N1 NA sequences, including those reported from America, Africa, Asia, Europe, Oceania, and specifically from Mexico. The molecular distributions of the AASs were obtained at the secondary structure domain level for both the active and catalytic sites, and compared between geographic regions. Our results showed that NA AASs from America, Asia, Europe, Oceania and Mexico followed similar molecular distribution patterns. The compiled data of this study showed that highly conserved amino acids from the NA active site and catalytic site are indeed being affected by mutations. The reported NA AASs follow a similar molecular distribution pattern worldwide. Although most AASs are distributed distantly from the active site, this study shows the emergence of mutations affecting the previously conserved active and catalytic site. A significant number of unique AASs were reported simultaneously on different continents.
Url:
DOI: 10.6026/97320630009673
PubMed: 23930018
PubMed Central: 3732439
Links to Exploration step
PMC:3732439Le document en format XML
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<author><name sortKey="Quiliano, Miguelmiguel" sort="Quiliano, Miguelmiguel" uniqKey="Quiliano M" first="Miguelmiguel" last="Quiliano">Miguelmiguel Quiliano</name>
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<affiliation><nlm:aff id="A2">Drug R&D Unit, Center for Applied Pharmacobiology Research, University of Navarra, C/ Irunlarrea s/n, 31008, Pamplona, Spain</nlm:aff>
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<author><name sortKey="Valdivia Olarte, Hugo" sort="Valdivia Olarte, Hugo" uniqKey="Valdivia Olarte H" first="Hugo" last="Valdivia-Olarte">Hugo Valdivia-Olarte</name>
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<affiliation><nlm:aff id="A3">Department of Physics, PUC-Rio, Rua Marquês de São Vicente, 225, Gávea - Rio de Janeiro, Brazil</nlm:aff>
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<author><name sortKey="Requena, David" sort="Requena, David" uniqKey="Requena D" first="David" last="Requena">David Requena</name>
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<author><name sortKey="Gutierrez, Andres H" sort="Gutierrez, Andres H" uniqKey="Gutierrez A" first="Andrés H" last="Gutiérrez">Andrés H. Gutiérrez</name>
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<author><name sortKey="Reyes Loyola, Paola" sort="Reyes Loyola, Paola" uniqKey="Reyes Loyola P" first="Paola" last="Reyes-Loyola">Paola Reyes-Loyola</name>
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<author><name sortKey="Tolentino Lopez, Luis E" sort="Tolentino Lopez, Luis E" uniqKey="Tolentino Lopez L" first="Luis E" last="Tolentino-Lopez">Luis E. Tolentino-Lopez</name>
<affiliation><nlm:aff id="A4">Laboratorio de Modelado Molecular y Bioinformática de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México. Plan de San Luis Y Diaz Mirón S/N, Col. Casco de Santo Tomas, Mexico city, México</nlm:aff>
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<author><name sortKey="Sheen, Patricia" sort="Sheen, Patricia" uniqKey="Sheen P" first="Patricia" last="Sheen">Patricia Sheen</name>
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<author><name sortKey="Briz, Ver Nica" sort="Briz, Ver Nica" uniqKey="Briz V" first="Ver Nica" last="Briz">Ver Nica Briz</name>
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</affiliation>
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<author><name sortKey="Mu Oz Fernandez, Maria A" sort="Mu Oz Fernandez, Maria A" uniqKey="Mu Oz Fernandez M" first="Maria A" last="Mu Oz-Fernández">Maria A. Mu Oz-Fernández</name>
<affiliation><nlm:aff id="A5">Laboratorio de Inmunobiología Molecular, Hospital Universitario Gregorio Marañón, Madrid, España, CIBER BBN, Madrid, Spain</nlm:aff>
</affiliation>
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<author><name sortKey="Correa Basurto, Jose" sort="Correa Basurto, Jose" uniqKey="Correa Basurto J" first="José" last="Correa-Basurto">José Correa-Basurto</name>
<affiliation><nlm:aff id="A4">Laboratorio de Modelado Molecular y Bioinformática de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México. Plan de San Luis Y Diaz Mirón S/N, Col. Casco de Santo Tomas, Mexico city, México</nlm:aff>
</affiliation>
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<author><name sortKey="Zimic, Mirko" sort="Zimic, Mirko" uniqKey="Zimic M" first="Mirko" last="Zimic">Mirko Zimic</name>
<affiliation><nlm:aff id="A1">Laboratorio de Bioinformática y Biología Molecular, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia. Av. Honorio Delgado, 430. SMP. Lima, Peru</nlm:aff>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Molecular distribution of amino acid substitutions on neuraminidase from the 2009 (H1N1) human influenza pandemic virus</title>
<author><name sortKey="Quiliano, Miguelmiguel" sort="Quiliano, Miguelmiguel" uniqKey="Quiliano M" first="Miguelmiguel" last="Quiliano">Miguelmiguel Quiliano</name>
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</affiliation>
<affiliation><nlm:aff id="A2">Drug R&D Unit, Center for Applied Pharmacobiology Research, University of Navarra, C/ Irunlarrea s/n, 31008, Pamplona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Valdivia Olarte, Hugo" sort="Valdivia Olarte, Hugo" uniqKey="Valdivia Olarte H" first="Hugo" last="Valdivia-Olarte">Hugo Valdivia-Olarte</name>
