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Identification and Attenuation of the Immunosuppressive Domains in Fusion Proteins of Enveloped RNA Viruses

20240150409 ยท 2024-05-09

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to enveloped RNA viruses. The invention in particular relates to the generation of superior antigens for mounting an immune response by first identifying then mutating the immunosuppressive domains in fusion proteins of enveloped RNA viruses resulting in decreased immunosuppressive properties of viral envelope proteins from the viruses.

    Claims

    1. (canceled)

    2. A synthetic peptide comprising a dimeric form of an amino acid sequence, the amino acid sequence comprising a variant of SEQ ID NO:4, said variant differing from SEQ ID NO:4 at 1 or 2 or 3 point mutation(s), wherein each of said point mutation(s) consists of at least one exchange of an amino acid of SEQ ID NO:4 with another amino acid.

    3. The synthetic peptide according to claim 2, comprising a cysteine residue at an N-terminal or C-terminal position of the amino acid sequence or synthetic peptide.

    4. The synthetic peptide according to claim 3, wherein said amino acid sequence is dimerized through said N-terminal or C-terminal cysteine residue.

    5. A synthetic peptide comprising a dimeric form of an amino acid sequence, the amino acid sequence comprising a variant of SEQ ID NO:214, said variant differing from SEQ ID NO:214 at 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 point mutation(s).

    6. The synthetic peptide according to claim 5, wherein said amino acid sequence comprises 1 or 2 or 3 point mutation(s).

    7. The synthetic peptide according to claim 5, comprising a cysteine residue at an N-terminal or C-terminal position of the amino acid sequence or synthetic peptide.

    8. The synthetic peptide according to claim 7, wherein said amino acid sequence is dimerized through said N-terminal or C-terminal cysteine residue.

    9. The synthetic peptide according to claim 5, wherein said amino acid sequence has at least 75% sequence identity to SEQ ID NO:214.

    10. The synthetic peptide according to claim 9, comprising a cysteine residue at an N-terminal or C-terminal position of the amino acid sequence or synthetic peptide

    11. The synthetic peptide according to claim 10, wherein said amino acid sequence is dimerized through said N-terminal or C-terminal cysteine residue.

    12. A nucleic acid sequence encoding the synthetic peptide according to claim 2.

    13. A pharmaceutical composition comprising the synthetic peptide according to claim 2.

    14. The pharmaceutical composition according to claim 13, further comprising at least one pharmaceutically acceptable excipient, diluent or carrier.

    Description

    BRIEF DESCRIPTION OF THE DRAWINGS

    [0104] FIG. 1 shows the result of an experiment using Influenza derived peptides, and the effect of the dimeric pepides on proliferation of CTLL-2 cells. The peptides are coupled through an ss-bond involving the cysteine residues. The wt INF peptide inhibits synthesis of new DNA, whereas the non-IS #1 peptide has a much less and the non-IS #2 peptide no significant effect.

    TABLE-US-00001 INFwt: (SEQIDNO:214) GLFGAIAGFIENGWEGCGGEKEKEK INFnon-IS#1: (SEQIDNO:215) GLFGAAGFIENGWEGCGGEKEKEK INFnon-IS#2: (SEQIDNO:216) GLFAGFIENGWEGCGGEKEKEK

    [0105] FIG. 2 shows the result of two independent experiments on Flavi virus derived peptides.

    [0106] FLV IS/1 and FLV IS/2 are two independent experiments using the dimerized peptide: In both cases, a significant inhibition of proliferation of CTLL-2 cells is evident, while the monomeric peptide has no effect.

    TABLE-US-00002 FLVIS/1andFLVIS/2:dimeric (SEQIDNO:2) DRGWGNGCGLFGKG FLVISmono/1:monomeric (SEQIDNO:2) DRGWGNGCGLFGKG

    [0107] Control peptide: a dimerized non-immune suppressive control peptide.

    [0108] The concentrations are given in ?M.

    [0109] FIG. 3 shows another experimental result. The dimeric peptide derived from Hepatits C surface protein inhibits proliferation of T-cells in a concentration dependent manner.

    [0110] Hep C IS peptide has the sequence:

    TABLE-US-00003 (SEQIDNO:217) PALSTGLIHLHQNIVDVQCGGEKEKEK

    [0111] FIG. 4 shows yet an experimental result. The effect of the dimeric pepides derived from Flavi viruses on proliferation of CTLL-2 cells. The peptides are coupled through an ss-bond using the cysteine residues. FLV FUS non-IS is representative of a non-immune suppressive mutant.

    TABLE-US-00004 DenH3: (SEQIDNO:218) GDTAWDFGSIGGVFTSVGKCGGEKEKEK FLVFUSnon-IS: (SEQIDNO:202) DRGWGNGCGDFGKG

    DETAILED DESCRIPTION OF THE INVENTION

    [0112] Table 1 provides a list of viruses and their immunosuppressive domain(s). Asterix denotes extremely conserved sequence in the immunosuppressive domain for a given class, group, family or species of viruses. New immunosuppressive domains identified and tested in CTLL-2 assay for a given class, group, family or species of viruses are listed. Both the columns with Putative ISU as described in this application for identification of immunosuppressive domains and Peptides from domains from fusion proteins exhibiting immunosuppressive activity (ISU) are candidates for domains which are immunosuppressive. Note that all of the entries of the latter column, were originally identified by the inventors as a member of the former column. Due to the redundancy, the entries of the latter column were not included in the former column.

    [0113] 1: The inventors have identified immunosuppressive domains in the fusion proteins among enveloped RNA viruses with a type II fusion mechanism. Insofar immunosuppressive domains have not been previously described for type II enveloped RNA viruses. The immunosuppressive domain has been identified at two positions in the fusion protein in two different groups of viruses A: Co-localizing with the fusion peptide exemplified by the identification of an common immunosuppressive domain in the fusion peptide of Flavirus (Dengue virus, westNile virus etc.) and B: in the hydrophobic alpha helix N-terminal of the transmembrane domain in the fusion protein exemplified by the finding of an immunosuppressive domain in said helixes of Flaviridae e.g. Hepatitis C virus, Dengue, WestNile virus etc, cf. Table 1.

    [0114] 2: The inventors have identified immunosuppressive domains in the fusion protein among enveloped RNA viruses with type I fusion mechanism (excluding lentivirus, retrovirus and filovirus). This new position co-localizes with the fusion peptide of said fusion protein as demonstrated by the identification of a common immunosuppressive domain in the fusion peptide of all Influenza A and B types, cf. Table 1.

    [0115] 3: The inventors have identified potential immunosuppressive domains located at various positions of type I enveloped RNA viruses (excluding lentivirus, retrovirus and filovirus) and enveloped RNA viruses with neither Type I nor type II fusion mechanism, cf. Table 1.

