Rhiza Labs FluTracker Forum

The Indonesian Ministy of Health has released the H5N1 HA sequences (at GISAID) from the 3 recent fatal cases in Bali (29F, 5F, 10M)

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The three HA sequences are

A/Indonesia/NIHRD11766/2011 11/07/2011 5F
A/Indonesia/NIHRD11771/2011 11/07/2011 10M
A/Indonesia/NIHRD11815/2011 11/16/2011 29F

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Receptor binding domain changes include D187N, A188G, R193M

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R193M Pedigree

EPI341634 A/Indonesia/NIHRD11815/2011(H5N1) (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI341633 A/Indonesia/NIHRD11771/2011(H5N1) (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI341632 A/Indonesia/NIHRD11766/2011(H5N1) (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI341332 A/Indonesia/NIHRD11073/2011(H5N1) (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI340810 A/chicken/Lampung/BPPVRIII-10-161/2010 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI340790 A/bird/Gunung Kidul/BBVW-52-I/2010 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI340788 A/chicken/Klaten/BBVW-109-II/2010 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI340786 A/chicken/Jombang/BBVW-166-III/2010 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI340784 A/chicken/Sleman/BBVW-150-III/2010 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI340782 A/chicken/Sleman/BBVW-180-III/2010 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI340780 A/chicken/Lamongan/BBVW-170-III/2010 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI340778 A/chicken/Temanggung/BBVW-1203d-VIII/2009 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI340776 A/chicken/Temanggung/BBVW-1203b-VIII/2009 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI340774 A/chicken/Tasikmalaya/BBVW-991-VI/2009 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI340768 A/chicken/Kuningan/BBVW-1004-VI/2009 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI340766 A/chicken/Kudus/BBVW-1186-IX/2009 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI324615 A/tree sparrow/Indonesia/D10013/2010 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI324340 A/chicken/Indonesia/D10014/2010 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI321329 A/chicken/Indonesia/Tanggerang_1/2007 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI307911 A/chicken/Indonesia/SmiWN18/2009 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI287380 A/poultry/Egypt/3982-55/2010 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI228556 A/Chicken/Nakornsawan-2-07/2004 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI181390 A/Indonesia/5/2005 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI165824 A/chicken/Nakornsawan/NIAH6-3-0009/2005 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI164763 A/Indonesia/7272/2008 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI164208 A/Indonesia/8228/2008 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI162940 A/Indonesia/7261/2008 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI117660 A/chicken/Nakornsawan/NIAH6-3-0009/2005 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)
EPI100500 A/Chinese pond heron/Hong Kong/18/2005 (A/H5N1) segment 4 (HA) 27.0 7.209453e+00 14/14 (100%)