<affiliation><nlm:aff id="A1">Laboratorio de Bioinformática y Biología Molecular, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia. Av. Honorio Delgado, 430. SMP. Lima, Peru</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Olivares, Carlos" sort="Olivares, Carlos" uniqKey="Olivares C" first="Carlos" last="Olivares">Carlos Olivares</name>
<affiliation><nlm:aff id="A1">Laboratorio de Bioinformática y Biología Molecular, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia. Av. Honorio Delgado, 430. SMP. Lima, Peru</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Department of Physics, PUC-Rio, Rua Marquês de São Vicente, 225, Gávea - Rio de Janeiro, Brazil</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Requena, David" sort="Requena, David" uniqKey="Requena D" first="David" last="Requena">David Requena</name>
<affiliation><nlm:aff id="A1">Laboratorio de Bioinformática y Biología Molecular, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia. Av. Honorio Delgado, 430. SMP. Lima, Peru</nlm:aff>
</affiliation>
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<author><name sortKey="Gutierrez, Andres H" sort="Gutierrez, Andres H" uniqKey="Gutierrez A" first="Andrés H" last="Gutiérrez">Andrés H. Gutiérrez</name>
<affiliation><nlm:aff id="A1">Laboratorio de Bioinformática y Biología Molecular, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia. Av. Honorio Delgado, 430. SMP. Lima, Peru</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Reyes Loyola, Paola" sort="Reyes Loyola, Paola" uniqKey="Reyes Loyola P" first="Paola" last="Reyes-Loyola">Paola Reyes-Loyola</name>
<affiliation><nlm:aff id="A4">Laboratorio de Modelado Molecular y Bioinformática de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México. Plan de San Luis Y Diaz Mirón S/N, Col. Casco de Santo Tomas, Mexico city, México</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tolentino Lopez, Luis E" sort="Tolentino Lopez, Luis E" uniqKey="Tolentino Lopez L" first="Luis E" last="Tolentino-Lopez">Luis E. Tolentino-Lopez</name>
<affiliation><nlm:aff id="A4">Laboratorio de Modelado Molecular y Bioinformática de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México. Plan de San Luis Y Diaz Mirón S/N, Col. Casco de Santo Tomas, Mexico city, México</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sheen, Patricia" sort="Sheen, Patricia" uniqKey="Sheen P" first="Patricia" last="Sheen">Patricia Sheen</name>
<affiliation><nlm:aff id="A1">Laboratorio de Bioinformática y Biología Molecular, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia. Av. Honorio Delgado, 430. SMP. Lima, Peru</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Briz, Ver Nica" sort="Briz, Ver Nica" uniqKey="Briz V" first="Ver Nica" last="Briz">Ver Nica Briz</name>
<affiliation><nlm:aff id="A5">Laboratorio de Inmunobiología Molecular, Hospital Universitario Gregorio Marañón, Madrid, España, CIBER BBN, Madrid, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mu Oz Fernandez, Maria A" sort="Mu Oz Fernandez, Maria A" uniqKey="Mu Oz Fernandez M" first="Maria A" last="Mu Oz-Fernández">Maria A. Mu Oz-Fernández</name>
<affiliation><nlm:aff id="A5">Laboratorio de Inmunobiología Molecular, Hospital Universitario Gregorio Marañón, Madrid, España, CIBER BBN, Madrid, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Correa Basurto, Jose" sort="Correa Basurto, Jose" uniqKey="Correa Basurto J" first="José" last="Correa-Basurto">José Correa-Basurto</name>
<affiliation><nlm:aff id="A4">Laboratorio de Modelado Molecular y Bioinformática de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México. Plan de San Luis Y Diaz Mirón S/N, Col. Casco de Santo Tomas, Mexico city, México</nlm:aff>
</affiliation>
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<author><name sortKey="Zimic, Mirko" sort="Zimic, Mirko" uniqKey="Zimic M" first="Mirko" last="Zimic">Mirko Zimic</name>
<affiliation><nlm:aff id="A1">Laboratorio de Bioinformática y Biología Molecular, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia. Av. Honorio Delgado, 430. SMP. Lima, Peru</nlm:aff>
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<series><title level="j">Bioinformation</title>
<idno type="ISSN">0973-8894</idno>
<idno type="eISSN">0973-2063</idno>
<imprint><date when="2013">2013</date>
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<front><div type="abstract" xml:lang="en"><p>The pandemic influenza AH1N1 (2009) caused an outbreak of human infection that spread to the world. Neuraminidase (NA) is an
antigenic surface glycoprotein, which is essential to the influenza infection process, and is the target of anti-flu drugs oseltamivir
and zanamivir. Currently, NA inhibitors are the pillar pharmacological strategy against seasonal and global influenza. Although
mutations observed after NA-inhibitor treatment are characterized by changes in conserved amino acids of the enzyme catalytic
site, it is possible that specific amino acid substitutions (AASs) distant from the active site such as H274Y, could confer oseltamivir
or zanamivir resistance. To better understand the molecular distribution pattern of NA AASs, we analyzed NA AASs from all
available reported pandemic AH1N1 NA sequences, including those reported from America, Africa, Asia, Europe, Oceania, and