    TABLE-US-00005 TABLE1 PutativeISUas identifiedusing thecriteria describedinthis applicationfor identificationof Species Species immunosuppressive Family Genus (group) (Strain) domains Flavi- Flavi-virus Aroavirus Bussuquaravirus SEQIDNO:85 viridae guapevirus NRGWNNGCGLFGKG Naranjalvirus ************** SEQIDNO:7 GDAAWDFGSVGGVFNSLGK **o****o*****oo*o** Denguevirus Dengue1 SEQIDNO:8 GGTAWDFGSIGGVFTSVGK *o***************** Dengue2 SEQIDNO:9 GDTAWDFGSLGGVFTSVGK ****************o** SEQIDNO:173 KGSSIGKMFEATARGARRMAILG Dengue3 SEQIDNO:174 KGSSIGQMFETTMRGAKRMAILG Dengue4 SEQIDNO:10 GETAWDFGSVGGLLTSLGK ************oo***** SEQIDNO:173 KGSSIGKMFEATARGARRMAILG Japanese Japaneseencephalitisvirus SEQIDNO:11 encephalitis LGDTAWDFGSIGGVFNSIG virusgroup ***o*************** Koutangovirus SEQIDNO:12 LGDTAWDFGSVGGIFTSLG MurrayValleyencephalitisVirus SEQIDNO:13 LGDTAWDFGSVGGVFNSIG St.Louisencephalitisvirus SEQIDNO:11 LGDTAWDFGSIGGVFNSIG ******************* Usutuvirus SEQIDNO:14 LGDTAWDFGSVGGIFNSVG ******************* WestNilevirus SEQIDNO:15 LGDTAWDFGSVGGVFTSVG **********o******** Kokoberavirus KokoberavirusunclassifiedKokobera SEQIDNO:16 group virusgroup IGDDAWDFGSVGGILNSVG ModocVirusgroup ModocVirus SEQIDNO:17 VGSAFWNSDQRFSAINLMD SEQIDNO:18 DRGWGNGCALFGKG CowboneRidgevirus Jutiapavirus SalViejavirus SanPerlitavirus mosquito-borne Ilheusvirus SEQIDNO:84 viruses LGDTAWDFGSVGGIFNSIG Sepikvirus SEQIDNO:19 TGEHSWDFGSTGGFFASVG Ntayavirusgroup Bagazavirus SEQIDNO:20 LGDTAWDFGSVGGFFTSLG Tembusuvirus SEQIDNO:83 LGDTAWDFGSVGGVLTSIG Yokosevirus SEQIDNO:21 IGDDAWDFGSTGGIFNTIG RioBravovirus Apoivirus SEQIDNO:22 group SSAFWNSDEPFHFSNLISII Entebbebatvirus SEQIDNO:23 GDDAWDFGSTGGIFNTIGKA RioBravovirus SEQIDNO:24 SSAYWSSSEPFTSAGIMRIL Saboyavirus SEQIDNO:18 DRGWGNGCALFGKG SEQIDNO:25 GSSSWDFSSAGGFFGSIGKA Seabornetick- Meabanvirus SEQIDNO:26 bornevirusgroup GDAAWDFGSVGGFMTSIGRA SEQIDNO:27 DRGWGNHCGLFGKG SaumarezReefvirus SEQIDNO:28 GETAWDFGSAGGFFTSVGRG SEQIDNO:27 DRGWGNHCGLFGKG Tyuleniyvirus SEQIDNO:29 GEAAWDFGSAGGFFQSVGRG SEQIDNO:27 DRGWGNHCGLFGKG Spondwenivirus Zikavirus SEQIDNO:30 group LGDTAWDFGSVGGVFNSLGK *************oo**o** Kyasanurforestdiseasevirus SEQIDNO:31 VGEHAWDFGSVGGMLSSVG *************o***** SEQIDNO:27 DRGWGNHCGLFGKG Langatvirus SEQIDNO:32 VLGEHAWDFGSVGGVMTSIG SEQIDNO:27 DRGWGNHCGLFGKG Loupingillvirus SEQIDNO:33 IGEHAWDFGSAGGFFSSIG **********o***oo*o* SEQIDNO:27 DRGWGNHCGLFGKG Omskhemorrhagicfevervirus SEQIDNO:34 LGEHAWDFGSTGGFLSSIG SEQIDNO:27 DRGWGNHCGLFGKG Powassanvirus SEQIDNO:35 VGEHAWDFGSVGGILSSVG *************o***** SEQIDNO:36 DRGWGNHCGFFGKG ************* RoyalFarmvirus SEQIDNO:27 DRGWGNHCGLFGKG Tick-borneencephalitisvirus SEQIDNO:37 IGEHAWDFGSAGGFLSSIG SEQIDNO:38 IGEHAWDFGSTGGFLTSVG SEQIDNO:39 IGEHAWDFGSTGGFLASVG SEQIDNO:27 DRGWGNHCGLFGKG Yaoundevirus SEQIDNO:40 LGDTAWDFGSIGGVFTSLG Yellowfever Banzivirus SEQIDNO:41 virusgroup VGSSSWDFSSTSGFFSSVG Boubouivirus SEQIDNO:42 VGRSSWDFSSAGGFFSSVG EdgeHillvirus UgandaSvirus Wesselsbronvirus Yellowfevervirus SEQIDNO:43 MGDTAWDFSSAGGFFTSVG ***o*************** unclassifiedFlavivirus BatuCavevirus SEQIDNO:44 Cacipacorevirus NRGWGTGCFKWGIG Calbertadovirus SEQIDNO:45 Cellfusingagentvirus NRGWGTGCFEWGLG Chaoyangvirus ChimericTick-borneencephalitis virus/Denguevirus4 Culextheileriflavivirus Donggangvirus Duckhemorrhagicovaritisvirus FlavivirusAedes/MO-Ac/ITA/2009 FlavivirusAnopheles/PV-Am/ITA/2009 FlavivirusCbaAr4001 FlavivirusFSME FlavivirusPhlebotomine/76/Arrabida/2007 GadgetsGullyvirus Greekgoatencephalitisvirus Jugravirus Kadamvirus KamitiRivervirus Kedougouvirus Montanamyotisleukoencephalitisvirus Mosquitoflavivirus Ngoyevirus Nounanevirus PhlebotomusflavivirusAlg_F19 PhlebotomusflavivirusAlg_F8 QuangBinhvirus RussianSpring-Summerencephalitisvirus Sokolukvirus Spanishsheepencephalitisvirus THovirus TaiforestvirusB31 Tamanabatvirus Tick-borneflavivirus WangThongvirus Flavivirussp. Aedesflavivirus SEQIDNO:45 NRGWGTGCFEWGLG SEQIDNO:46 HVAGRYSKHGMAGIGSV WEDLVR Culexflavivirus SEQIDNO:44 NRGWGTGCFKWGIG SEQIDNO:47 VDKYRRFGTAGVGG Hepacivirus HepatitisCvirus HepatitisCvirusgenotype1a HepatitisCvirusgenotype1b SEQIDNO:48 GLIHLHRNIVDVQYLYG SEQIDNO:176 PALSTGLIHLHRNIVDVQ HepatitisCvirusgenotype2 SEQIDNO:49 GLIHLHQNIVDVQYMYG SEQIDNO:175 PALSTGLIHLHQNIVDVQ HepatitisCvirusgenotype3 SEQIDNO:175 PALSTGLIHLHQNIVDVQ HepatitisCvirusgenotype4 SEQIDNO:175 PALSTGLIHLHQNIVDVQ HepatitisCvirusgenotype5 SEQIDNO:50 GLIHLHQNIVDTQYLYG SEQIDNO:177 PALSTGLIHLHQNIVDTQ HepatitisCvirusgenotype6 SEQIDNO:175 PALSTGLIHLHQNIVDVQ AllHepatitisCvirus Pestivirus Borderdisease Borderdiseasevirus- SEQIDNO:51 virus Borderdiseasevirus-X818 NTTLLNGSAFQLICPYGWVGRVEC Borderdiseasevirus1 SEQIDNO:52 Borderdiseasevirus2 SYFQQYMLKGQYQYWFDLE Borderdiseasevirus3 Borderdiseasevirusisolates Bovineviral Bovineviraldiarrheavirus1-CP7 SEQIDNO:53 diarrheavirus1 Bovineviraldiarrheavirus1-NADL NTTLLNGPAFQMVCPLGWTGTVSC Bovineviraldiarrheavirus1-Osloss SEQIDNO:54 Bovineviraldiarrheavirus1-SD1 SYFQQYMLKGEYQYWFDLE Bovineviraldiarrheavirusisolates andstrains Bovineviraldiarrheavirustype1a Bovineviraldiarrheavirustype1b Pestivirusisolate97-360 PestivirusisolateHay87/2210 Pestivirusstrainmousedeer Pestivirustype1isolates Bovineviral Bovineviraldiarrheavirus2 SEQIDNO:55 diarrheavirus2 Pestivirussp.strain178003 SLLNGPAFQMVCPQGWTGTIEC (BVDV-2) Pestivirussp.strain5250Giessen-3 SEQIDNO:56 Bovineviraldiarrheavirus-2 DRYFQQYMLKGKWQYWFDLD isolate SCP Classicalswine Classicalswinefevervirus SEQIDNO:57 fevervirus HogcholeravirusstrainZoelen TLLNGSAFYLVCPIGWTGVIEC SEQIDNO:58 SYFQQYMLKGEYQYWFDLD unclassified Bovineviraldiarrheavirus3 SEQIDNO:59 Pestivirus SEQIDNO:82 TLLNGPAFQLVCPYGWTGTIEC SEQIDNO:60 DNYFQQYMLKGKYQYWFDLEATD Chamoispestivirus1 SEQIDNO:61 TLLNGSAFQMVCPFGWTGQVEC SEQIDNO:62 DSYFQQYMLKGEYQYWFDLDAKD Porcinepestivirusisolate SEQIDNO:205 Bungowannah TLLNGPAFQLVCPYGWTGTI ECDSYYQ SEQIDNO:206 QYIIKSGYQYWFDLTAKD Unnclassified Barkedjivirus Flaviviridae CaninehepacivirusAAK-2011 GBvirusA DouroucoulihepatitisGBvirusA GBV-A-likeagents GBvirusD GBV-C/HGVgroup GBvirusC HepatitisGBvirusC-likevirus HepatitisGBvirusB Lammivirus MarmosethepatitisGBvirusA Nakiwogovirus Turkeymeningoencephalitisvirus Toga- Alpha-virus Auravirus SEQIDNO:63 viridae BarmahForest GVYPFMWGGAYCFCDTENTQVS virus **********o****o**o*o* Middelburgvirus SEQIDNO:64 Ndumuvirus APFGCEIYTNPIRAENCAVGSIP Salmonpancreas *****o*ooo*o**oo*oo*oo* diseasevirus SEQIDNO:65 Getahvirus SDFGGIATVKYSASKSGKCAVH Mayarovirus o***oooooo*ooooo*o*oo* Trocaravirus SEQIDNO:66 EEEVcomplex FSTANIHPEFRLQICTSY VTCKGDCHPP WEEVcomplex FortMorganvirus *oooooooo*oooo HighlandsJvirus *ooooo*ooo*o** Sindbisvirus Westernequineencephalomyelitis virus Whataroavirus Cabassouvirus VEEVcomplex Mucambovirus Pixunavirus Venezuelanequineencephalitis virus SEQIDNO:67 GVYPFMWGGAYCFCD *************** SEQIDNO:68 GDCHPPKDHIVTHPQYHAQ ************o**o*o* SEQIDNO:69 AVSKTAWTWLTS *********oo* SFVcomplex Bebaruvirus SEQIDNO:63 O'nyong-nyongvirus GVYPFMWGGAYCFCDTENTQVS RossRivervirus **********o****o**o*o* Semlikiforestvirus SEQIDNO:64 Unavirus APFGCEIYTNPIRAENCAVGSIP *****o*ooo*o**oo*oo*oo* SEQIDNO:65 SDFGGIATVKYSASKSGKCAVH o***oooooo*ooooo*o*oo* SEQIDNO:66 FSTANIHPEFRLQICTSYV TCKGDCHPP *oooooooo*oooo*oooo o*ooo*o** Chikungunyavirus SEQIDNO:67 GVYPFMWGGAYCFCD *************** SEQIDNO:70 VHCAAECHPPKDHIVNY oo*o*o**o******** SEQIDNO:71 PASHTTLGVQDISATAMSWV o****oo******o****** Rubivirus Rubellavirus Rubellavirus(strainBRD1) SEQIDNO:72 Rubellavirus(strainBRDII) ACTFWAVNAYSSGGYAQLA Rubellavirus(strainCendehill) SYFNPGGSYYK Rubellavirus(strainM33) ***o*o****o**oo**** Rubellavirus(strainRN-UK86) o**o******o Rubellavirus(strainTHERIEN) SEQIDNO:73 Rubellavirus(strainTO-336vaccine) QYHPTACEVEPAFGHSDAACWGFPTDT Rubellavirus(strainTO-336) ***o*o*o*o****o********o*** Rubellavirus(vaccinestrainRA27/3) SEQIDNO:74 MSVFALASYVQHPHKTVRVKFHT ***oo*****o**o**o****** SEQIDNO:159 ETRTVWQLSVAGVSC o*o*********oo* SEQIDNO:76 NVTTEHPFCNMPHGQLEVQVPP o*o*o**oo*o*o****o*oo* SEQIDNO:77 DPGDLVEYIMNYTGNQQSRW ****o******o*o****** SEQIDNO:78 GSPNCHGPDWASPVCQRHSPDCS ****o***o************** SEQIDNO:79 RLVGATPERPRLRLV o***o**o**o**** SEQIDNO:80 DADDPLLRTAPGP *oo********** SEQIDNO:81 GEVWVTPVIGSQARKCGL oo*o**o**o*****o** SEQIDNO:86 HIRAGPYGHATVEM oo***********o SEQIDNO:87 PEWIHAHTTSDPWHP o**oooo*o***o*o SEQIDNO:88 PGPLGLKFKTVRPVALPR ****o***o**o*oo*** SEQIDNO:89 ALAPPRNVRVTGCYQCGTPAL oooo**o*o*o**o******* SEQIDNO:90and SEQIDNO:91 EGLAPGGGNCHLTVNGEDVG ***o*****o**oo*o*oo* SEQIDNO:207 LLNTPPPYQVSCGG ******o*o*o*** SEQIDNO:92 RASARVIDPAAQSFTGVVYGTHT **o***oo*o************* SEQIDNO:93 TAVSETRQTWAEWAAAHWWQLTLG o*******ooo*****o******* Bunya- Hanta-virus Amurvirus SEQIDNO:94 viridae (continued Bayouvirus NPPDCPGVGTGCTACGVYLD onnextpage) BlackCreekCanal **o****o********o*** virus SEQIDNO:95 CanoDelgadito RKVCIQLGTEQTCKTIDSNDC virus *oo*o*o*o*oo**oo*v*** Calabazovirus SEQIDNO:96 Catacamasvirus DTLLFLGPLEEGGMIFKQWC TTTCQFGDPGDIM Choclovirus SEQIDNO:97 Dobrava-Belgrade GSFRKKCSFATLPSCQYDGNTVSG virus *o***o*o***o*o*ooo**oo** ElMoroCanyon SEQIDNO:98 virus ATKDSFQSFNITEPH Hantaanvirus **o****o**oooo* IslaVistavirus SEQIDNO:99 Khabarovskvirus GSGVGFNLVCSVSLTEC LagunaNegra ******o*o*ooo**** virus SEQIDNO:100 LimestoneCanyon KACDSAMCYGSSTANLVRGQNT virus ****o*o***ooooo*o**o** Monongahelavirus SEQIDNO:101 Muleshoevirus GKGGHSGSKFMCCHDKKC SATGLVAAAPHL Mujuvirus ********o*o***ooo* ooo**o*oo*** NewYorkvirus SEQIDNO:102 Oranvirus DDGAPQCGVHCWFKKSGEW PlayadeOro ***o*o*ooo***oo**** virus ProspectHill virus Puumalavirus RioMamorevirus RioSegundovirus Saaremaavirus Seoulvirus SinNombrevirus Soochongvirus Thailandvirus Thottapalayam virus Topografovvirus Tulavirus Ortho-bunya-virus AnophelesAvirus SEQIDNO:103 AnophelesBvirus KHDELCTGPCPVNINHQTGWLT Bakauvirus *o*o***o**oooooooo*o*o Batamavirus SEQIDNO:104 Bwambavirus WGCEEFGCLAVSDGCVFGSCQD Caraparuvirus **o*oo**o*ooo**oo***** KaengKhoivirus SEQIDNO:105 Kairivirus GNGVPRFDYLCHLASRKEVIVRKC Madridvirus *o*ooo*ooo*oooo*ooooo*o* MainDrainvirus SEQIDNO:106 Maritubavirus SCAGCINCFQNIHC Nyandovirus *o**ooooooooo* Oribocavirus Oropouchevirus Sathuperivirus Shamondavirus Shunivirus Simbuvirus Tacaiumavirus Tetevirus Turlockvirus unclassified Orthobunyavirus Akabanevirus Sabovirus Tinaroovirus Yaba-7virus Bunyamweravirus Bataivirus Biraovirus Bozovirus CacheValleyvirus FortShermanvirus Germistonvirus Guaroavirus Iacovirus Ileshavirus Lokernvirus Maguarivirus Mbokevirus Ngarivirus Northwayvirus Playasvirus Potosivirus Shokwevirus Tensawvirus Tlacotalpanvirus Xinguvirus California Californiaencephalitisserogroupvirus Encephalitis LEIV virus Californiaencephalitisvirus-BFS-283 Chatangavirus Inkoovirus JamestownCanyonvirus JamestownCanyon-likevirus JerrySloughvirus Keystonevirus LaCrossevirus Lumbovirus Melaovirus MorroBayvirus SanAngelovirus SerradoNaviovirus Snowshoeharevirus SouthRivervirus Tahynavirus Trivittatusvirus Caraparuvirus Apeuvirus Bruconhavirus Ossavirus Vincesvirus Manzanillavirus Buttonwillowvirus Ingwavumavirus Mermetvirus Maritubavirus GumboLimbovirus Murutucuvirus Nepuyovirus Restanvirus Wyeomyiavirus Anhembivirus BeAr328208virus Macauavirus Sororocavirus Taiassuivirus Phlebovirus Bujaruvirus Candiruvirus Chilibrevirus Frijolesvirus Punta Tor_|Salehabad virus Sandflyfever Naplesvirus Uukuniemiviruso virus RiftValley SEQIDNO:107 fevervirus KTVSSELSCREGQSYWT **oo**oo*o**o*o** SEQIDNO:108 GSFSPKCLSSRRC *******oooooo SEQIDNO:109 ENKCFEQCGGWGCGCFN VNPSCLFVHT **o*o**o*oo*oo*** ooo***o**o SEQIDNO:110 WGSVSLSLDAEGISGSNSFSF **ooo*o**o*o*o*o*oo** SEQIDNO:111 RQGFLGEIRCNSE *o*****o**oo* SEQIDNO:112 AHESCLRAPNLVSYKPMIDQLEC *oo**oo**oooo*o*oo*ooo* SEQIDNO:113 DPFVVFERGSLPQTR **ooo*oo*o***o* SEQIDNO:114 QAFSKGSVQADLTLMFD **ooo*ooo*oooooo* SEQIDNO:115 CDAAFLNLTGCYSCNAG *o*o*o*oo*****oo* SEQIDNO:116 CQILHFTVPEVEEEFMYSC *ooo*ooo*ooooooo*o* SEQIDNO:117 STVVNPKSGSWN *o*o**oooooo SEQIDNO:118 FFDWFSGLMSWFGGPLK *o***oo*o**oooooo unclassified Anhangavirus Phlebovirus(continued Arumowotvirus onnextpage) Chagresvirus Corfouvirus GabekForestvirus Itaporangavirus PhlebovirusAdria/ALB1/2005 PhlebovirusAdria/ALB5/2005 PhlebovirusAH12 PhlebovirusAH12/China/2010 PhlebovirusAH15/China/2010 PhlebovirusB105-05 PhlebovirusB151-04 PhlebovirusB43-02 PhlebovirusB68-03 PhlebovirusB79-02 PhlebovirusChios-A PhlebovirusCyprus PhlebovirusHB29/China/2010 PhlebovirusHN13/China/2010 PhlebovirusHN6/China/2010 PhlebovirusHu/Xinyang1/China/2010 PhlebovirusHu/Xinyang2/China/2010 PhlebovirusIB13-04 PhlebovirusJS2007-01 PhlebovirusJS24 PhlebovirusJS26 PhlebovirusJS3/China/2010 PhlebovirusJS4/China/2010 PhlebovirusJS6 PhlebovirusJSD1 PhlebovirusLN2/China/2010 PhlebovirusLN3/China/2010 Phlebovirussandflies/Gr29/Spain/2004 Phlebovirussandflies/Gr36/Spain/2004 Phlebovirussandflies/Gr44/Spain/2004 Phlebovirussandflies/Gr49/Spain/2004 Phlebovirussandflies/Gr52/Spain/2004 Phlebovirussandflies/Gr65/Spain/2004 Phlebovirussandflies/Gr98/Spain/2004 PhlebovirusSD24/China/2010 PhlebovirusSD4/China/2010 Phlebovirustick/XCQ-2011 PhlebovirusXLL/China/2009 RioGrandevirus Salobovirus Sandflyfeversicilianvirus SandflySicilianTurkeyvirus Utiquevirus Phlebovirussp. Phlebovirussp.BeAn24262 Phlebovirussp.BeAn356637 Phlebovirussp.BeAn416992 Phlebovirussp.BeAn578142 Phlebovirussp.BeAr371637 Phlebovirussp.CoAr170255 Phlebovirussp.CoAr171616 Phlebovirussp.GML902878 Phlebovirussp.PaAr2381 Phlebovirussp.PAN479603 Phlebovirussp.PAN483391 Phlebovirussp.VP-161A Phlebovirussp.VP-334K Phlebovirussp.VP-366G Ortho- InfluenzavirusA InfluenzaAvirus INFAH1 SEQIDNO:119 myxo- GLFGAIAGFIEGGWTG viridae SEQIDNO:178 WTYNAELLVLLENERTLD SEQIDNO:179 NAELLVLLENERTLDYHD INFAH2 SEQIDNO:120 GLFGAIAGFIEGGWQG SEQIDNO:180 WTYNAELLVLMENERTLD SEQIDNO:181 