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LOCUS GQ149235 1764 bp cRNA linear VRL 03-JUN-2009
DEFINITION Influenza A virus (A/Indonesia/5/2005(H5N1)) escape mutant R189M
hemagglutinin (HA) gene, complete cds.
ACCESSION GQ149235
VERSION GQ149235.1 GI:238627128
KEYWORDS .
SOURCE Influenza A virus (A/Indonesia/5/2005(H5N1))
ORGANISM Influenza A virus (A/Indonesia/5/2005(H5N1))
Viruses; ssRNA negative-strand viruses; Orthomyxoviridae;
Influenzavirus A.
REFERENCE 1 (bases 1 to 1764)
AUTHORS Chen,Y., Qin,K., Wu,W.L., Li,G., Zhang,J., Du,H., Ng,M.H.,
Shih,J.W., Peiris,J.S., Guan,Y., Chen,H. and Xia,N.
TITLE Broad cross-protection against H5N1 avian influenza virus infection
by means of monoclonal antibodies that map to conserved viral
epitopes
JOURNAL J. Infect. Dis. 199 (1), 49-58 (2009)
PUBMED 19032063
REFERENCE 2 (bases 1 to 1764)
AUTHORS Wu,W.L., Chen,Y., Qin,K., Lau,S.Y., Tai,H., Cheung,C.L., Xia,N.,
Guan,Y. and Chen,H.
TITLE Direct Submission
JOURNAL Submitted (07-MAY-2009) Microbiology, The University of Hong Kong,
Laboratory Block, Faculty of Medicine Building, 21 Sasson Road,
Pokfulam, Hong Kong SAR, China
FEATURES Location/Qualifiers
source 1..1764
/organism="Influenza A virus (A/Indonesia/5/2005(H5N1))"
/mol_type="viral cRNA"
/strain="A/Indonesa/5/2005"
/serotype="H5N1"
/db_xref="taxon:400788"
/segment="4"
/note="escape mutant R189M; escape mutant from h5
monoclonal antibody 13D4; cocultured with mAb in
embryonated egg and plaque purified"
gene 1..1707
/gene="HA"
CDS 1..1707
/gene="HA"
/note="receptor binding and fusion protein"
/codon_start=1
/product="hemagglutinin"
/protein_id="ACR48872.1"
/db_xref="GI:238627129"
/translation="MEKIVLLLAIVSLVKSDQICIGYHANNSTEQVDTIMEKNVTVTH
AQDILEKTHNGKLCDLDGVKPLILRDCSVAGWLLGNPMCDEFINVPEWSYIVEKANPT
NDLCYPGSFNDYEELKHLLSRINHFEKIQIIPKSSWSDHEASSGVSSACPYLGSPSFF
RNVVWLIKKNSTYPTIKKSYNNTNQEDLLVLWGIHHPNDAAEQTMLYQNPTTYISIGT
STLNQRLVPKIATRSKVNGQSGRMEFFWTILKPNDAINFESNGNFIAPEYAYKIVKKG
DSAIMKSELEYGNCNTKCQTPMGAINSSMPFHNIHPLTIGECPKYVKSNRLVLATGLR
NSPQRESRRKKRGLFGAIAGFIEGGWQGMVDGWYGYHHSNEQGSGYAADKESTQKAID
GVTNKVNSIIDKMNTQFEAVGREFNNLERRIENLNKKMEDGFLDVWTYNAELLVLMEN
ERTLDFHDSNVKNLYDKVRLQLRDNAKELGNGCFEFYHKCDNECMESIRNGTYNYPQY
SEEARLKREEISGVKLESIGTYQILSIYSTVASSLALAIMMAGLSLWMCSNGSLQCRI
CI"
ORIGIN
1 atggagaaaa tagtgcttct tcttgcaata gtcagtcttg ttaaaagtga tcagatttgc
61 attggttacc atgcaaacaa ttcaacagag caggttgaca caatcatgga aaagaacgtt
121 actgttacac atgcccaaga catactggaa aagacacaca acgggaagct ctgcgatcta
181 gatggagtga agcctctaat tttaagagat tgtagtgtag ctggatggct cctcgggaac
241 ccaatgtgtg acgaattcat caatgtaccg gaatggtctt acatagtgga gaaggccaat
301 ccaaccaatg acctctgtta cccagggagt ttcaacgact atgaagaact gaaacaccta
361 ttgagcagaa taaaccattt tgagaaaatt caaatcatcc ccaaaagttc ttggtccgat
421 catgaagcct catcaggagt gagctcagca tgtccatacc tgggaagtcc ctcctttttt
481 agaaatgtgg tatggcttat caaaaagaac agtacatacc caacaataaa gaaaagctac
541 aataatacca accaagaaga tcttttggta ctgtggggaa ttcaccatcc taatgatgcg
601 gcagagcaga caatgctata tcaaaaccca accacctata tttccattgg gacatcaaca
661 ctaaaccaga gattggtacc aaaaatagct actagatcca aagtaaacgg gcaaagtgga
721 aggatggagt tcttctggac aattttaaaa cctaatgatg caatcaactt cgagagtaat
781 ggaaatttca ttgctccaga atatgcatac aaaattgtca agaaagggga ctcagcaatt
841 atgaaaagtg aattggaata tggtaactgc aacaccaagt gtcaaactcc aatgggggcg
901 ataaactcta gtatgccatt ccacaacata caccctctca ccatcgggga atgccccaaa
961 tatgtgaaat caaacagatt agtccttgca acagggctca gaaatagccc tcaaagagag
1021 agcagaagaa aaaagagagg actatttgga gctatagcag gttttataga gggaggatgg
1081 cagggaatgg tagatggttg gtatgggtac caccatagca atgagcaggg gagtgggtac
1141 gctgcagaca aagaatccac tcaaaaggca atagatggag tcaccaataa ggtcaactca
1201 atcattgaca aaatgaacac tcagtttgag gccgttggaa gggaatttaa taacttagaa
1261 aggagaatag agaatttaaa caagaagatg gaagacgggt ttctagatgt ctggacttat
1321 aatgccgaac ttctggttct catggaaaat gagagaactc tagactttca tgactcaaat
1381 gttaagaacc tctacgacaa ggtccgacta cagcttaggg ataatgcaaa ggagctgggt
1441 aacggttgtt tcgagttcta tcacaaatgt gataatgaat gtatggaaag tataagaaac
1501 ggaacgtaca actatccgca gtattcagaa gaagcaagat taaaaagaga ggaaataagt
1561 ggggtaaaat tggaatcaat aggaacttac caaatactgt caatttattc aacagtggcg
1621 agttccctag cactggcaat catgatggct ggtctatctt tatggatgtg ctccaatgga
1681 tcgttacaat gcagaatttg catttaaatt tgtgagttca gattgtagtt aaaaacaccc
1741 ttgtttctac taatacaaaa caat

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Commentary

http://www.recombinomics.com/News/11071 ... _Bali.html

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The characteristics of our broadly cross-reactive H5 MAbs strongly suggest that they may recognize 1 or more highly conserved antigenic determinants in the HA protein of H5N1 virus. To understand the molecular basis of how 13D4 recognizes proteins in antigenically diverse H5N1 viruses, we mapped 13D4 MAb binding sites in the HA protein. The following 3 escape mutants were generated: R189M, derived from A/IDN/5/2005, and K152E and N182K, derived from A/VNM/1194/2004. Hemagglutination inhibition assays with 13D4 and other cross-reactive MAbs showed that these escape mutants still retained hemagglutination inhibition, albeit at a lower level than their parental viruses (table 3). Because A/VNM/1194/2004 and A/IDN/5/2005 belong to the antigenically distinct H5N1 virus clades 1 and 2.1, respectively, they may represent different natural immune escape mutants. Amino acid position 189, which corresponds to antigenic site B of H3N2, may represent an immunodominant epitope, and mutations at this position may thus be subject to strong positive selection [36]. As demonstrated previously [15], A/VNM/1194/2004 contains a mutation in position 189, R189K. Its continued recognition by 13D4, together with the generation of alternate-site escape mutants observed here, suggests that 13D4 binds to multiple sites in HA, possibly preventing immune escape associated with single-site mutations.

http://jid.oxfordjournals.org/content/199/1/49.long

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Hi Dr Niman, presence of HA 193 may indicate drug resistance?

Commentary

http://www.recombinomics.com/News/11071 ... _Bali.html

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No, the R193M change signals immunological escape allowing the H5N1 to spread in humans (and form clusters like the one seen in Bali).

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