specifically from Mexico. The molecular distributions of the AASs were obtained at the secondary structure domain level for both
the active and catalytic sites, and compared between geographic regions. Our results showed that NA AASs from America, Asia,
Europe, Oceania and Mexico followed similar molecular distribution patterns. The compiled data of this study showed that highly
conserved amino acids from the NA active site and catalytic site are indeed being affected by mutations. The reported NA AASs
follow a similar molecular distribution pattern worldwide. Although most AASs are distributed distantly from the active site, this
study shows the emergence of mutations affecting the previously conserved active and catalytic site. A significant number of
unique AASs were reported simultaneously on different continents.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Bioinformation</journal-id>
<journal-id journal-id-type="iso-abbrev">Bioinformation</journal-id>
<journal-id journal-id-type="publisher-id">Bioinformation</journal-id>
<journal-title-group><journal-title>Bioinformation</journal-title>
</journal-title-group>
<issn pub-type="ppub">0973-8894</issn>
<issn pub-type="epub">0973-2063</issn>
<publisher><publisher-name>Biomedical Informatics</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">23930018</article-id>
<article-id pub-id-type="pmc">3732439</article-id>
<article-id pub-id-type="publisher-id">97320630009673</article-id>
<article-id pub-id-type="doi">10.6026/97320630009673</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Hypothesis</subject>
</subj-group>
</article-categories>
<title-group><article-title>Molecular distribution of amino acid substitutions on neuraminidase from the 2009 (H1N1) human influenza pandemic virus</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Quiliano</surname>
<given-names>MiguelMiguel</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Valdivia-Olarte</surname>
<given-names>Hugo</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Olivares</surname>
<given-names>Carlos</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Requena</surname>
<given-names>David</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gutiérrez</surname>
<given-names>Andrés H</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Reyes-Loyola</surname>
<given-names>Paola</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tolentino-Lopez</surname>
<given-names>Luis E</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sheen</surname>
<given-names>Patricia</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Briz</surname>
<given-names>Verónica</given-names>
</name>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Muñoz-Fernández</surname>
<given-names>Maria A</given-names>
</name>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Correa-Basurto</surname>
<given-names>José</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zimic</surname>
<given-names>Mirko</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="corresp" rid="COR1">*</xref>
</contrib>
<aff id="A1"><label>1</label>
Laboratorio de Bioinformática y Biología Molecular, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia. Av. Honorio Delgado, 430. SMP. Lima, Peru</aff>
<aff id="A2"><label>2</label>
Drug R&D Unit, Center for Applied Pharmacobiology Research, University of Navarra, C/ Irunlarrea s/n, 31008, Pamplona, Spain</aff>
<aff id="A3"><label>3</label>
Department of Physics, PUC-Rio, Rua Marquês de São Vicente, 225, Gávea - Rio de Janeiro, Brazil</aff>
<aff id="A4"><label>4</label>
Laboratorio de Modelado Molecular y Bioinformática de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México. Plan de San Luis Y Diaz Mirón S/N, Col. Casco de Santo Tomas, Mexico city, México</aff>
<aff id="A5"><label>5</label>
Laboratorio de Inmunobiología Molecular, Hospital Universitario Gregorio Marañón, Madrid, España, CIBER BBN, Madrid, Spain</aff>
</contrib-group>
<author-notes><corresp id="COR1"><label>*</label>
Mirko Zimic: <email>mirko.zimic@upch.pe</email>
, <email>mzimic@jhsph.edu</email>
Phone: +511-3190000; ext 2604</corresp>
</author-notes>
<pub-date pub-type="collection"><year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>17</day>
<month>7</month>
<year>2013</year>
</pub-date>
<volume>9</volume>
<issue>13</issue>
<fpage>673</fpage>
<lpage>679</lpage>
<history><date date-type="received"><day>07</day>
<month>5</month>
<year>2013</year>
</date>
<date date-type="accepted"><day>08</day>
<month>5</month>
<year>2013</year>
</date>
</history>
<permissions><copyright-statement>© 2013 Biomedical Informatics</copyright-statement>
<copyright-year>2013</copyright-year>
<license license-type="open-access"><license-p>This is an open-access article, which permits unrestricted use, distribution, and reproduction in any medium,
for non-commercial purposes, provided the original author and source are credited.</license-p>
</license>
</permissions>
<abstract><p>The pandemic influenza AH1N1 (2009) caused an outbreak of human infection that spread to the world. Neuraminidase (NA) is an
antigenic surface glycoprotein, which is essential to the influenza infection process, and is the target of anti-flu drugs oseltamivir
and zanamivir. Currently, NA inhibitors are the pillar pharmacological strategy against seasonal and global influenza. Although