NAELLVLMENERTLDYHD INFAH3 SEQIDNO:121 GIFGAIAGFIENGWEG SEQIDNO:182 WSYNAELLVALENQHTID SEQIDNO:183 NAELLVALENQHTIDLTD INFAH4 SEQIDNO:122 GLFGAIAGFIENGWQG SEQIDNO:182 WSYNAELLVALENQHTID SEQIDNO:184 NAELLVALENQHTIDVTD INFAH5 SEQIDNO:120 GLFGAIAGFIEGGWQG SEQIDNO:180 WTYNAELLVLMENERTLD SEQIDNO:185 NAELLVLMENERTLDFHD INFAH6 SEQIDNO:123 GIFGAIAGFIEGGWTG SEQIDNO:119 GLFGAIAGFIEGGWTG SEQIDNO:178 WTYNAELLVLLENERTLD SEQIDNO:186 NAELLVLLENERTLDMHD INFAH7 SEQIDNO:187 WSYNAELLVAMENQHTID SEQIDNO:208 WSYNAELLVAMENQHLAD INFAH8 SEQIDNO:124 GLFGAIAGFIEGGWSG SEQIDNO:189 WAYNAELLVLLENQKTLD SEQIDNO:190 NAELLVLLENQKTLDEHD INFAH9 SEQIDNO:125 GLFGAIAGFIEGGWPG SEQIDNO:124 GLFGAIAGFIEGGWSG SEQIDNO:189 WAYNAELLVLLENQKTLD SEQIDNO:190 NAELLVLLENQKTLDEHD INFAH10 SEQIDNO:191 WTYQAELLVAMENQHTID SEQIDNO:192 QAELLVAMENQHTIDMAD INFAH11 SEQIDNO:125 GLFGAIAGFIEGGWPG SEQIDNO:193 WSYNAQLLVLLENEKTLD SEQIDNO:194 NAQLLVLLENEKTLDLHD INFAH12 SEQIDNO:125 GLFGAIAGFIEGGWPG SEQIDNO:189 WAYNAELLVLLENQKTLD SEQIDNO:190 NAELLVLLENQKTLDEHD INFAH13 SEQIDNO:125 GLFGAIAGFIEGGWPG SEQIDNO:195 WSYNAKLLVLLENDKTLD SEQIDNO:196 NAKLLVLLENDKTLDMHD INFAH14 SEQIDNO:122 GLFGAIAGFIENGWQG SEQIDNO:182 WSYNAELLVALENQHTID SEQIDNO:184 NAELLVALENQHTIDVTD INFAH15 SEQIDNO:187 WSYNAELLVAMENQHTID SEQIDNO:188 NAELLVAMENQHTIDLAD INFAH16 SEQIDNO:125 GLFGAIAGFIEGGWPG SEQIDNO:197 WSYNAKLLVLIENDRTLD SEQIDNO:198 NAKLLVLIENDRTLDLHD InfluenzavirusB InfluenzaBvirus Allstrains SEQIDNO:126 GFFGAIAGFLEGGWEG SEQIDNO:199 ISSQIELAVLLSNEGIIN SEQIDNO:200 QIELAVLLSNEGIINSED InfluenzavirusC InfluenzaCvirus Paramyxo- Paramyxovirinae Avulavirus Avianparamyxovirus2Yucaipavirus SEQIDNO:127 viridae Avianparamyxovirus3 GAIALGVATAAAVTAG Avianparamyxovirus3b oooo*o*oo*o*oo** Avianparamyxovirus4 Avianparamyxovirus5 Avianparamyxovirus6 Avianparamyxovirus7 Avianparamyxovirus8 Avianparamyxovirus9 Newcastlediseasevirus Pigeonparamyxovirus1 unclassifiedAvulavirus Avianparamyxovirus10_Avian paramyxovirusduck/Miyagi/885/05 Avianparamyxoviruspenguin/Falkland Islands/324/2007 GoosramyxovirusHZ GooseparamyxovirusJS/1/97/Go GooseparamyxovirusSF02 Henipavirus HendravirusHendravirus horse/Australia/Hendra/1994 Nipahvirus unclassifiedHenipavirus Batparamyxovirus Eid.hel/GH45/2008 Morbillivirus Caninedistempervirus Cetaceanmorbillivirus_Dolphin morbillivirus_Pilotwhalemorbillivirus Porpoisemorbillivirus Measlesvirus Peste-des-petits-ruminantsvirus Phocinedistempervirus Phocinedistempervirus1 Phocinedistempervirus-2 Rinderpestvirus Respirovirus Bovineparainfluenzavirus3 PorcineparamyxovirusstrainFrost PorcineparamyxovirusstrainTexas Humanparainfluenzavirus1 Humanparainfluenzavirus3 SimianAgent10 Sendaivirus unclassifiedRespirovirus Atlanticsalmonrespirovirus GuineapigparainfluenzavirusTS-9 Pacificsalmonparamyxovirus TraskRiver1983Swineparainfluenza virus3 Tursiopstruncatusparainfluenzavirus 1 Rubulavirus Humanparainfluenzavirus2 Humanparainfluenzavirus2(strain Greer) Humanparainfluenzavirus2(strain Toshiba) Humanparainfluenzavirus4 Humanparainfluenzavirus4a Humanparainfluenzavirus4b Mapueravirus Mumpsvirus Parainfluenzavirus5 Porcinerubulavirus Simianvirus41 unclassifiedRubulavirus Porcineparainfluenzavirus Tuhokovirus1 Tuhokovirus2 Tuhokovirus3 unclassified Atlanticsalmonparamyxovirus Paramyxovirinae Beilongvirus Canineparainfluenzavirus Chimerichumanparainfluenzavirus rPIV3-2 Fer-de-lancevirus J-virus Menanglevirus Mossmanvirus Murayamavirus Ovineparainfluenzavirus3 Pacificsalmonparamyxovirus ParamyxovirusGonoGER85 RecombinantPIV3/PIV1virus Reptilianparamyxovirus Salemvirus Salmosalarparamyxovirus SnakeATCC-VR-1408paramyxovirus SnakeATCC-VR-1409paramyxovirus Tiomanvirus Tupaiaparamyxovirus Pneumovirus Humanrespiratory HumanrespiratorysyncytialvirusA SEQIDNO:128 syncytialvirus Humanrespiratorysyncytialvirus FLGLILGLGAAVTAGVA (strainRSB1734) ***oo**o*o*ooo*o* Humanrespiratorysyncytialvirus SEQIDNO:129 (strainRSB5857) TNEAVVSLTNGMSVL Humanrespiratorysyncytialvirus **o*****o**o*** (strainRSB6190) SEQIDNO:130 Humanrespiratorysyncytialvirus VIRFQQLNKRLLE (strainRSB6256) **o***o*o**** Humanrespiratorysyncytialvirus SEQIDNO:131 (strainRSB642) REFSSNAGLT Humanrespiratorysyncytialvirus ****o***o* (strainRSB6614) SEQIDNO:132 HumanrespiratorysyncytialvirusA MLTDRELTSIVGGM strainLongLinkOut ***oo**o*oooo* HumanrespiratorysyncytialvirusA2 SEQIDNO:133 HumanrespiratorysyncytialvirusB YVIQLPLFGVMDTDCW Humanrespiratorysyncytial *oo***oo**o**o** virus(subgroupB/strain18537) SEQIDNO:134 Humanrespiratorysyncytialvirus CLARADNGWYCHNAGSLSYFP (subgroupBstrain8/60) **ooo*o**o*o****o*o** HumanRespiratorysyncytialvirus9320 SEQIDNO:135 HumanrespiratorysyncytialvirusB1 DTLKSLTVPVTSRECN HumanrespiratorysyncytialvirusS2 **oo***o*ooooo** Humanrespiratorysyncytialvirus SEQIDNO:136 strainRSS-2 YDCKISTSKTYVSTAVLTTMG unclassifiedHumanrespiratory *o*o*o***ooo*oo*o*oo* syncytialvirus SEQIDNO:137 VSCYGHNSCTVIN *****ooo**oo* SEQIDNO:209 GIIRTLPDGCHYISNKGVDR VQVGNTVYYLSKEVGK ***o*ooo**o*o**o* o*o*o****o**oo*oo** SEQIDNO:139 PLSFPDDKFDVAIRDVEHSIN QTRTFLKASDQLL **o**o*o*ooo*oo*oo o***ooo*ooo**o** SEQIDNO:140 KIMTSKTDISSSVITSIGAIVSCYG o*o***ooo*oo*o*oo*oo***** Bovine Allstrains SEQIDNO:128 respiratory FLGLILGLGAAVTAGVA syncytialvirus ***oo**o*o*ooo*o* Metapneumovirus Avianmetapneumo- Allstrains SEQIDNO:134 virus CLARADNGWYCHNAGSLSYFP **ooo*o**o*o****o*o** Humanmetapneumo- Allstrains SEQIDNO:133 virus YVIQLPLFGVMDTDCW *oo***oo**o**o** Corona- Coronavirinae Alphacorona-virus Alphacoronavirus1 SEQIDNO:141 viridae Coronavirusgroup1b RSAIEDLLFDKVKLSDVG Humancoronavirus229E **oo****oo**ooo*o* HumancoronavirusNL63 SEQIDNO:142 Miniopterusbatcoronavirus1 VPFYLNVQYRINGLGVT MiniopterusbatcoronavirusHKU8 o**ooooo**o**o*** Porcineepidemicdiarrheavirus SEQIDNO:143 RhinolophusbatcoronavirusHKU2 VLSQNQKLIANAFNNALHAIQ Scotophilusbatcoronavirus512 **oo***o*ooo*oo*ooo** unclassifiedAlphacoronavirus SEQIDNO:144 Betacorona- Betacoronavirus1 TNSALVKIQAVVNANA virus Coronavirusgroup2b *oo**o*o*o***oo* Coronavirusgroup2c SEQIDNO:145 HumancoronavirusHKU1 AEAQIDRLINGRLTALNAYVSQQL Murinecoronavirus *oo******o***oo*oo*oo*** PipistrellusbatcoronavirusHKU5 SEQIDNO:146 RousettusbatcoronavirusHKU9 SAAQAMEKVNECVKSQSSR Severeacuterespiratorysyndrome- INFCGNGNHIIS relatedcoronavirusrecombinantSARSr- o*oo*oo*oo***oo*oo* CoV oo***o*o*oo* SARScoronavirus SEQIDNO:147 TylonycterisbatcoronavirusHKU4 APYGLYFIHFNYVP unclassifiedBetacoronavirus **o*oo*o*oo*o* SEQIDNO:148 LQEAIKVLNHSYINLKDI GTYEYYVKWPWYVW oo*oo*o**o*ooo*ooo*oo* o*o*****o* Gammacorona-virus Aviancoronavirus BelugaWhalecoronavirusSW1 unclassified AlpacacoronavirusCA08-1/2008 coronaviruses Batcoronavirus Birddroppingscoronavirus Bovinerespiratorycoronavirus Chickenentericcoronavirus CoronavirusAnas Coronavirusoystercatcher/p17/2006/GBR Coronavirusredknot/p60/2006/GBR Ferretentericcoronavirus1202 FerretsystemiccoronavirusMSU-S FerretsystemiccoronavirusWADL Guangxicoronaviridae HumancoronavirusNO Humanentericcoronavirusstrain4408 Kenyabatcoronavirus MinkcoronavirusstrainWD1133 ParrotcoronavirusAV71/99 QuailcoronavirusItaly/Elvia/2005 TaiForestcoronavirus unidentifiedcoronavirus unidentifiedhumancoronavirus Arena- Arena-virus LCMV-Lassavirus Ippyvirus SEQIDNO:149 viridae (OldWorld) Lassavirus NALINDQLIMKNHLRDIMGIPYC complex Lujovirus *o**o***o*o***o*o**o*** Lymphocyticchoriomeningitisvirus SEQIDNO:150 Mobalavirus FTWTLSDSEGKDTPGGYCLT Mopeiavirus oo*ooo*oo*ooo***o**o SEQIDNO:151 KCFGNTAIAKCNQKHDEEF CDMLRLFDFN ***o*ooo****oo* oo****ooo*ooo* SEQIDNO:152 MLQKEYMERQGKTPLGLVDLFVFS *ooo*oo**oo**oo*o*oooo*o Tacaribevirus Amaparivirus SEQIDNO:150 (NewWorld) Chaparevirus FTWTLSDSEGKDTPGGYCLT complex Flexalvirus oo*ooo*oo*ooo***o**o Guanaritovirus SEQIDNO:151 Juninvirus KCFGNTAIAKCNQKHD Latinovirus EEFCDMLRLFDFN Machupovirus ***o*ooo****oo* Oliverosvirus oo****ooo*ooo* Paranavirus SEQIDNO:152 Pichindevirus MLQKEYMERQGKTPLGLVDLFVFS Piritalvirus *ooo*oo**oo**oo*o*oooo*o Sabiavirus Tacaribevirus Tamiamivirus WhitewaterArroyovirus Hepadna- Genus HepatitisBvirus HBVgenotypeA SEQIDNO:153 viridae Orthohepadnavirus HBVgenotypeB FNPLGFFPSHQLDPLF HBVgenotypeC o***o*o*o*o*o*o* HBVgenotypeD SEQIDNO:154 HBVgenotypeE ADWDKNPNKDPWP HBVgenotypeF o*o*o*oo*oooo HBVgenotypeG SEQIDNO:155 HBVgenotypeH MESITSGFLGPLLVLQAVFF HepatitisBvirusalpha1 oooooooo*ooooo**oooo HepatitisBvirusLSH/chimpanzee SEQIDNO:156 HepatitisBvirusstraincpz LLTRILTIPQSLDSWWTSLNFLGGA HepatitisBvirussubtypeadr oooooo*oooo*oooo***o*o*oo HepatitisBvirussubtypeadw SEQIDNO:157 HepatitisBvirussubtypeadyw CPPTCPGYRWMC HepatitisBvirussubtypeayw oo*o*****o*o SEQIDNO:158 LFILLLCLIFLLVLLDYQ *oo*ooo*oo*oo*oooo Rhabdo- Dimarhabdovirus Ephemerovirus Bovineephemeralfevervirus SEQIDNO:160 viridae LDGYLCRKQKWEVTCTETWYFVTD *o*oo****o*ooo*o*****o*o SEQIDNO:161 KYQIIEVIPTENEC o***o**o*oooo* SEQIDNO:162 LKGEYIPPYYPPTNCVWNAIDTQE oo*oo*******oo*o**oooo** SEQIDNO:163 IEDPVTMTLMDSKFTKPC ooo*oooooo**o*oo** SEQIDNO:164 LHCQIKSWECIPV o**oo*o****o* SEQIDNO:165 SHRNMMEALYLESPD *oo*oo*o*oo*o** SEQIDNO:166 LTFCGYNGILLDNGEWWSIY o****oo**oooo****** SEQIDNO:167 ELEHEKCLGTLEKLQNGE *****o**o*oo*oo*o* SEQIDNO:168 LDLSYLSPSNPGKHYAY **o***o*oo**oo*** SEQIDNO:169 IRAVCYYHTFSMNLD o**o*o*oo*oooo* Vesiculovirus Carajasvirus SEQIDNO:170 Chandipuravirus EWKTTCDYRWYGPQYITHSI Cocalvirus o*o****o*****o*o*o* Isfahanvirus SEQIDNO:171 Marabavirus LGFPPQSCGWASVTT Piryvirus o****oo**oooooo recombinantVesiculovirus SEQIDNO:1 Springviraemiaofcarpvirus VQVTPHHVLVDEYTGEW VesicularstomatitisAlagoasvirus VDSQFINGKC VesicularstomatitisIndianavirus ooooo*o*oooo*o*o* VesicularstomatitisNewJerseyvirus o*oooooooo Lyssavirus Aravanvirus Australianbat lyssavirus Duvenhagevirus Europeanbat lyssavirus1 Europeanbat lyssavirus2 Irkutvirus Khujandvirus Lagosbatvirus Mokolavirus WestCaucasian batvirus Rabiesvirus RabiesvirusAB21 SEQIDNO:5 RabiesvirusAB22 GFTCTGVVTEAETYTNFVGYVT RabiesvirusAVO1 *o****o**o*oo*oooo*** RabiesvirusBNG4 SEQIDNO:6 RabiesvirusBNG5 SLHNPYPDYRWLRTVKTT RabiesvirusChina/DRV *ooooooooooo***o* RabiesvirusChina/MRV SEQIDNO:210 RabiesvirusCVS-11 ESLVIISPSVADLDPYDRSLHS RabiesvirusERA *ooo***oooo*o**ooo RabiesvirusEth2003 SEQIDNO:211 RabiesvirusHEP-FLURY CKLKLCGVLGLRLMDGT RabiesvirusIndia *ooo****oooo*ooo* RabiesvirusNishigaharaRCEH SEQIDNO:212 RabiesvirusOntariofox ILGPDGNVLIPEMQSS RabiesvirusOntarioskunk o**o*ooo*******o RabiesvirusPM SEQIDNO:213 Rabiesvirusredfox/08RS- QHMELLESSVIPLVHPL 1981/Udine/2008 *ooo**o*ooo**oo** RabiesvirusSADB19 Rabiesvirussilver-hairedbat- associatedSHBRV RabiesvirusstrainPasteurvaccin RabiesvirusstrainStreet Rabiesvirusvnukovo-32 Thailandgenotype1doglyssavirus unclassified Bokelohbatlyssavirus Lyssavirus Europeanbatlyssavirus LyssavirusOzernoe Shimonibatvirus Novirhabdovirus Hirame rhabdovirus Infectious hematopoietic necrosisvirus Snakehead rhabdovirus Viralhemorrhagic septicemiavirus unassignedRhabdoviridae Bangoranvirus Bimbovirus BivensArmvirus Flandersvirus Garbavirus Klamathvirus MalpaisSpring virus Nasoulevirus Ngainganvirus Ouangovirus Sigmavirus Tupaiavirus Wongabelvirus Peptidesfromdomainsfrom knock-out(K.O.) fusionproteinsexhibiting mutantsofthe Species Species immunosuppressiveactivity immunosuppressive Family Genus (group) (Strain) (ISU) domain(ISU) Flavi- Flavi-virus Aroavirus Bussuquaravirus SEQIDNO:202 viridae guapevirus DRGWGNGCGDFGKG Naranjalvirus Denguevirus Dengue1 SEQIDNO:2 DRGWGNGCGLFGKG ************** SEQIDNO:172 KGSSIGKMFESTYRGAKRMAILG Dengue2 SEQIDNO:2 DRGWGNGCGLFGKG ************** Dengue3 SEQIDNO:2 DRGWGNGCGLFGKG ************** SEQIDNO:204 GDTAWDFGSVGGVLNSLGK ******************* Dengue4 SEQIDNO:2 DRGWGNGCGLFGKG ************** Japanese Japaneseencephalitisvirus SEQIDNO:2 encephalitis DRGWGNGCGLFGKG virusgroup ************** Koutangovirus SEQIDNO:2 DRGWGNGCGLFGKG ************** MurrayValleyencephalitisVirus SEQIDNO:2 DRGWGNGCGLFGKG ************** St.Louisencephalitisvirus SEQIDNO:2 DRGWGNGCGLFGKG ************** Usutuvirus SEQIDNO:2 DRGWGNGCGLFGKG ************** WestNilevirus SEQIDNO:2 DRGWGNGCGLFGKG ************** Kokoberavirus KokoberaVirus SEQIDNO:2 group unclassifiedKokobera DRGWGNGCGLFGKG virusgroup ModocVirusgroup ModocVirus CowboneRidgevirus Jutiapavirus SalViejavirus SanPerlitavirus mosquito-borne Ilheusvirus SEQIDNO:2 viruses DRGWGNGCGLFGKG Sepikvirus SEQIDNO:2 DRGWGNGCGLFGKG Ntayavirusgroup Bagazavirus SEQIDNO:2 DRGWGNGCGLFGKG Tembusuvirus SEQIDNO:2 DRGWGNGCGLFGKG Yokosevirus SEQIDNO:2 DRGWGNGCGLFGKG RioBravovirus Apoivirus SEQIDNO:2 group DRGWGNGCGLFGKG Entebbebatvirus SEQIDNO:2 DRGWGNGCGLFGKG RioBravovirus SEQIDNO:2 DRGWGNGCGLFGKG Saboyavirus Seabornetick- Meabanvirus bornevirusgroup SaumarezReefvirus Tyuleniyvirus Spondwenivirus Zikavirus SEQIDNO:2 group DRGWGNGCGLFGKG Kyasanurforestdiseasevirus Langatvirus Loupingillvirus Omskhemorrhagicfevervirus Powassanvirus RoyalFarmvirus Tick-borneencephalitisvirus Yaoundevirus SEQIDNO:2 DRGWGNGCGLFGKG Yellowfever Banzivirus SEQIDNO:2 virusgroup DRGWGNGCGLFGKG Boubouivirus SEQIDNO:2 DRGWGNGCGLFGKG EdgeHillvirus UgandaSvirus Wesselsbronvirus Yellowfevervirus SEQIDNO:2 DRGWGNGCGLFGKG unclassified BatuCavevirus SEQIDNO:2 Flavivirus Cacipacorevirus DRGWGNGCGLFGKG Calbertadovirus Cellfusingagentvirus Chaoyangvirus ChimericTick-borneencephalitis virus/Denguevirus4 Culextheileriflavivirus Donggangvirus Duckhemorrhagicovaritisvirus FlavivirusAedes/MO-Ac/ITA/2009 FlavivirusAnopheles/ PV-Am/ITA/2009 FlavivirusCbaAr4001 FlavivirusFSME FlavivirusPhlebotomine/76/ Arrabida/2007 GadgetsGullyvirus Greekgoatencephalitisvirus Jugravirus Kadamvirus KamitiRivervirus Kedougouvirus Montanamyotis leukoencephalitisvirus Mosquitoflavivirus Ngoyevirus Nounanevirus PhlebotomusflavivirusAlg_F19 PhlebotomusflavivirusAlg_F8 QuangBinhvirus RussianSpring-Summer encephalitisvirus