mutations observed after NA-inhibitor treatment are characterized by changes in conserved amino acids of the enzyme catalytic
site, it is possible that specific amino acid substitutions (AASs) distant from the active site such as H274Y, could confer oseltamivir
or zanamivir resistance. To better understand the molecular distribution pattern of NA AASs, we analyzed NA AASs from all
available reported pandemic AH1N1 NA sequences, including those reported from America, Africa, Asia, Europe, Oceania, and
specifically from Mexico. The molecular distributions of the AASs were obtained at the secondary structure domain level for both
the active and catalytic sites, and compared between geographic regions. Our results showed that NA AASs from America, Asia,
Europe, Oceania and Mexico followed similar molecular distribution patterns. The compiled data of this study showed that highly
conserved amino acids from the NA active site and catalytic site are indeed being affected by mutations. The reported NA AASs
follow a similar molecular distribution pattern worldwide. Although most AASs are distributed distantly from the active site, this
study shows the emergence of mutations affecting the previously conserved active and catalytic site. A significant number of
unique AASs were reported simultaneously on different continents.</p>
</abstract>
<kwd-group><kwd>Influenza</kwd>
<kwd>Pandemic H1N1 (2009)</kwd>
<kwd>Neuraminidase</kwd>
<kwd>Molecular distribution pattern</kwd>
<kwd>Geographic regions</kwd>
<kwd>amino acid substitution</kwd>
</kwd-group>
</article-meta>
</front>
<body><sec id="s1"><title>Background</title>
<p>In the last century, many different deadly influenza epidemics
have affected humanity. The 1918 Spanish flu epidemic killed
approximately 20 to 50 million people worldwide, and the
Asian flu epidemic (1957), the Hong Kong flu epidemic (1968),
and the Russian flu epidemic (1977) had severe fatal
consequences for human populations
[<xref ref-type="bibr" rid="R01">1</xref>
]. According to WHO,
influenza pandemic occurs when a newly mutated influenza
virus appears in a human population with no immunity,
resulting in worldwide spread with high morbidity and
mortality. In 2009, the global pandemic of AH1N1 influenza, or
“swine flu,” emerged in Mexico and the United States, arising
from a genome reassortment of multiple known influenza
viruses (swine, avian and humans) [<xref ref-type="bibr" rid="R02">2</xref>
,
<xref ref-type="bibr" rid="R03">3</xref>
]. By February 5, 2010,
WHO statistics reported that the AH1N1 (2009) virus had been
confirmed across 209 countries and killed at least 15,174
people. Given Mexico's status as one of the countries where the
virus first emerged [<xref ref-type="bibr" rid="R02">2</xref>
], the high morbidity and mortality there
[<xref ref-type="bibr" rid="R04">4</xref>
], and the increased vigilance of the Latin American
epidemiological surveillance network, Mexico is clearly an
important epidemiological site to compare with the rest of the
world. The lack of adequate influenza vaccines resulting from
the continuous seasonal viral reassortment process [<xref ref-type="bibr" rid="R05">5</xref>
,
<xref ref-type="bibr" rid="R06">6</xref>
] makes
anti-influenza drugs, including NA-inhibitors, a crucial
weapon against influenza infection. Hemagglutinin and NA
are important antigenic surface proteins from influenza A
virus. Influenza A NA activity facilitates the release of progeny
virions from infected cells [<xref ref-type="bibr" rid="R07">7</xref>
]. NA-inhibitors block NA activity
by targeting the highly conserved enzyme active site (AS) and
catalytic site (CS). Based on NA crystal structure for 2009
pandemic AH1N1 human influenza [<xref ref-type="bibr" rid="R08">8</xref>
], six amino acids (R156,
W178, I222, E227, E277 and N294) compose and serve as
framework residues (FR) in the stabilization of the AS
structure, and another nine amino acids (R118, E119, D151,
R152, R224, E276, R292, R371 and Y406) act as catalytic residues
in direct contact with the substrate [<xref ref-type="bibr" rid="R09">9</xref>
,
<xref ref-type="bibr" rid="R10">10</xref>
]. NA-inhibitors
currently constitute the most important anti-viral agents for
influenza A and B viruses. Recently, strains of seasonal and
pandemic AH1N1 virus have been associated with resistance to
first-line NA-inhibitor oseltamivir [<xref ref-type="bibr" rid="R04">4</xref>
,
<xref ref-type="bibr" rid="R11">11</xref>
]. Specific AASs in AS,
and particularly in CS residues have been shown to confer viral
resistance to NA-inhibitors [<xref ref-type="bibr" rid="R12">12</xref>
,
<xref ref-type="bibr" rid="R13">13</xref>
]. The association between
AH1N1 NA AASs and resistance to oseltamivir has revealed
the importance of specific AASs.</p>
<p>A well-characterized case is the amino acid substitution H274Y
(crystallographic nomenclature: PDB code 3NSS), implicated in
a distant effect of a structural change at the AS level
[<xref ref-type="bibr" rid="R14">14</xref>
]. Since
the first report of oseltamivir-resistant AH1N1 in June 2009
(Oseltamivir resistance in immunocompromised hospital
patients: pandemic H1N1 2009 briefing note by WHO), clinical
studies have been published about the use of oseltamivir and
its impact on the emergence of NA-inhibitor resistant influenza
[<xref ref-type="bibr" rid="R15">15</xref>
–<xref ref-type="bibr" rid="R19">19</xref>
].