Sokolukvirus Spanishsheepencephalitisvirus THovirus TaiforestvirusB31 Tamanabatvirus Tick-borneflavivirus WangThongvirus Flavivirussp. Aedesflavivirus Culexflavivirus Hepacivirus HepatitisC HepatitisCvirusgenotype1a SEQIDNO:3 virus GLIHLHQNIVDVQYLYG SEQIDNO:175 PALSTGLIHLHQNIVDVQ HepatitisCvirusgenotype1b HepatitisCvirusgenotype2 HepatitisCvirusgenotype3 SEQIDNO:3 GLIHLHQNIVDVQYLYG HepatitisCvirusgenotype4 SEQIDNO:3 GLIHLHQNIVDVQYLYG HepatitisCvirusgenotype5 HepatitisCvirusgenotype6 SEQIDNO:3 GLIHLHQNIVDVQYLYG AllHepatitisCvirus SEQIDNO:3 GLIHLHQNIVDVQYLYG Pestivirus Borderdisease Borderdiseasevirus- virus Borderdiseasevirus-X818 Borderdiseasevirus1 Borderdiseasevirus2 Borderdiseasevirus3 Borderdiseasevirusisolates Bovineviral Bovineviraldiarrheavirus1-CP7 diarrhea Bovineviraldiarrheavirus1-NADL virus1 Bovineviraldiarrhea virus1-Osloss Bovineviraldiarrheavirus1-SD1 Bovineviraldiarrheavirus isolatesandstrains Bovineviraldiarrheavirustype1a Bovineviraldiarrheavirustype1b Pestivirusisolate97-360 PestivirusisolateHay87/2210 Pestivirusstrainmousedeer Pestivirustype1isolates Bovineviral Bovineviraldiarrheavirus2 diarrheavirus2 Pestivirussp.strain178003 (BVDV-2) Pestivirussp.strain5250Giessen-3 Bovineviraldiarrheavirus-2isolate SCP Classicalswine Classicalswinefevervirus fevervirus HogcholeravirusstrainZoelen unclassified Bovineviraldiarrheavirus3 Pestivirus Chamoispestivirus1 PorcinepestivirusisolateBungowannah Unnclassified Barkedjivirus Flaviviridae CaninehepacivirusAAK-2011 GBvirusA DouroucoulihepatitisGBvirusA GBV-A-likeagents GBvirusD GBV-C/HGVgroup GBvirusC HepatitisGBvirusC-likevirus HepatitisGBvirusB Lammivirus MarmosethepatitisGBvirusA Nakiwogovirus Turkeymeningoencephalitisvirus Toga- Alpha-virus Auravirus viridae BarmahForest virus Middelburgvirus Ndumuvirus Salmonpancreas diseasevirus Getahvirus Mayarovirus Trocaravirus EEEVcomplex WEEVcomplex FortMorganvirus HighlandsJvirus Sindbisvirus Westernequineencephalomyelitisvirus Whataroavirus VEEVcomplex Cabassouvirus Mucambovirus Pixunavirus Venezuelanequineencephalitisvirus SFVcomplex Bebaruvirus O'nyong-nyongvirus RossRivervirus Semlikiforestvirus Unavirus Chikungunyavirus Rubivirus Rubellavirus Rubellavirus(strainBRD1) Rubellavirus(strainBRDII) Rubellavirus(strainCendehill) Rubellavirus(strainM33) Rubellavirus(strainRN-UK86) Rubellavirus(strainTHERIEN) Rubellavirus(strainTO-336vaccine) Rubellavirus(strainTO-336) Rubellavirus(vaccinestrainRA27/3) Bunya- Hanta-virus Amurvirus viridae (continuedon Bayouvirus nextpage) BlackCreekCanal virus CanoDelgadito virus Calabazovirus Catacamasvirus Choclovirus Dobrava-Belgrade virus ElMoroCanyon virus Hantaanvirus IslaVistavirus Khabarovskvirus LagunaNegra virus LimestoneCanyon virus Monongahelavirus Muleshoevirus Mujuvirus NewYorkvirus Oranvirus PlayadeOro virus ProspectHill virus Puumalavirus RioMamorevirus RioSegundovirus Saaremaavirus Seoulvirus SinNombrevirus Soochongvirus Thailandvirus Thottapalayam virus Topografovvirus Tulavirus Ortho-bunya-virus AnophelesAvirus AnophelesBvirus Bakauvirus Batamavirus Bwambavirus Caraparuvirus KaengKhoivirus Kairivirus Madridvirus MainDrainvirus Maritubavirus Nyandovirus Oribocavirus Oropouchevirus Sathuperivirus Shamondavirus Shunivirus Simbuvirus Tacaiumavirus Tetevirus Turlockvirus unclassified Orthobunyavirus Akabanevirus Sabovirus Tinaroovirus Yaba-7virus Bunyamweravirus Bataivirus Biraovirus Bozovirus CacheValleyvirus FortShermanvirus Germistonvirus Guaroavirus Iacovirus Ileshavirus Lokernvirus Maguarivirus Mbokevirus Ngarivirus Northwayvirus Playasvirus Potosivirus Shokwevirus Tensawvirus Tlacotalpanvirus Xinguvirus California Californiaencephalitis Encephalitis serogroupvirus virus LEIV Californiaencephalitisvirus- BFS-283 Chatangavirus Inkoovirus JamestownCanyonvirus JamestownCanyon-likevirus JerrySloughvirus Keystonevirus LaCrossevirus Lumbovirus Melaovirus MorroBayvirus SanAngelovirus SerradoNaviovirus Snowshoeharevirus SouthRivervirus Tahynavirus Trivittatusvirus Caraparuvirus Apeuvirus Bruconhavirus Ossavirus Vincesvirus Manzanillavirus Buttonwillowvirus Ingwavumavirus Mermetvirus Maritubavirus GumboLimbovirus Murutucuvirus Nepuyovirus Restanvirus Wyeomyiavirus Anhembivirus BeAr328208virus Macauavirus Sororocavirus Taiassuivirus Phlebovirus Bujaruvirus Candiruvirus Chilibrevirus Frijolesvirus Punta Tor_|Salehabad virus Sandflyfever Naplesvirus Uukuniemiviruso virus RiftValley fevervirus unclassified Anhangavirus Phlebovirus Arumowotvirus (continuedon Chagresvirus nextpage) Corfouvirus GabekForestvirus Itaporangavirus PhlebovirusAdria/ALB1/2005 PhlebovirusAdria/ALB5/2005 PhlebovirusAH12 PhlebovirusAH12/China/2010 PhlebovirusAH15/China/2010 PhlebovirusB105-05 PhlebovirusB151-04 PhlebovirusB43-02 PhlebovirusB68-03 PhlebovirusB79-02 PhlebovirusChios-A PhlebovirusCyprus PhlebovirusHB29/China/2010 PhlebovirusHN13/China/2010 PhlebovirusHN6/China/2010 PhlebovirusHu/Xinyang1/China/2010 PhlebovirusHu/Xinyang2/China/2010 PhlebovirusIB13-04 PhlebovirusJS2007-01 PhlebovirusJS24 PhlebovirusJS26 PhlebovirusJS3/China/2010 PhlebovirusJS4/China/2010 PhlebovirusJS6 PhlebovirusJSD1 PhlebovirusLN2/China/2010 PhlebovirusLN3/China/2010 Phlebovirussandflies/Gr29/Spain/2004 Phlebovirussandflies/Gr36/Spain/2004 Phlebovirussandflies/Gr44/Spain/2004 Phlebovirussandflies/Gr49/Spain/2004 Phlebovirussandflies/Gr52/Spain/2004 Phlebovirussandflies/Gr65/Spain/2004 Phlebovirussandflies/Gr98/Spain/2004 PhlebovirusSD24/China/2010 PhlebovirusSD4/China/2010 Phlebovirustick/XCQ-2011 PhlebovirusXLL/China/2009 RioGrandevirus Salobovirus Sandflyfeversicilianvirus SandflySicilianTurkeyvirus Utiquevirus Phlebovirussp. Phlebovirussp.BeAn24262 Phlebovirussp.BeAn356637 Phlebovirussp.BeAn416992 Phlebovirussp.BeAn578142 Phlebovirussp.BeAr371637 Phlebovirussp.CoAr170255 Phlebovirussp.CoAr171616 Phlebovirussp.GML902878 Phlebovirussp.PaAr2381 Phlebovirussp.PAN479603 Phlebovirussp.PAN483391 Phlebovirussp.VP-161A Phlebovirussp.VP-334K Phlebovirussp.VP-366G Ortho- InfluenzavirusA InfluenzaA INFAH1 INFF#2DELTA6: myxo- virus SEQIDNO:201 viridae GLFGAAGFIENGWEG InFAH1-3:SEQIDNO:203 INFAH2 INFAH3 SEQIDNO:4 GLFGAIAGFIENGWEG INFAH4 INFAH5 INFAH6 INFAH7 SEQIDNO:4 GLFGAIAGFIENGWEG INFAH8 INFAH9 INFAH10 SEQIDNO:4 GLFGAIAGFIENGWEG INFAH11 INFAH12 INFAH13 INFAH14 INFAH15 SEQIDNO:4 GLFGAIAGFIENGWEG INFAH16 InfluenzavirusB InfluenzaBvirus Allstrains InfluenzavirusC InfluenzaCvirus Paramyxo- Paramyxovirinae Avulavirus Avianparamyxovirus2Yucaipavirus viridae Avianparamyxovirus3 Avianparamyxovirus3b Avianparamyxovirus4 Avianparamyxovirus5 Avianparamyxovirus6 Avianparamyxovirus7 Avianparamyxovirus8 Avianparamyxovirus9 Newcastlediseasevirus Pigeonparamyxovirus1 unclassifiedAvulavirus Avianparamyxovirus10_Avian paramyxovirusduck/Miyagi/885/05 Avianparamyxoviruspenguin/Falkland Islands/324/2007 GoosramyxovirusHZ GooseparamyxovirusJS/1/97/Go GooseparamyxovirusSF02 Henipavirus HendravirusHendravirus horse/Australia/Hendra/1994 Nipahvirus unclassifiedHenipavirus Batparamyxovirus Eid.hel/GH45/2008 Morbillivirus Caninedistempervirus Cetaceanmorbillivirus_Dolphin morbillivirus_Pilotwhalemorbillivirus Porpoisemorbillivirus Measlesvirus Peste-des-petits-ruminantsvirus Phocinedistempervirus Phocinedistempervirus1 Phocinedistempervirus-2 Rinderpestvirus Respirovirus Bovineparainfluenzavirus3 PorcineparamyxovirusstrainFrost PorcineparamyxovirusstrainTexas Humanparainfluenzavirus1 Humanparainfluenzavirus3 SimianAgent10 Sendaivirus unclassifiedRespirovirus Atlanticsalmonrespirovirus GuineapigparainfluenzavirusTS-9 Pacificsalmonparamyxovirus TraskRiver1983Swineparainfluenza virus3 Tursiopstruncatusparainfluenzavirus1 Rubulavirus Humanparainfluenzavirus2 Humanparainfluenzavirus2(strain Greer) Humanparainfluenzavirus2(strain Toshiba) Humanparainfluenzavirus4 Humanparainfluenzavirus4a Humanparainfluenzavirus4b Mapueravirus Mumpsvirus Parainfluenzavirus5 Porcinerubulavirus Simianvirus41 unclassifiedRubulavirus Porcineparainfluenzavirus Tuhokovirus1 Tuhokovirus2 Tuhokovirus3 unclassified Atlanticsalmonparamyxovirus Paramyxovirinae Beilongvirus Canineparainfluenzavirus Chimerichumanparainfluenzavirus rPIV3-2 Fer-de-lancevirus J-virus Menanglevirus Mossmanvirus Murayamavirus Ovineparainfluenzavirus3 Pacificsalmonparamyxovirus ParamyxovirusGonoGER85 RecombinantPIV3/PIV1virus Reptilianparamyxovirus Salemvirus Salmosalarparamyxovirus SnakeATCC-VR-1408paramyxovirus SnakeATCC-VR-1409paramyxovirus Tiomanvirus Tupaiaparamyxovirus Pneumovirus Humanrespiratory HumanrespiratorysyncytialvirusA syncytialvirus Humanrespiratorysyncytialvirus (strainRSB1734) Humanrespiratorysyncytialvirus (strainRSB5857) Humanrespiratorysyncytialvirus (strainRSB6190) Humanrespiratorysyncytialvirus (strainRSB6256) Humanrespiratorysyncytialvirus (strainRSB642) Humanrespiratorysyncytialvirus (strainRSB6614) HumanrespiratorysyncytialvirusA strainLongLinkOut HumanrespiratorysyncytialvirusA2 HumanrespiratorysyncytialvirusB Humanrespiratorysyncytial virus(subgroupB/strain18537) Humanrespiratorysyncytialvirus (subgroupBstrain8/60) HumanRespiratorysyncytialvirus9320 HumanrespiratorysyncytialvirusB1 HumanrespiratorysyncytialvirusS2 Humanrespiratorysyncytialvirusstrain RSS-2 unclassifiedHumanrespiratorysyncytial virus Bovine Allstrains respiratory syncytialvirus Metapneum Avianmetapneumo- Allstrains virus Humanmetapneumo- Allstrains virus Corona- Coronavirinae Alphacorona-virus Alphacoronavirus1 viridae Coronavirusgroup1b Humancoronavirus229E HumancoronavirusNL63 Miniopterusbatcoronavirus1 MiniopterusbatcoronavirusHKU8 Porcineepidemicdiarrheavirus RhinolophusbatcoronavirusHKU2 Scotophilusbatcoronavirus512 unclassifiedAlphacoronavirus Betacorona- Betacoronavirus1 virus Coronavirusgroup2b Coronavirusgroup2c HumancoronavirusHKU1 Murinecoronavirus PipistrellusbatcoronavirusHKU5 RousettusbatcoronavirusHKU9 Severeacuterespiratorysyndrome- relatedcoronavirusrecombinantSARSr- CoV SARScoronavirus TylonycterisbatcoronavirusHKU4 unclassifiedBetacoronavirus Gammacorona- Aviancoronavirus virus BelugaWhalecoronavirusSW1 unclassified AlpacacoronavirusCA08-1/2008 coronaviruses Batcoronavirus Birddroppingscoronavirus Bovinerespiratorycoronavirus Chickenentericcoronavirus CoronavirusAnas Coronavirusoystercatcher/p17/2006/GBR Coronavirusredknot/p60/2006/GBR Ferretentericcoronavirus1202 FerretsystemiccoronavirusMSU-S FerretsystemiccoronavirusWADL Guangxicoronaviridae HumancoronavirusNO Humanentericcoronavirusstrain4408 Kenyabatcoronavirus MinkcoronavirusstrainWD1133 ParrotcoronavirusAV71/99 QuailcoronavirusItaly/Elvia/2005 TaiForestcoronavirus unidentifiedcoronavirus unidentifiedhumancoronavirus Arena- Arena-virus LCMV-Lassavirus Ippyvirus viridae (OldWorld) Lassavirus complex Lujovirus Lymphocyticchoriomeningitisvirus Mobalavirus Mopeiavirus Tacaribevirus Amaparivirus (NewWorld) Chaparevirus complex Flexalvirus Guanaritovirus Juninvirus Latinovirus Machupovirus Oliverosvirus Paranavirus Pichindevirus Piritalvirus Sabiavirus Tacaribevirus Tamiamivirus WhitewaterArroyovirus Hepadna- Genus HepatitisBvirus HBVgenotypeA viridae Orthohepadnavirus HBVgenotypeB HBVgenotypeC HBVgenotypeD HBVgenotypeE HBVgenotypeF HBVgenotypeG HBVgenotypeH HepatitisBvirusalpha1 HepatitisBvirusLSH/chimpanzee HepatitisBvirusstraincpz HepatitisBvirussubtypeadr HepatitisBvirussubtypeadw HepatitisBvirussubtypeadyw HepatitisBvirussubtypeayw Rhabdo- Dimarhabdovirus Ephemerovirus Bovineephemeralfevervirus viridae Vesiculovirus Carajasvirus Chandipuravirus Cocalvirus Isfahanvirus Marabavirus Piryvirus recombinantVesiculovirus Springviraemiaofcarpvirus VesicularstomatitisAlagoasvirus VesicularstomatitisIndianavirus VesicularstomatitisNewJerseyvirus Lyssavirus Aravanvirus Australianbat lyssavirus Duvenhagevirus Europeanbat lyssavirus1 Europeanbat lyssavirus2 Irkutvirus Khujandvirus Lagosbatvirus Mokolavirus WestCaucasian batvirus Rabiesvirus RabiesvirusAB21 RabiesvirusAB22 RabiesvirusAVO1 RabiesvirusBNG4 RabiesvirusBNG5 RabiesvirusChina/DRV RabiesvirusChina/MRV RabiesvirusCVS-11 RabiesvirusERA RabiesvirusEth2003 RabiesvirusHEP-FLURY RabiesvirusIndia RabiesvirusNishigaharaRCEH RabiesvirusOntariofox RabiesvirusOntarioskunk RabiesvirusPM Rabiesvirusredfox/08RS- 1981/Udine/2008 RabiesvirusSADB19 Rabiesvirussilver-hairedbat- associatedSHBRV RabiesvirusstrainPasteurvaccin RabiesvirusstrainStreet Rabiesvirusvnukovo-32 Thailandgenotype1doglyssavirus unclassified Bokelohbatlyssavirus Lyssavirus Europeanbatlyssavirus LyssavirusOzernoe Shimonibatvirus Novirhabdo- Hirame virus rhabdovirus Infectious hematopoietic necrosisvirus Snakehead rhabdovirus Viralhemorrhagic septicemiavirus unassigned Bangoranvirus Rhabdoviridae Bimbovirus BivensArmvirus Flandersvirus Garbavirus Klamathvirus MalpaisSpring virus Nasoulevirus Ngainganvirus Ouangovirus Sigmavirus Tupaiavirus Wongabelvirus Nameof Species Species envelopeattachment/ IUgroupand Family Genus (group) (Strain) fusionprotein fusiontype Flavi- Flavi-virus Aroavirus Bussuquaravirus EnvelopeproteinprME Group1TypeII viridae guapevirus FusionproteinE Fusionmechanism Naranjalvirus Denguevirus Dengue1 Dengue2 Dengue3 Dengue4 Japanese Japaneseencephalitisvirus encephalitis virusgroup Koutangovirus MurrayValleyencephalitisVirus St.Louisencephalitisvirus Usutuvirus WestNilevirus Kokoberavirus KokoberaVirusunclassifiedKokobera group virusgroup ModocVirusgroup ModocVirus CowboneRidgevirus Jutiapavirus SalViejavirus SanPerlitavirus mosquito-borne Ilheusvirus viruses Sepikvirus Ntayavirusgroup Bagazavirus Tembusuvirus Yokosevirus RioBravovirus Apoivirus group Entebbebatvirus RioBravovirus Saboyavirus Seabornetick- Meabanvirus bornevirusgroup SaumarezReefvirus Tyuleniyvirus Spondwenivirus Zikavirus group Kyasanurforestdiseasevirus