Several NA sequences and crystallographic structures
for multiple strains are currently available in public databases,
and the launch of the Influenza Genome Sequencing Project
[<xref ref-type="bibr" rid="R20">20</xref>
]
has led to a rapid increase in the availability of sequence
information, as well as epidemiological and clinical data. The
contribution of different influenza virus databases to the
scientific community has been notably important [<xref ref-type="bibr" rid="R21">21</xref>
,
<xref ref-type="bibr" rid="R22">22</xref>
].
Nevertheless, recent studies of NA sequencing and protein
structure analysis have mostly been applied to drug
development [<xref ref-type="bibr" rid="R23">23</xref>
]. To date, the rapid large-scale sequencing,
data sharing in influenza and the use of analytical and
visualization tools, such as GENGIS [<xref ref-type="bibr" rid="R24">24</xref>
] and SUPRAMAP
[<xref ref-type="bibr" rid="R25">25</xref>
],
have let the integration of phylogenetic data and geographic
information. Global geographic maps of NA AASs,
phylogenetic relationships and geographical location are
frequently reported. However, the molecular distribution
patterns of NA AASs at the sequence and structural level and
its relationship to geographic regions or NA-inhibitor
resistance have never been reported. The present study aims to
fill this gap, showing the molecular distribution patterns of NA
AASs in different sequences of 2009 pandemic AH1N1 human
influenza virus at protein sequence levels, in Mexico and global
geographic regions.</p>
</sec>
<sec sec-type="methods" id="s2"><title>Methodology</title>
<sec id="s2a"><title><italic>NA sequences</italic>
:</title>
<p>NA sequences from 2009 pandemic AH1N1 influenza virus
strains were obtained from the Influenza Virus Sequence
Database [<xref ref-type="bibr" rid="R22">22</xref>
] (April 26, 2011) using the following filters:
selected sequence type (protein), type (A), host (human),
country/region (America, Asia, Oceania, Europa, Africa and
Mexico), protein (NA), subtype (H1N1), full-length only,
required segments (NA), get sequences from (only pandemic
H1N1 2009 and include The Flu project). To prevent bias when
estimating the distribution of AASs, only complete sequences
(469 amino acids length) were included.</p>
</sec>
<sec id="s2b"><title><italic>Detection of NA amino acid substitutions</italic>
:</title>
<p>A multiple sequence alignment of the NA protein sequences
was performed using ClustalW-MPI [<xref ref-type="bibr" rid="R26">26</xref>
]. Amino acid
substitutions were automatically determined using a python
script developed for us (<ext-link ext-link-type="uri" xlink:href="http://code.google.com/p/neuraminidase-scripts/">http://code.google.com/p/neuraminidase-scripts/</ext-link>
) for this specific purpose. All
substitutions were compared to the native reference pandemic
NA amino acid sequence (id: ACQ73395) reported by the
Mexican health authorities. A random sample of 100 sequences
was manually analyzed to determine NA AASs. Manual
inspection correlated 100% with the automatic process. NA
AASs associated with oseltamivir and zanamivir resistance
were obtained from the Drug resistance prediction tool,
[<xref ref-type="bibr" rid="R27">27</xref>
,
<xref ref-type="bibr" rid="R28">28</xref>
], implemented in Influenza Virus Resource. NA AASs
associated with oseltamivir and zanamivir resistance reported
in different subtypes of seasonal influenza and pandemic
AH1N1 (2009) influenza were also included [<xref ref-type="bibr" rid="R19">19</xref>
,
<xref ref-type="bibr" rid="R29">29</xref>
–<xref ref-type="bibr" rid="R31">31</xref>
]. In
addition, based on the scientific literature AASs related with
resistance were classified in confirmed [<xref ref-type="bibr" rid="R15">15</xref>
–<xref ref-type="bibr" rid="R18">18</xref>
,
<xref ref-type="bibr" rid="R25">25</xref>
] and potential
(confirmed in different subtypes). The positions of these AASs
were named as RRAP (reported resistance-associated position)
and PRAP (potentially resistance-associated position),
respectively. The amino acids found in FR of the AS, CS, RRAP
and PRAP were extracted, joined in pseudo-sequences and
aligned using CLC Main Workbench 6.8.2. Sequence logos
were made with these using no duplicated pseudo-sequences
and the software WebLogo 3.3 [<xref ref-type="bibr" rid="R32">32</xref>
].</p>
</sec>
<sec id="s2c"><title><italic>Molecular distribution patterns of NA amino acid substitutions.</italic>
:</title>
<p>The molecular distribution patterns of NA AASs were
determined by mapping the AASs in the protein sequence. To
prevent selection bias, only unique AASs were considered (i.e.
only one AAS of a particular type was used regardless the
number of times the AAS was reported). Mexican and global
AASs were compiled for different continents (Africa, America,
Asia, Europe and Oceania). The mapping of AASs was
determined according to the localization of the substitutions
within each of the 59 domains of the secondary structure.
Secondary structure was determined according to the reference
NA crystal structure for 2009 pandemic AH1N1 human
influenza (PDB code 3nss) [<xref ref-type="bibr" rid="R08">8</xref>
]. The secondary structure of NA is
comprised of two alpha helices (a1, a2), 27 beta sheets (β1, β2,
β3, …, β27)) and 30 loops (L1, L2, L3, …, L30). The transmembrane
and linker regions were included as independent
domains. Given the importance of the AS and CS in enzymatic
function, AASs occurring particularly in the AS (R156, W178,
I222, E227, and N294), and in the CS (R118, E119, D151, R152,
R224, E276, R292, and R371), were recognized separately.