Langatvirus Loupingillvirus Omskhemorrhagicfevervirus Powassanvirus RoyalFarmvirus Tick-borneencephalitisvirus Yaoundevirus Yellowfever Banzivirus virusgroup Boubouivirus EdgeHillvirus UgandaSvirus Wesselsbronvirus Yellowfevervirus unclassified BatuCavevirus Flavivirus Cacipacorevirus Calbertadovirus Cellfusingagentvirus Chaoyangvirus ChimericTick-borneencephalitis virus/Denguevirus4 Culextheileriflavivirus Donggangvirus Duckhemorrhagicovaritisvirus FlavivirusAedes/MO-Ac/ITA/2009 FlavivirusAnopheles/PV-Am/ITA/2009 FlavivirusCbaAr4001 FlavivirusFSME FlavivirusPhlebotomine/76/Arrabida/2007 GadgetsGullyvirus Greekgoatencephalitisvirus Jugravirus Kadamvirus KamitiRivervirus Kedougouvirus Montanamyotisleukoencephalitisvirus Mosquitoflavivirus Ngoyevirus Nounanevirus PhlebotomusflavivirusAlg_F19 PhlebotomusflavivirusAlg_F8 QuangBinhvirus RussianSpring-Summerencephalitisvirus Sokolukvirus Spanishsheepencephalitisvirus THovirus TaiforestvirusB31 Tamanabatvirus Tick-borneflavivirus WangThongvirus Flavivirussp. Aedesflavivirus Culexflavivirus Hepacivirus HepatitisCvirus HepatitisCvirusgenotype1a E1/E2 HepatitisCvirusgenotype1b HepatitisCvirusgenotype2 HepatitisCvirusgenotype3 HepatitisCvirusgenotype4 HepatitisCvirusgenotype5 HepatitisCvirusgenotype6 AllHepatitisCvirus Pestivirus Borderdisease Borderdiseasevirus- E1/E2 virus Borderdiseasevirus-X818 Borderdiseasevirus1 Borderdiseasevirus2 Borderdiseasevirus3 Borderdiseasevirusisolates Bovineviral Bovineviraldiarrheavirus1-CP7 diarrheavirus1 Bovineviraldiarrheavirus1-NADL Bovineviraldiarrheavirus1-Osloss Bovineviraldiarrheavirus1-SD1 Bovineviraldiarrheavirusisolatesand strains Bovineviraldiarrheavirustype1a Bovineviraldiarrheavirustype1b Pestivirusisolate97-360 PestivirusisolateHay87/2210 Pestivirusstrainmousedeer Pestivirustype1isolates Bovineviral Bovineviraldiarrheavirus2 diarrheavirus2 Pestivirussp.strain178003 (BVDV-2) Pestivirussp.strain5250Giessen-3 Bovineviraldiarrheavirus-2isolate SCP Classicalswine Classicalswinefevervirus fevervirus HogcholeravirusstrainZoelen unclassified Bovineviraldiarrheavirus3 Pestivirus Chamoispestivirus1 PorcinepestivirusisolateBungowannah Unnclassified Barkedjivirus Flaviviridae CaninehepacivirusAAK-2011 GBvirusA DouroucoulihepatitisGBvirusA GBV-A-likeagents GBvirusD GBV-C/HGVgroup GBvirusC HepatitisGBvirusC-likevirus HepatitisGBvirusB Lammivirus MarmosethepatitisGBvirusA Nakiwogovirus Turkeymeningoencephalitisvirus Toga- Alpha-virus Auravirus E2/E1 viridae BarmahForest virus Middelburgvirus Ndumuvirus Salmonpancreas diseasevirus Getahvirus Mayarovirus Trocaravirus EEEVcomplex WEEVcomplex FortMorganvirus HighlandsJvirus Sindbisvirus Westernequineencephalomyelitisvirus Whataroavirus VEEVcomplex Cabassouvirus Mucambovirus Pixunavirus Venezuelanequineencephalitisvirus SFVcomplex Bebaruvirus O'nyong-nyongvirus RossRivervirus Semlikiforestvirus Unavirus Chikungunyavirus Rubivirus Rubellavirus Rubellavirus(strainBRD1) Rubellavirus(strainBRDII) Rubellavirus(strainCendehill) Rubellavirus(strainM33) Rubellavirus(strainRN-UK86) Rubellavirus(strainTHERIEN) Rubellavirus(strainTO-336vaccine) Rubellavirus(strainTO-336) Rubellavirus(vaccinestrainRA27/3) Bunya- Hanta-virus Amurvirus Gn(G2)/Gc(G1) viridae (continuedon Bayouvirus nextpage) BlackCreekCanal virus CanoDelgadito virus Calabazovirus Catacamasvirus Choclovirus Dobrava-Belgrade virus ElMoroCanyon virus Hantaanvirus IslaVistavirus Khabarovskvirus LagunaNegra virus LimestoneCanyon virus Monongahelavirus Muleshoevirus Mujuvirus NewYorkvirus Oranvirus PlayadeOro virus ProspectHill virus Puumalavirus RioMamorevirus RioSegundovirus Saaremaavirus Seoulvirus SinNombrevirus Soochongvirus Thailandvirus Thottapalayam virus Topografovvirus Tulavirus Ortho-bunya- AnophelesAvirus virus AnophelesBvirus Bakauvirus Batamavirus Bwambavirus Caraparuvirus KaengKhoivirus Kairivirus Madridvirus MainDrainvirus Maritubavirus Nyandovirus Oribocavirus Oropouchevirus Sathuperivirus Shamondavirus Shunivirus Simbuvirus Tacaiumavirus Tetevirus Turlockvirus unclassified Orthobunyavirus Akabanevirus Sabovirus Tinaroovirus Yaba-7virus Bunyamweravirus Bataivirus Biraovirus Bozovirus CacheValleyvirus FortShermanvirus Germistonvirus Guaroavirus Iacovirus Ileshavirus Lokernvirus Maguarivirus Mbokevirus Ngarivirus Northwayvirus Playasvirus Potosivirus Shokwevirus Tensawvirus Tlacotalpanvirus Xinguvirus California Californiaencephalitisserogroupvirus Encephalitis LEIV virus Californiaencephalitisvirus-BFS-283 Chatangavirus Inkoovirus JamestownCanyonvirus JamestownCanyon-likevirus JerrySloughvirus Keystonevirus LaCrossevirus Lumbovirus Melaovirus MorroBayvirus SanAngelovirus SerradoNaviovirus Snowshoeharevirus SouthRivervirus Tahynavirus Trivittatusvirus Caraparuvirus Apeuvirus Bruconhavirus Ossavirus Vincesvirus Manzanillavirus Buttonwillowvirus Ingwavumavirus Mermetvirus Maritubavirus GumboLimbovirus Murutucuvirus Nepuyovirus Restanvirus Wyeomyiavirus Anhembivirus BeAr328208virus Macauavirus Sororocavirus Taiassuivirus Phlebovirus Bujaruvirus Candiruvirus Chilibrevirus Frijolesvirus Punta Tor_|Salehabad virus Sandflyfever Naplesvirus Uukuniemiviruso virus RiftValley fevervirus unclassified Anhangavirus Phlebovirus Arumowotvirus (continuedon Chagresvirus nextpage) Corfouvirus GabekForestvirus Itaporangavirus PhlebovirusAdria/ALB1/2005 PhlebovirusAdria/ALB5/2005 PhlebovirusAH12 PhlebovirusAH12/China/2010 PhlebovirusAH15/China/2010 PhlebovirusB105-05 PhlebovirusB151-04 PhlebovirusB43-02 PhlebovirusB68-03 PhlebovirusB79-02 PhlebovirusChios-A PhlebovirusCyprus PhlebovirusHB29/China/2010 PhlebovirusHN13/China/2010 PhlebovirusHN6/China/2010 PhlebovirusHu/Xinyang1/China/2010 PhlebovirusHu/Xinyang2/China/2010 PhlebovirusIB13-04 PhlebovirusJS2007-01 PhlebovirusJS24 PhlebovirusJS26 PhlebovirusJS3/China/2010 PhlebovirusJS4/China/2010 PhlebovirusJS6 PhlebovirusJSD1 PhlebovirusLN2/China/2010 PhlebovirusLN3/China/2010 Phlebovirussandflies/Gr29/Spain/2004 Phlebovirussandflies/Gr36/Spain/2004 Phlebovirussandflies/Gr44/Spain/2004 Phlebovirussandflies/Gr49/Spain/2004 Phlebovirussandflies/Gr52/Spain/2004 Phlebovirussandflies/Gr65/Spain/2004 Phlebovirussandflies/Gr98/Spain/2004 PhlebovirusSD24/China/2010 PhlebovirusSD4/China/2010 Phlebovirustick/XCQ-2011 PhlebovirusXLL/China/2009 RioGrandevirus Salobovirus Sandflyfeversicilianvirus SandflySicilianTurkeyvirus Utiquevirus Phlebovirussp. Phlebovirussp.BeAn24262 Phlebovirussp.BeAn356637 Phlebovirussp.BeAn416992 Phlebovirussp.BeAn578142 Phlebovirussp.BeAr371637 Phlebovirussp.CoAr170255 Phlebovirussp.CoAr171616 Phlebovirussp.GML902878 Phlebovirussp.PaAr2381 Phlebovirussp.PAN479603 Phlebovirussp.PAN483391 Phlebovirussp.VP-161A Phlebovirussp.VP-334K Phlebovirussp.VP-366G Orthomyxo- InfluenzavirusA Influenza INFAH1 HA Group2TypeI viridae Avirus (HA1/HA2) fusionmechanism INFAH2 INFAH3 INFAH4 INFAH5 INFAH6 INFAH7 INFAH8 INFAH9 INFAH10 INFAH11 INFAH12 INFAH13 INFAH14 INFAH15 INFAH16 InfluenzavirusB InfluenzaBvirus Allstrains InfluenzavirusC InfluenzaCvirus Paramyxo- Paramyxovirinae Avulavirus Avianparamyxovirus2Yucaipavirus F0 viridae Avianparamyxovirus3 (F2/F1) Avianparamyxovirus3b Avianparamyxovirus4 Avianparamyxovirus5 Avianparamyxovirus6 Avianparamyxovirus7 Avianparamyxovirus8 Avianparamyxovirus9 Newcastlediseasevirus Pigeonparamyxovirus1 unclassifiedAvulavirus Avianparamyxovirus10_Avian paramyxovirusduck/Miyagi/885/05 Avianparamyxoviruspenguin/Falkland Islands/324/2007 GoosramyxovirusHZ GooseparamyxovirusJS/1/97/Go GooseparamyxovirusSF02 Henipavirus HendravirusHendravirus horse/Australia/Hendra/1994 Nipahvirus unclassifiedHenipavirus Batparamyxovirus Eid.hel/GH45/2008 Morbillivirus Caninedistempervirus Cetaceanmorbillivirus_Dolphin morbillivirus_Pilotwhalemorbillivirus Porpoisemorbillivirus Measlesvirus Peste-des-petits-ruminantsvirus Phocinedistempervirus Phocinedistempervirus1 Phocinedistempervirus-2 Rinderpestvirus Respirovirus Bovineparainfluenzavirus3 PorcineparamyxovirusstrainFrost PorcineparamyxovirusstrainTexas Humanparainfluenzavirus1 Humanparainfluenzavirus3 SimianAgent10 Sendaivirus unclassifiedRespirovirus Atlanticsalmonrespirovirus GuineapigparainfluenzavirusTS-9 Pacificsalmonparamyxovirus TraskRiver1983Swineparainfluenza virus3 Tursiopstruncatusparainfluenzavirus1 Rubulavirus Humanparainfluenzavirus2 Humanparainfluenzavirus2(strain Greer) Humanparainfluenzavirus2(strain Toshiba) Humanparainfluenzavirus4 Humanparainfluenzavirus4a Humanparainfluenzavirus4b Mapueravirus Mumpsvirus Parainfluenzavirus5 Porcinerubulavirus Simianvirus41 unclassifiedRubulavirus Porcineparainfluenzavirus Tuhokovirus1 Tuhokovirus2 Tuhokovirus3 unclassified Atlanticsalmonparamyxovirus Paramyxovirinae Beilongvirus Canineparainfluenzavirus Chimerichumanparainfluenzavirus rPIV3-2 Fer-de-lancevirus J-virus Menanglevirus Mossmanvirus Murayamavirus Ovineparainfluenzavirus3 Pacificsalmonparamyxovirus ParamyxovirusGonoGER85 RecombinantPIV3/PIV1virus Reptilianparamyxovirus Salemvirus Salmosalarparamyxovirus SnakeATCC-VR-1408paramyxovirus SnakeATCC-VR-1409paramyxovirus Tiomanvirus Tupaiaparamyxovirus Pneumovirus Humanrespiratory HumanrespiratorysyncytialvirusA Group3 syncytialvirus Humanrespiratorysyncytialvirus TypeIfusionmechanism (strainRSB1734) Humanrespiratorysyncytialvirus (strainRSB5857) Humanrespiratorysyncytialvirus (strainRSB6190) Humanrespiratorysyncytialvirus (strainRSB6256) Humanrespiratorysyncytialvirus (strainRSB642) Humanrespiratorysyncytialvirus (strainRSB6614) HumanrespiratorysyncytialvirusA strainLongLinkOut HumanrespiratorysyncytialvirusA2 HumanrespiratorysyncytialvirusB Humanrespiratorysyncytial virus(subgroupB/strain18537) Humanrespiratorysyncytialvirus (subgroupBstrain8/60) HumanRespiratorysyncytialvirus9320 HumanrespiratorysyncytialvirusB1 HumanrespiratorysyncytialvirusS2 Humanrespiratorysyncytialvirusstrain RSS-2 unclassifiedHumanrespiratorysyncytial virus Bovine Allstrains Group3 respiratory TypeI syncytialvirus fusion Metapneum Avianmetapneumo- Allstrains virus Humanmetapneumo- Allstrains virus Corona- Coronavirinae Alphacorona- Alphacoronavirus1 S Group3TypeI viridae virus Coronavirusgroup1b (S1/S2) fusionmechanism Humancoronavirus229E HumancoronavirusNL63 Miniopterusbatcoronavirus1 MiniopterusbatcoronavirusHKU8 Porcineepidemicdiarrheavirus RhinolophusbatcoronavirusHKU2 Scotophilusbatcoronavirus512 unclassifiedAlphacoronavirus Betacorona- Betacoronavirus1 virus Coronavirusgroup2b Coronavirusgroup2c HumancoronavirusHKU1 Murinecoronavirus PipistrellusbatcoronavirusHKU5 RousettusbatcoronavirusHKU9 Severeacuterespiratorysyndrome- relatedcoronavirusrecombinantSARSr- CoV SARScoronavirus TylonycterisbatcoronavirusHKU4 unclassifiedBetacoronavirus Gammacorona- Aviancoronavirus virus BelugaWhalecoronavirusSW1 unclassified AlpacacoronavirusCA08-1/2008 coronaviruses Batcoronavirus Birddroppingscoronavirus Bovinerespiratorycoronavirus Chickenentericcoronavirus CoronavirusAnas Coronavirusoystercatcher/p17/2006/GBR Coronavirusredknot/p60/2006/GBR Ferretentericcoronavirus1202 FerretsystemiccoronavirusMSU-S FerretsystemiccoronavirusWADL Guangxicoronaviridae HumancoronavirusNO Humanentericcoronavirusstrain4408 Kenyabatcoronavirus MinkcoronavirusstrainWD1133 ParrotcoronavirusAV71/99 QuailcoronavirusItaly/Elvia/2005 TaiForestcoronavirus unidentifiedcoronavirus unidentifiedhumancoronavirus Arena- Arena-virus LCMV-Lassavirus Ippyvirus GpC Group3TypeI viridae (OldWorld) Lassavirus (Gp1/Gp2) fusionmechanism complex Lujovirus Lymphocyticchoriomeningitisvirus Mobalavirus Mopeiavirus Tacaribevirus Amaparivirus (NewWorld) Chaparevirus complex Flexalvirus Guanaritovirus Juninvirus Latinovirus Machupovirus Oliverosvirus Paranavirus Pichindevirus Piritalvirus Sabiavirus Tacaribevirus Tamiamivirus WhitewaterArroyovirus Hepadna- Genus HepatitisBvirus HBVgenotypeA LandMandS Group3Fusion viridae Orthohepadnavirus HBVgenotypeB WhereSmediatesfusion mechanism-Neither HBVgenotypeC typeInortypeII HBVgenotypeD HBVgenotypeE HBVgenotypeF HBVgenotypeG HBVgenotypeH HepatitisBvirusalpha1 HepatitisBvirusLSH/chimpanzee HepatitisBvirusstraincpz HepatitisBvirussubtypeadr HepatitisBvirussubtypeadw HepatitisBvirussubtypeadyw HepatitisBvirussubtypeayw Rhabdo- Dimarhabdovirus Ephemerovirus Bovineephemeralfevervirus GlycoproteinG Group3 viridae NeithertypeInor TypeIIfusion mechanism Vesiculovirus Carajasvirus Chandipuravirus Cocalvirus Isfahanvirus Marabavirus Piryvirus recombinantVesiculovirus Springviraemiaofcarpvirus VesicularstomatitisAlagoasvirus VesicularstomatitisIndianavirus VesicularstomatitisNewJerseyvirus Lyssavirus Aravanvirus Australianbat lyssavirus Duvenhagevirus Europeanbat lyssavirus1 Europeanbat lyssavirus2 Irkutvirus Khujandvirus Lagosbatvirus Mokolavirus WestCaucasian batvirus Rabiesvirus RabiesvirusAB21 RabiesvirusAB22 RabiesvirusAVO1 RabiesvirusBNG4 RabiesvirusBNG5 RabiesvirusChina/DRV RabiesvirusChina/MRV RabiesvirusCVS-11 RabiesvirusERA RabiesvirusEth2003 RabiesvirusHEP-FLURY RabiesvirusIndia RabiesvirusNishigaharaRCEH RabiesvirusOntariofox RabiesvirusOntarioskunk RabiesvirusPM Rabiesvirusredfox/08RS- 1981/Udine/2008 RabiesvirusSADB19 Rabiesvirussilver-hairedbat- associatedSHBRV RabiesvirusstrainPasteurvaccin RabiesvirusstrainStreet Rabiesvirusvnukovo-32 Thailandgenotype1doglyssavirus unclassified Bokelohbatlyssavirus Lyssavirus Europeanbatlyssavirus LyssavirusOzernoe Shimonibatvirus Novirhabdovirus Hirame rhabdovirus Infectious hematopoietic necrosisvirus Snakehead rhabdovirus Viralhemorrhagic septicemiavirus unassigned Bangoranvirus Rhabdoviridae Bimbovirus BivensArmvirus Flandersvirus Garbavirus Klamathvirus MalpaisSpring virus Nasoulevirus Ngainganvirus Ouangovirus Sigmavirus Tupaiavirus Wongabelvirus

    [0116] According to an embodiment, the invention concerns a method for identifying an immunosuppressive domain in the fusion protein of an enveloped RNA virus having a lipid membrane, said method comprising: [0117] a. Identifying at least one well conserved domain among the group consisting of the membrane associated domains of the fusion protein and the surface associated domains of the fusion protein; [0118] b. Providing at least one peptide with the sequence of said identified at least one well conserved domain; [0119] c. Optionally dimerizing or multimerizing said at least one peptide; and [0120] d. Confirming the immunosuppressive activity of said at least one optionally dimerized or multimerized peptide by testing said at least one optionally dimerized or multimerized peptide for immunosuppressive activity.

    [0121] The at least one well conserved domain may be identified among domains, which are membrane associated and domains, which are surface associated. Naturally, a domain which is both membrane and surface associated may be a well conserved domain.

    [0122] The fusion protein may be identified by searching NCBI taxonomy (www.ncbi.nlm.nih.gov/Taxonomy/), and selecting proteins of the Family, Subfamily, Genus or Species to be investigated, and subsequently search these for fusion or the specific name of the fusion protein, e.g. as listed in Table 1.

    [0123] The dimerized peptide could be synthetic, the multimerized peptide could be displayed as dimerized or trimerized fusion proteins either displayed alone or on membranes such as a viral particle.

    [0124] One way of testing the immunosuppressive activity of the at least one dimerized or multimerized peptide is to test the immunosuppressive activity of the fusion protein in the absence and presence of the at least one dimerized or multimerized peptide, and comparing the results.

    [0125] According to other embodiments, the invention concerns the method, wherein the identification of said at least one well conserved domain is done among the group consisting of the surface associated domains of the fusion protein in one or more of the different conformations of the fusion protein undergoing fusion.