Equivalence position of amino acids between crystallographic
and sequence lineal nomenclature is shown in Table S1,
(available at <ext-link ext-link-type="uri" xlink:href="http://code.google.com/p/neuraminidasescripts/">http://code.google.com/p/neuraminidasescripts/</ext-link>
).</p>
</sec>
<sec id="s2d"><title><italic>Statistical analysis of the molecular distribution patterns</italic>
:</title>
<p>The molecular distributions of AASs at the level of secondary
structure domain were compared with AASs reported from
America, Europe, Asia and Oceania, and Africa (i.e. America
with Europe, America with Asia and Oceania, America with
Africa). In addition, we compared AASs reported in Mexico
with those reported in the rest of the world. The frequency of
AASs in each domain was calculated as the accumulated
number of AASs per normalized domain by the total number
of AASs. Using statistical software STATA® 10, the equality of
the distribution functions between continents, and between
Mexico and the rest of the world, was verified with the
Kolmogorov-Smirnov test. The independence of the
frequencies of AASs between continents, and between Mexico
and rest of the world, were tested using Spearman's rank
correlation test.</p>
</sec>
</sec>
<sec id="s3"><title>Results and Discussion</title>
<p>This study shows for the first time the compilation and
comparison of all globally reported NA AASs from the 2009
pandemic AH1N1 influenza virus in different geographic
areas. We compared the molecular distribution pattern of AASs
in the NA secondary structure and active and catalytic site
levels between continents and particularly with Mexico.</p>
<sec id="s3a"><title><italic>Pandemic human influenza (AH1N1) NA sequences</italic>
:</title>
<p>A total of 3740 NA protein sequences were downloaded from
the Influenza Virus Sequence Database corresponding to the
2009 pandemic AH1N1 human influenza virus (Dataset S1,
available at <ext-link ext-link-type="uri" xlink:href="http://code.google.com/p/neuraminidasescripts/">http://code.google.com/p/neuraminidasescripts/</ext-link>
).
Of these, 112 were from Mexico and 3628 were from
the rest of the world. In addition, sequences were classified
according to the continent of origin: 59 from Africa, 2298 from
America, 521 from Asia, 772 from Europe and 89 from Oceania.
Excluded from the analysis were 1254 incomplete sequences,
the majority of which lacked the amino and carboxy-terminal
extremes.</p>
</sec>
<sec id="s3b"><title><italic>Amino acid substitutions in 2009 human AH1N1 NA</italic>
:</title>
<p>A total of 530 unique AASs were detected. From these, 312
were reported in America, 204 in Asia and Oceania, 219 in
Europe, 26 in Africa, and 38 in Mexico. According to the
Influenza Virus Sequence Database, NA AASs H274Y and
N294S were associated with resistance to oseltamivir (seasonal
H3N2). Based on clinical data, substitutions H274Y and I222R
were potentially associated with oseltamivir and zanamivir
resistance (pandemic AH1N1 2009). AASs reported in NAs
from related viruses that confer resistance to oseltamivir were
D198N (seasonal B), S248N (seasonal H1N1) and K261R
(seasonal H1N1), and those that confer resistance to oseltamivir
and zanamivir were Y155H and S246N (seasonal H1N1). AASs
specifically located in residues of NA AS or CS were D151N
and I222T, and are potentially associated with resistance to
zanamivir and both oseltamivir and zanamivir, respectively.
The occurrence of these variations is showed in
<xref ref-type="supplementary-material" rid="SD1">Figure S1</xref>
(see
supplementary material). Reported variants were found
(D151N, Y155H, D198N, I222R, I222T, S246N, K261R, H274Y).
But, new variants were found: E119K and Y406H (Asia, in CS),
D198G and D198Y (Europe), G248R and G248E (Asia and
Mexico). Each pseudo-sequence represents a group of NA
sequences by its most important reported amino acids.