    [0126] According to an embodiment, the invention concerns a method, wherein the enveloped RNA virus is not selected among Retroviruses, Lentiviruses or Filoviruses. In particular, according to an embodiment, the invention concerns a method, wherein said at least one well conserved immunosuppressive domain is not located in the linker between the two heptad repeat structures just N-terminal of the transmembrane domain in the fusion protein of either Retrovirus, Lentivirus or Filovirus. More particularly, according to an embodiment, the invention concerns a method, wherein said at least one well conserved domain does not include some of the 22 amino acids located N-terminal to the first of two well conserved cysteine residues that are found in these structures in the fusion protein of either Retrovirus, Lentivirus or Filovirus. These cysteine residues are between 4 and 6 amino acid residues from one another and in many cases are believed to form disulfide bridges that stabilize the fusion proteins.

    [0127] According to other embodiments, the invention concerns the method, wherein said at least one well conserved domain is selected among the group consisting of Putative ISUs and Identified ISUs of Table 1 and Seq. Id. 1-200.

    [0128] According to an embodiment, the invention concerns an immunosuppressive domain identified according to the invention.

    [0129] According to an embodiment, the invention concerns an immunosuppressive domain selected among the sequences of Table 1 and Seq. Id. 1-200.

    [0130] According to an embodiment, the invention concerns a method for decreasing or completely abrogating the immunosuppressive properties of an immunosuppressive domain of the fusion protein of an enveloped RNA virus having a lipid membrane, said method comprising the steps of: [0131] e. Mutating an immunosuppressive domain to provide at least one mutated peptide; [0132] f. Optionally dimerizing or multimerizing said at least one mutated peptide; [0133] g. Selecting one of said optionally dimerized or multimerized mutated peptides showing reduced immunosuppressive properties; [0134] h. Mutating the fusion protein of the enveloped RNA virus to contain said selected mutated peptide having reduced immunosuppressive properties; [0135] i. Confirming expression by testing the viral envelope protein encompassing said mutated fusion protein for capability of being expressed by at least one of cellular or viral surfaces.

    [0136] The envelope protein may be identified by searching NCBI taxonomy (www.ncbi.nlm.nih.gov/Taxonomy/) and selecting proteins of the Family, Subfamily, Genus or Species to be investigated and subsequently searching these for envelope or the specific name for the envelope protein or the attachment and fusion protein, e.g. as listed in Table 1.

    [0137] According to other embodiments, the invention concerns the method, wherein: [0138] e. Said immunosuppressive domain is mutated to provide a plurality of mutated peptides; [0139] f. Said plurality of mutated peptides are optionally dimerized or multimerized; [0140] g. One of said optionally dimerized or multimerized mutated peptides showing reduced immunosuppressive properties is selected; [0141] h. The fusion protein of the enveloped RNA virus is mutated to contain said selected optionally dimerized or multimerized peptide having reduced immunosuppressive properties; [0142] i. Expression is confirmed by testing the viral envelope protein encompassing said mutated fusion protein for capability of being expressed by at least one of cellular or viral surfaces.

    [0143] According to other embodiments, the invention concerns the method, wherein: [0144] g. One of said optionally dimerized or multimerized mutated peptide(s) is selected, which has reduced immunosuppressive properties as shown by at least 25% reduction as compared to a dimerized Wildtype peptide.

    [0145] According to other embodiments, the invention concerns the method, wherein: [0146] e. Said mutated immunosuppressive domain is mutated to provide a knock-out mutant of Table 1 or selected among the sequences of Seq. Id. 201-203.

    [0147] According to an embodiment, a proven knock-out (i.e. a mutation of the immunosuppressive domain abrogating the immunosuppressive properties of the peptide) from one family, genus, group and/or strain, may be used for another family, genus, group and/or strain.

    [0148] According to an embodiment, the invention concerns a mutated peptide providing reduced immunosuppressive properties, said mutated peptide having a sequence according to Table 1 or any of Seq. Id.202 to 203 or obtainable as said selected mutated peptide of a method according to the invention.

    [0149] Preliminary experiments indicate the immunosuppressive domains may have a size of 4-30 amino acids.

    [0150] According to an embodiment, the invention concerns a method for generating an enhanced immune response, comprising a method according to the invention, and further comprising the step of: [0151] j. Using said viral envelope protein encompassing said mutated fusion protein with reduced immunosuppressive properties as an antigen for generation of an enhanced immune response.

    [0152] According to an embodiment, the invention concerns a method for making an envelope protein having diminished immunosuppressive activity, comprising: [0153] Mutating or modifying an immunosuppressive domain, identifiable according to the invention, of an enveloped RNA virus with a lipid membrane surrounding the core, to include a peptide obtainable according to the invention.

    [0154] The diminished immunosuppressive activity is suitably measured by comparing to the immunosuppressive activity from an envelope of a wildtype peptide. It is preferably demonstrated by an increased proliferation of at least 25% in a cell proliferation assay of homodimers of said mutated peptide as compared to the homodimers of said non-mutated wildtype peptide at the same concentration. More preferably the cell assay is either the CTLL-2 or the PBMC assay.

    [0155] According to an embodiment, the invention concerns the method, for making a envelope protein encompassing a mutated fusion protein from a enveloped RNA virus for medical use, such as therapeutic or prophylactic purpose, preferably for use as a vaccine.

    [0156] According to an embodiment, the invention concerns the method, for making an enveloped protein encompassing a mutated fusion protein from an envelope RNA virus for vaccination purposes or for the generation of neutralizing antibodies.

    [0157] According to an embodiment, the invention concerns the method, wherein the enveloped RNA virus has a fusion protein with a type II fusion mechanism.

    [0158] According to an embodiment, the invention concerns the method, wherein the enveloped RNA virus, preferably excluding lentivius, retrovirus and filovirus, has a fusion protein with a type I fusion mechanism and where the immunosuppressive domains co-localizes with the fusion peptide in the fusion protein, preferably as demonstrated by the identification of a common immunosuppressive domain in the fusion peptide of all H1 to H16 of Influenza A and influenza B.

    [0159] According to an embodiment, the invention concerns the method, wherein the enveloped RNA virus, preferably excluding lentivius, retrovirus and filovirus, has a fusion protein with a type I fusion mechanism excluding viruses with a type I fusion mechanism where the ISU co-localizes with the fusion peptide or the fusion protein has a structure that is neither a type I nor a type II fusion structure.

    [0160] According to an embodiment, the invention concerns an envelope protein obtainable according to the invention.

    [0161] The immunosuppressive domain has so far been identified by the inventors at two positions in two different groups of viruses A: Co-localizing with the fusion peptide exemplified by the identification of an common immunosuppressive domain in the fusion peptide of all Flavirus (Dengue virus, west Nile virus etc) and Influenza A and B viruses and B: in the hydrophobic alpha helix N-terminal of the transmembrane domain in the fusion protein exemplified by the finding of an immunosuppressive domain in said helixes of Flaviridae like e.g. Hepatitis C virus, Dengue, WestNile, Yellow fever.

    [0162] The inventors have realized that the potential immunosuppressive domains are located at various positions in the fusion protein identifiable by [0163] 1): The peptide is preferably located in the fusion protein of enveloped RNA viruses; [0164] 2): The peptide is preferably capable of interacting with membranes; [0165] 3): Preferably a high degree of homology in the primary structure (sequence) of the peptide of said domain exists either within the viral species itself, in the family of viruses or in a group of viruses. This requirement is due to the immunosuppressive domain being under a dual selection pressures, one as an immunosuppressive entity ensuring protection of the viral particle from the host immune system, another as a peptide interacting with membranes; and/or [0166] 4): The position at the surface of the fusion protein at a given conformation is preferably a feature of immunosuppressive domains. This can be revealed either by position in a 3D structure or by antibody staining of cells expressing the fusion protein or on viral surfaces displaying the fusion protein.

    [0167] According to an embodiment, the invention concerns a mutated envelope protein according to the invention.

    [0168] According to an embodiment, the invention concerns a viral fusion protein from an enveloped RNA virus with reduced immunosuppressive properties, said fusion protein encompassing a mutated peptide, said mutated peptide displaying reduced immunosuppression, and said mutated peptide replacing an un-mutated wildtype peptide having a sequence of an ISU of Table 1 or is selected among Seq. Id. 1-200.

    [0169] According to an embodiment, the invention concerns the fusion protein, where the reduced immunosuppression is identified by comparing to the un-mutated wildtype peptide when said peptide is dimerized.

    [0170] According to an embodiment, the invention concerns the fusion protein, wherein said immunosuppressive activity being determined by at least 25% reduction, more preferred at least 40% reduction, in proliferation rate in a cell proliferation assay using a homodimer of said un-mutated peptide compared to the monomeric version of said peptide at the same concentration.

    [0171] According to an embodiment, the invention concerns the fusion protein, wherein said cell proliferation assay is selected among the group consisting of the CTLL-2 and the PBMC assay.

    [0172] According to an embodiment, the invention concerns the fusion protein, wherein said fusion protein has a type I or type II fusion mechanism.

    [0173] According to an embodiment, the invention concerns the fusion protein, wherein said fusion protein has neither a type I nor type II fusion mechanism.

    [0174] According to an embodiment, the invention concerns the fusion protein, wherein said mutated peptide is located either in the fusion peptide or in a, preferably amphipatic, helix upstream of the C-terminal transmembrane domain of said fusion protein.

    [0175] The fusion peptide is a small membrane penetrating peptide located in the fusion protein of enveloped viruses.

    [0176] According to another embodiment, the invention concerns the viral fusion protein, wherein said mutated peptide is derived from the fusion peptide from a flavivirus or Influenzavirus or from the amphipatic helix of the Flaviridae, such as the group consisting of Hepatitis C virus fusion protein, Dengue virus fusion protein, and WestNile virus fusion protein.

    [0177] According to an embodiment, the invention concerns an envelope protein, said mutated fusion protein being displayed on the surface of cells wherein said mutated fusion protein is expressed.

    [0178] According to an embodiment, the invention concerns the envelope protein, said mutated fusion protein being displayed on the surface of viral or viral like particles.

    [0179] According to an embodiment, the invention concerns the envelope protein, having retained some fusiogenic activity.

    [0180] According to an embodiment, the invention concerns the envelope protein, wherein the fusiogenic activity is measured by a technique for measuring cell-cell fusion, preferably selected among the group consisting of counting syncytia by light microscopy, resonance energy transfer based assays, and indirect reporter gene using techniques or by measuring infectious titers; alternatively, or in addition, the presence of fusiogenic activity may be indicated by the presence of at least one cell expressing the modified envelope and one cell expressing the receptor and/or coreceptors being fused together.

    [0181] According to an embodiment, the invention concerns an enveloped RNA virus, different from a virus selected among the group consisting of Retrovirus, Lentivirus and Filovirus, wherein an immunosuppressive domain has been modified or mutated to decrease or completely abrogate the immunosuppressive properties of an immunosuppressive domain of the fusion protein.

    [0182] According to an embodiment, the invention concerns a virus selected among the vira of Table 1, wherein an immunosuppressive domain has been modified or mutated to decrease or completely abrogate the immunosuppressive properties of an immunosuppressive domain of the fusion protein.

    [0183] According to an embodiment, the invention concerns an antigen obtainable by selecting a part of a mutated envelope protein according to any of the preceding claims, said part comprising the mutated domain of said envelope protein.

    [0184] According to an embodiment, the invention concerns an antigen comprising an mutated immunosuppressive domain selected among the sequences of Table 1 and Seq. Id. 201 to 202.

    [0185] According to an embodiment, the invention concerns an antigen of the invention furthermore harboring 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 point mutation(s) in any of the sequences of Table 1 or of Seq. Id. 1-200.

    [0186] According to an embodiment, the invention concerns an antigen, which mediates fusion of virus to host cells.

    [0187] According to an embodiment, the invention concerns an antigen, which is recombinant or obtained by recombinant technology.

    [0188] According to an embodiment, the invention concerns a nucleic acid sequence, preferably recombinant, encoding a mutated envelope protein, an envelope polypeptide or an antigen according to any of the preceding claims.

    [0189] According to an embodiment, the invention concerns an isolated eukaryotic expression vector comprising a nucleic acid sequence according to the invention.

    [0190] According to another embodiment, the invention concerns the vector, which is a virus vector, preferably a virus selected among the group consisting of vaccinia virus, measles virus, retroviridae, lentivirus, baculovirus and adeno virus.

    [0191] According to an embodiment, the invention concerns a method for producing an antibody, said method comprising the steps of: [0192] Administering an entity selected among a mutated envelope, an envelope polypeptide, an antigen, a nucleic acid sequence or a vector according to any of the preceding claims to a host, such as an animal; and [0193] Obtaining the antibody from said host.

    [0194] According to an embodiment, the invention concerns an antibody obtainable according to a method of the invention.

    [0195] According to another embodiment, the invention concerns an antibody, which is specific for an entity selected among a mutated peptide, an envelope protein, a mutated envelope protein, an antigen, a nucleic acid sequence or a vector according to any of the preceding claims.

    [0196] According to an embodiment, the invention concerns neutralizing antibodies obtained or identified by the use of at least one envelope protein according to any of the preceding claims.

    [0197] According to an embodiment, the invention concerns a method for manufacturing neutralizing antibodies comprising the use of at least one protein according to any of the preceding claims.

    [0198] According to an embodiment, the invention concerns a method for manufacturing humanized neutralizing antibodies, comprising the use of at least one sequence selected among the sequences of Table 1 and sequences 201 to 203

    [0199] According to an embodiment, the invention concerns a vaccine comprising a virus according to the invention.

    [0200] According to an embodiment, the invention concerns a vaccine comprising an envelope protein from a virus according to the invention.

    [0201] According to an embodiment, the invention concerns a vaccine composition comprising an envelope protein according to any of the preceding claims.

    [0202] According to an embodiment, the invention concerns a vaccine composition comprising a virus like particle (VLP).

    [0203] According to an embodiment, the invention concerns the vaccine composition, wherein the virus like particle is produced ex vivo in a cell culture.

    [0204] According to an embodiment, the invention concerns the vaccine composition, wherein the virus like particle is partly or completely assembled ex vivo.

    [0205] According to an embodiment, the invention concerns the vaccine composition, wherein the virus like particle is generated in vivo in the patient by infection, transfection and/or electroporation by expression vectors.

    [0206] According to an embodiment, the invention concerns the vaccine composition, comprising a vector derived from a measles or vaccinia virus.

    [0207] According to an embodiment, the invention concerns the vaccine composition, comprising an expression vector for DNA vaccination.

    [0208] According to an embodiment, the invention concerns the vaccine composition, comprising a purified envelope protein.

    [0209] According to an embodiment, the invention concerns the vaccine composition, comprising a multimerized purified envelope protein.

    [0210] According to an embodiment, the invention concerns the vaccine composition, comprising a dimerized purified envelope protein.

    [0211] According to an embodiment, the invention concerns the vaccine composition, comprising a trimerized purified envelope protein.

    [0212] According to an embodiment, the invention concerns a vaccine composition comprising an entity selected among the group consisting of a mutated envelope protein, an envelope polypeptide, an antigen, a nucleic acid sequence, a vector and an antibody according to any of the preceding claims, and in addition at least one excipient, carrier or diluent.