According these, we found only one type of strain in Africa,
Central America and Oceania. This sequence corresponds to
the predominant amino acids of the pseudo-sequences in the
other regions studied (Asia, Europe, Mexico and South
America). This would be due the low amount of sequences
analyzed for these regions (59 in Africa, 89 in Oceania and 153
in Central America) compared with the others (112 in Mexico
and >520 in each of the others). Most amino acid variations
were found in Europe and Asia.</p>
</sec>
<sec id="s3c"><title><italic>Molecular distribution patterns of NA amino acid substitutions.</italic>
:</title>
<p>The AASs in NA were non-uniformly distributed across the
protein sequence. The molecular distributions for continents
appeared qualitatively very similar, showing an identical
clustering pattern shown in <xref ref-type="supplementary-material" rid="SD1">Figure S2</xref>
&
<xref ref-type="supplementary-material" rid="SD1">Figure S3</xref>
(see
supplementary material). The molecular distribution of AASs
reported in America and Asia-Oceania were found to be
significantly different (P=0.005, Kolmogorov-Smirnov
nonparametric test). The same result was found between
America and Africa, and between Mexico and rest of the world
(P<0.001 and p=0.001 respectively, Kolmogorov-Smirnov
nonparametric test). There was no evidence to reject the null
hypothesis that the molecular distribution pattern of AASs
reported from America and Europe were different (P=0.432,
Kolmogorov-Smirnov nonparametric test). On the other hand,
Spearman correlation tests in all cases rejected the null
hypotheses that the molecular distribution frequencies were
independent (p<0.001), thus the evidence favors a similar
pattern of AASs distribution.</p>
<p>Thus, the molecular distribution of AASs were, qualitatively
and quantitatively, very similar between all continents with the
exception of Africa, likely due to a lack of AH1N1 NA
sequences reported from this region. In the particular case of
Mexico, only 38 unique AASs were available, therefore despite
the qualitative similarity in the molecular distribution of AASs
when compared to the rest of the world, there was a lack of
statistical significance. Since the type of AASs take relevance in
the study, it is important to mention that the study did not
include the frequency of each type of AAS at continental level
because it is directly related to the number of NA sequences
available, which could be associated to a reporting bias. In
addition, the remarkable similarity between the worldwide
molecular distribution of NA AASs stratified by continent, and
the presence of identical hot-spot regions, suggest the existence
of a global pattern of NA AASs associated to the 2009
pandemic originating in Mexico and United States.</p>
<p>The molecular distribution of AASs between Mexico and the
rest of the world is shown in <xref ref-type="supplementary-material" rid="SD1">Figure S2</xref>
(see supplementary
material). In all regions, the highest incidence of unique AAS
was localized on the trans-membrane and linker domains (TM,
L1, a1, Ll5, L17 and L30), which are not part of the CS or AS.
AASs reported in Mexico affected the domains TM, L1, a1, b2,
b4, L13, L15, b15, L17, b17, L21, b20, L23, L24, b23, b26 and L30.
Domains b2 and L13 included CS and AS residues,
respectively. AASs reported in the rest of the world affected the
domains TM, L1, b1, L2, a1, L3, b2, L4, b3, L5, b4, b5, L7, b6, b7,
b8, L10, b9, L11, b10, b11, L13, b12, b13, L15, b14, L16, b15, L17,
b16, L18, b17, L19, b18, L20 b19, L21, b20, L22, b21, L23, b22,
L24, b23, L25, b24, b25, a2, L28, b26, L29, b27 and L30. From
these regions β2, L4 and L7 included AASs affecting the CS,
while the b6, L13 and b25 domains included AASs affecting the
AS. Only domain L19 had reported AASs in both the CS and
the AS. The most conserved domains in Mexico and the rest of
the world included L6, L8, L9, L12, L14, L26 and L27.</p>
<p>"The molecular distribution of AASs stratified by continents is
shown in <xref ref-type="supplementary-material" rid="SD1">Figure S3</xref>
(see supplementary material). All
distributions appeared qualitatively similar showing an
identical clustering pattern. The stratified distributions for
continents let us identify nine domains with the highest
incidence of AAS. These were TM, L1, L7, L15, b14, L21, b22,
L24 and L30. America did not report AASs in domains L2, b6,
b18 regions, unlike Europe, Asia and Oceania. Europe did not
present AASs in domains b1, L3, L4, b3, b5, b8, b20 in contrast
to Asia, Oceania, and America. For Asia and Oceania, domains
β 12, L18, β 17 and L19 did not present AASs unlike America
and Europe. Africa presented a small number of AASs
probably due to underreporting.</p>
<p>AASs that affected the AS and CS were non-uniformly
distributed across the protein sequence in samples from both
Mexico and the rest of the world (<xref ref-type="fig" rid="F1">Figure 1</xref>
). AASs occurring
particularly in the AS and CS were recognized separately.
Three AASs were reported to affect the AS, and none of these
were reported in Mexico. Six AASs were reported to affect the
catalytic residues, and none of these were reported in Mexico.
Amino acids of the AS affected by substitutions were I222 and
N294. Amino acids of the CS affected by substitutions were
E119, D151, and Y406. AASs reported were: E119K, E119X,
D151N, D151B, I222R, I222T, N294X, Y406H, and Y406X. AASs
H274Y and I222R were clinically reported to be resistant to
oseltamivir and oseltamivir/zanamivir respectively.</p>
<p>It is important to highlight that all AH1N1 influenza NA AASs
reported at this time are primarily distributed in enzymatic
hot-spot regions that do not affect the AS or CS. This finding
partially substantiates the previous results reported by Maurer-
Stroh [<xref ref-type="bibr" rid="R33">33</xref>
]
that until 2009 there was a strict conservation of the
NA CS region and the drug-binding pocket, leaving these
regions free of AASs. Our study shows AASs affecting the AS
and CS directly, indicating that the hydrophobic core is no
longer intact. However, the region comprised of domains L6,
L8, L9, L12, L14, L26 and L27 has remained free of AASs, and
thus remains a potential zone for the design of an epitope
vaccine due to the low variability of its amino acids. Besides,
most AASs analyzed in this study are from clinical strains, thus
the few AASs associated with oseltamivir/zanamivir resistance
may have clinical significance with regard to future resistance
patterns and mechanisms. The distribution of AASs for total
data was reported by amino acid and continent
<xref ref-type="supplementary-material" rid="SD1">Figure S2</xref>
(available at <ext-link ext-link-type="uri" xlink:href="http://code.google.com/p/neuraminidasescripts/">http://code.google.com/p/neuraminidasescripts/</ext-link>
).
Each continent reported exclusive AASs (America 165,
Africa 5, Asia 91, Oceania 10, and Europa 94). AASs appearing
simultaneously in different regions are also reported.</p>
</sec>
<sec id="s3d"><title><italic>Amino acid substitutions and its possible relationship with a pharmacological selection pressure</italic>
:</title>
<p>Understanding the molecular distribution pattern of AASs
associated with drug resistance will help guide strategies to
prevent the emergence of resistance. Although more in-depth
research is needed, a first discussion of a possible relationship
between AASs and pharmacological selection pressure could
be made. In the 2009 AH1N1 influenza pandemic Mexico
reported few cases of oseltamivir/zanamivir resistance, an
AAS pattern that contrast with other pathogens under
pharmacological pressure such as <italic>Mycobacterium tuberculosis</italic>
[<xref ref-type="bibr" rid="R35">35</xref>
], HIV
[<xref ref-type="bibr" rid="R36">36</xref>
] and <italic>Plasmodium falciparum</italic>
[<xref ref-type="bibr" rid="R37">37</xref>
]. The lack of a
large number of AASs in the AS and CS relative to other areas
of the enzyme could be a good evidence for a lack of a past
pharmacological selection pressure, which is consistent with
the historically narrow use of NA-inhibitors as anti-influenza
treatment. However, the new incidence of NA AASs associated
with resistance to zanamivir and/or oseltamivir could suggest
that a neuraminidase-inhibitor pharmacological selection
pressure is beginning to emerge.</p>
<p>Zanamivir and oseltamivir were introduced in the market
around 1999-2002 [<xref ref-type="bibr" rid="R29">29</xref>
], and were used as effective alternative
anti-influenza drugs for the AH5N1 in 2003 and 2004, which
was resistant to amantandine and rimantadine (M2 proteininhibitors).
This success led to further reinforcement of their
use during the 2009 pandemic. With the continuous and
widespread use of these anti-influenza drugs, it is very likely
that a future AH1N1 pandemic will yield more predominant
zanamivir- and/or oseltamivir-resistant strains, in which NA
AASs tend to accumulate in hot-spots associated with the
active and catalytic sites. Given this possibility, it may be of
benefit to identify potential NA AASs in the AS and CS that
may cause drug-resistance in order to design effective alternate
anti-influenza drugs. Although AASs may evolve
spontaneously in reservoir populations, our compiled global
data show a significant number of unique NA AASs that were
reported simultaneously on different continents. For example,
among the 38 unique AASs reported in Mexico, 29 are also
reported elsewhere. Although not conclusive, this evidence
favors the hypothesis of global transmission of AH1N1 strains
carrying specific NA AASs. It is interesting to note the
emergence of new AAS in worldwide circulating strains that
are selected and share the same NAAAS.</p>
</sec>
</sec>
<sec id="s4"><title>Conclusion</title>
<p>NA AASs associated with secondary structure domains in
pandemic AH1N1 influenza suggest a conserved molecular
distribution pattern present worldwide. The majority of unique
AH1N1 NA AASs have incidence on multiple continents,
suggesting human transmission as an important factor in the
spread of new AASs. The majority of present NA AASs
continues to occur in sites distant from the AS and CS
suggesting a historic lack of pharmacological selection
pressures, however the recent identification of AASs affecting
the AS and CS may be evidence of emerging pharmacological
selection pressures associated with increased NA-inhibitor
use.</p>
</sec>
<sec sec-type="supplementary-material"><title>Supplementary material</title>
<supplementary-material content-type="loca-data" id="SD1"><caption><title>Data 1</title>
</caption>
<media xlink:href="97320630009673S1.pdf" xlink:type="simple" id="d35e482" position="anchor" mimetype="application" mime-subtype="pdf"></media>
</supplementary-material>
</sec>
</body>
<back><ack><p>The authors thank PhD(c) Myra E. Flores for her constructive
criticisms at the moment to write the manuscript. The work
was partially supported by grants from ICyTDF (PIRIVE09-9),
CONACYT and PIFI-SIP-COFAA-IPN.</p>
</ack>
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<floats-group><fig id="F1" position="float"><label>Figure 1</label>
<caption><p>Distribution of amino acid substitutions (AASs) from 2009 pandemic AH1N1 human influenza virus NA by active site
and catalytic site. (┼) Potentially resistant AASs. (*) Confirmed resistant AASs. The number of AASs reported in each section is
indicated with a gray bar. Circle color indicates residues that interact with oseltamivir (O, light blue), zanamivir (Z, light green)
and sialic acid (S, black). Catalytic residues shown in red rectangles indicate direct contact with sialic acid (substrate). Based on Liu
<italic>et al</italic>
[<xref ref-type="bibr" rid="R34">34</xref>
], the principal binding energy contribution for each site associated with an influenza drug or substrate is indicated with
letters Z, O, and S.</p>
</caption>
<graphic xlink:href="97320630009673F1"></graphic>
</fig>
</floats-group>
</pmc>
</record>
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