    [0213] According to an embodiment, the invention concerns the vaccine composition, further comprising at least one adjuvant.

    [0214] According to an embodiment, the invention concerns a medical composition comprising antibodies raised using a virus according to the invention.

    [0215] According to an embodiment, the invention concerns a pharmaceutical composition comprising a mutated peptide, an envelope protein, a mutated envelope protein, an antigen, a nucleic acid sequence, a vector, an antibody or a vaccine composition according to any of the preceding claims, and at least one pharmaceutically acceptable excipient, diluents or carrier.

    [0216] According to an embodiment, the invention concerns a use of a mutated peptide, an envelope protein, a mutated envelope protein, an antigen, a nucleic acid sequence, a vector or an antibody according to any of the preceding claims, for a medical purpose, such as for the treatment, amelioration or prevention of a clinical condition, such as for the manufacture of a medicament for the treatment, amelioration or prevention of a clinical condition.

    [0217] According to an embodiment, the invention concerns a method of treating or ameliorating the symptoms of an individual, or prophylactic treating an individual, comprising administering an amount of mutated peptide, an envelope protein, a mutated envelope protein, antigen, nucleic acid sequence, vector or vaccine composition according to any of the preceding claims.

    [0218] According to an embodiment, the invention may be used with human and/or animal vira.

    [0219] Table 2 below, provides the location of a number of identified immunosuppressive domains.

    TABLE-US-00006 TABLE2 Localizationofidentifiedimmunosuppressivedomains Family(-viridae), Subfamily(-virinae), Genus(-virus)or Species(-virus)of Localizationofprototype viruses immunosuppressivedomain Reference AllFlavirus ProteinE SeligmanSJ.Constancyand 98-DRGWGNXCGXFGKGXX-113 diversityintheflavivirus fusionpeptide.VirolJ.2008 Feb14;5:27. AllFlavirus ProteinE FIG.1 (e.g.Dengue3) 416-GDTAWDFGSVGGVLNSLGK-434 SchmidtAG,YangPL,HarrisonSC. Peptideinhibitorsof dengue-virusentrytargeta late-stagefusion intermediate.PLoSPathog. 2010Apr8;6(4):e1000851. HepatitisC E2(SEQIDNO:3) AlbeckaA,MontserretR,KreyT, 71-GLIHLHQNIVDVQYLYG-87 TarrAW,DiesisE,BallJK, DescampsV, DuverlieG,ReyF,PeninF, DubuissonJ.Identificationof newfunctionalregionsin hepatitisCvirusenvelope glycoproteinE2.JVirol.2011 Feb;85(4):1777-92. Epub2010Dec8. InfluenzaA1-16 HA2(SEQIDNO:4) CrossKJ,WhartonSA,SkehelJJ, InfluenzaB 1-GLFGAIAGFIENGWEG-16 WileyDC,SteinhauerDA. Studiesoninfluenza haemagglutininfusionpeptide mutantsgeneratedbyreverse genetics.EMBOJ.2001 Aug15;20(16):4432-42.

    [0220] According to an embodiment, an immunosuppressive domain may be identified by its position, e.g. as indicated in Table 2.

    [0221] According to an embodiment, the invention concerns an immunosuppressive domain identified by its position.

    [0222] According to an embodiment, the invention concerns an immunosuppressive domain identified by its secondary, tertiary or quaternary structure in the folded fusion protein.

    [0223] According to an embodiment, the invention concerns an entity selected among the group consisting of a mutated peptide, an envelope protein, a mutated envelope protein, an antigen, a nucleic acid sequence and a vector, wherein an immunosuppressive domain identified by its position, has been modified or mutated in order to suppress its immunosuppressive properties.

    [0224] All cited references are incorporated by reference.

    [0225] The accompanying Figures and Examples are provided to explain rather than limit the present invention. It will be clear to the person skilled in the art that aspects, embodiments and claims of the present invention may be combined.

    EXAMPLES

    Peptide Solutions

    [0226] The peptides were either dissolved in water or in cases of low water solubility, 5% DMSO solutions were used to dissolve the peptides.

    Assay to Measure the Immunosuppressive Activity of Peptides Derived From Viral Surface Proteins or Their Mutants

    [0227] The peptides can be prepared by different means including, but not limited to, solid phase synthesis commonly used for such purposes. The peptides can be dimerized using a cysteine residue either at the N- or C-terminal or in the middle of the peptide or by using any other molecule or atom that is covalently bound to peptide molecules.

    [0228] The peptides can be coupled to a carrier protein such as BSA by covalent bounds including, but not limited to, disulfide bridges between the peptide cysteine residues and the carrier protein or through amino groups including those in the side chain or Lysine residues.

    [0229] The peptides can have non-viral derived amino acids added to their C-terminal for increasing their water solubility.

    Assay to Test the Immunosuppressive Activity of Peptides

    Experiment Design

    [0230] Human Peripheral Blood Mononuclear Cells (PBMC) are prepared freshly from healthy donors. These are stimulated by Con A (5 ug/mL) concomitant to peptide addition at different concentrations (i.e. 25 uM, 50 uM and 100 uM). Cultures are maintained and lymphocyte proliferation is measured 72 hrs later by EdU incorporation and Click-iT labelling with Oregon Green (Invitrogen, Denmark) as recommended by the manufacturer. The degree of activated lymphocytes is proportional to the fluorescence detection.

    CTLL-2 Assay

    [0231] 100.000 CTLL-2 cells are seeded pr. well in a 48 well-plate (Nunc) in 200 uL of medium (RPMI+2 mM L-glutamine+1 mM Na-pyruvat+10% FCS+0.5 ng/mL IL-2) 2 hours later the peptides are added to the wells. 24 h later the cells are labeled using the Click-it reaction kit (Invitrogen cat. #C35002). The fluorescence of the cells is measured on a flow cytometer. The degree of proliferation in each sample is proportional to the detected fluorescence.

    Test of Immunosuppression From Monomer and Dimeric Peptides

    [0232] 100.000 CTLL-2 cells were seeded pr. well in a 48 well-plate (Nunc) in 200 uL of medium (RPMI+2 mM L-glutamine+1 mM Na-pyruvat+10% FCS+0.5 ng/mL IL-2) 2 hours later the peptides were added to the wells. 24 h later the cells were labeled using the Click-it reaction kit (Invitrogen cat. #C35002). The fluorescence of the cells was measured on a flow cytometer. The degree of proliferation in each sample is proportional to the detected fluorescence.

    Quantification of Proliferation Inhibition

    [0233] The degree of inhibition of proliferation of CTLL-2 cells is visualized in the diagrams in the figures. The ratios are calculated by dividing the number of labeled cells (growing cells) in cultures in presence of peptide with cultures in absence of peptides, but added the same volume of the solute that was used to dissolve the peptides. That is in cases where the peptides were dissolved in 5% DMSO, the same volume of 5% DMSO was added to the control cells.

    Appendix

    Classes of Enveloped RNA Viruses That Contain Human Pathogens

    Flaviridae (Type II Fusion)

    [0234] Flaviviridae have monopartite, linear, single-stranded RNA genomes of positive polarity, 9.6- to 12.3-kilobase in length. Virus particles are enveloped and spherical, about 40-60 nm in diameter.

    [0235] Major diseases caused by the Flaviviridae family include: [0236] Dengue fever [0237] Japanese encephalitis [0238] Kyasanur Forest disease [0239] Murray Valley encephalitis [0240] St. Louis encephalitis [0241] Tick-borne encephalitis [0242] West Nile encephalitis [0243] Yellow fever [0244] Hepatitis C Virus Infection

    Existing Vaccines for Flaviridae

    [0245] The successful yellow fever 17D vaccine, introduced in 1937, produced dramatic reductions in epidemic activity. Effective killed Japanese encephalitis and Tick-borne encephalitis vaccines were introduced in the middle of the 20th century. Unacceptable adverse events have prompted change from a mouse-brain killed Japanese encephalitis vaccine to safer and more effective second generation Japanese encephalitis vaccines. These may come into wide use to effectively prevent this severe disease in the huge populations of AsiaNorth, South and Southeast. The dengue viruses produce many millions of infections annually due to transmission by a successful global mosquito vector. As mosquito control has failed, several dengue vaccines are in varying stages of development. A tetravalent chimeric vaccine that splices structural genes of the four dengue viruses onto a 17D yellow fever backbone is in Phase III clinical testing.

    Genus Flavivirus

    [0246] Flaviviruses share a common size (40-65 nm), symmetry (enveloped, icosahedral nucleocapsid), nucleic acid (positive-sense, single stranded RNA approximately 10,000-11,000 bases), and appearance in the electron microscope.

    [0247] These viruses are transmitted by the bite from an infected arthropod (mosquito or tick). Human infections with these viruses are typically incidental, as humans are unable to replicate the virus to high enough titres to reinfect arthropods and thus continue the virus life cycle. The exceptions to this are yellow fever and dengue viruses, which still require mosquito vectors, but are well-enough adapted to humans as to not necessarily depend upon animal hosts (although both continue have important animal transmission routes as well).

    [0248] Genus Hepacivirus (type species Hepatitis C virus, the single member)

    [0249] Hepatitis C is an infectious disease affecting the liver, caused by the hepatitis C virus (HCV). The infection is often asymptomatic, but once established, chronic infection can progress to scarring of the liver (fibrosis), and advanced scarring (cirrhosis), which is generally apparent after many years. In some cases, those with cirrhosis will go on to develop liver failure or other complications of cirrhosis, including liver cancer or life threatening esophageal varices and gastric varices. The hepatitis C virus is spread by blood-to-blood contact. Most people have few, if any symptoms after the initial infection, yet the virus persists in the liver in about 85% of those infected. Persistent infection can be treated with medication, peg-interferon and ribavirin being the standard-of-care therapy. Overall, 51% are cured. Those who develop cirrhosis or liver cancer may require a liver transplant, and the virus universally recurs after the transplant takes place. An estimated 180 million people worldwide are infected with hepatitis C. Hepatitis C is not known to cause disease in other animals. No vaccine against hepatitis C is currently available. The existence of hepatitis C (originally non-A non-B hepatitis) was postulated in the 1970s and proven in 1989. It is one of five known hepatitis viruses: A, B, C, D, and E.

    [0250] The hepatitis C virus is a small (50 nm in size), enveloped, single-stranded, positive sense RNA virus. There are six major genotypes of the hepatitis C virus, which are indicated numerically (e.g., genotype 1, genotype 2, etc.). Based on the NS5 gene there are three major and eleven minor genotypes. The major genotypes diverged about 300-400 years ago from the ancestor virus. The minor genotypes diverged about 200 years ago from their major genotypes. All of the extant genotypes appear to have evolved from genotype 1 subtype 1b.

    [0251] The hepatitis C virus is transmitted by blood-to-blood contact. In developed countries, it is estimated that 90% of persons with chronic HCV infection were infected through transfusion of unscreened blood or blood products or via injecting drug use or sexual exposure. In developing countries, the primary sources of HCV infection are unsterilized injection equipment and infusion of inadequately screened blood and blood products.

    Genus Pestivirus

    TogaviridaeType II Fusion

    [0252] The Togaviridae are a family of viruses, including the following genera:

    Genus Alphavirus

    [0253] Alphaviruses have a positive sense single stranded RNA genome. There are 27 alphaviruses, able to infect various vertebrates such as humans, rodents, fish, birds, and larger mammals such as horses as well as invertebrates. Transmission between species and individuals occurs mainly via mosquitoes making the alphaviruses a contributor to the collection of Arboviruses- or Arthropod Borne Viruses. Alphaviruses particles are enveloped, have a 70 nm diameter, tend to be spherical and have a 40 nm isometric nucleocapsid.

    [0254] There are two open reading frames (ORF's) in the genome, non-structural and structural. The first is non structural and encodes proteins for transcription and replication of viral RNA, and the second encodes three structural proteins: the core nucleocapsid protein C, and the envelope proteins P62 and E1 that associate as a heterodimer. The viral membrane-anchored surface glycoproteins are responsible for receptor recognition and entry into target cells through membrane fusion. The proteolytic maturation of P62 into E2 and E3 causes a change in the viral surface. Together the E1, E2, and sometimes E3, glycoprotein spikes form an E1/E2 dimer or an E1/E2/E3 trimer, where E2 extends from the centre to the vertices, E1 fills the space between the vertices, and E3, if present, is at the distal end of the spike. Upon exposure of the virus to the acidity of the endosome, E1 dissociates from E2 to form an E1 homotrimer, which is necessary for the fusion step to drive the cellular and viral membranes together. The alphaviral glycoprotein E1 is a class II viral fusion protein. The structure of the Semliki Forest virus revealed a structure that is similar to that of flaviviral glycoprotein E, with three structural domains in the same primary sequence arrangement. The E2 glycoprotein functions to interact with the nucleocapsid through its cytoplasmic domain, while its ectodomain is responsible for binding a cellular receptor. Most alphaviruses lose the peripheral protein E3, but in Semliki viruses it remains associated with the viral surface.

    Genus Rubivirus

    Genus Rubivirus

    Bunyaviridae Type II Fusion Mechanism

    [0255] Bunyaviridae is a family of negative-stranded RNA viruses. Though generally found in arthropods or rodents, certain viruses in this family occasionally infect humans. Some of them also infect plants.

    [0256] Bunyaviridae are vector-borne viruses. With the exception of Hantaviruses, transmission occurs via an arthropod vector (mosquitos, tick, or sandfly). Hantaviruses are transmitted through contact with deer mice feces. Incidence of infection is closely linked to vector activity, for example, mosquito-borne viruses are more common in the summer.

    [0257] Human infections with certain Bunyaviridae, such as Crimean-Congo hemorrhagic fever virus, are associated with high levels of morbidity and mortality, consequently handling of these viruses must occur with a Biosafety level 4 laboratory. They are also the cause of severe fever with thrombocytopenia syndrome.

    [0258] Hanta virus or Hantavirus Hemorrhagic fever, common in Korea, Scandinavia, Russia, and the American southwest, is associated with high fever, lung edema and pulmonary failure. Mortality is around 55%.

    [0259] The antibody reaction plays an important role in decreasing levels of viremia.

    [0260] Genus Hantavirus; type species: Hantaan virus

    [0261] Hantaviruses are negative sense RNA viruses in the Bunyaviridae family. Humans may be infected with hantaviruses through rodent bites, urine, saliva or contact with rodent waste products. Some hantaviruses cause potentially fatal diseases in humans, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), but others have not been associated with human disease. HPS cannot be transmitted person-to-person. The name hantavirus is derived from the Hantan River area in South Korea, which provided the founding member of the group: Hantaan virus (HTNV), isolated in the late 1970s by Ho-Wang Lee and colleagues. HTNV is one of several hantaviruses that cause HFRS, formerly known as Korean hemorrhagic fever.

    Genus Ortho-Bunya-Virus

    [0262] The orthobunyaviruses are maintained in nature by sylvatic transmission cycles between hematophagous mosquitoes and susceptible mammalian hosts, principally rodents and other small mammals. Several members of the California serogroup of orthobunyaviruses, including La Crosse (LAC) and Tahyna (TAH) viruses, are significant human pathogens. LAC virus is an important cause of pediatric encephalitis and aseptic meningitis in the Midwestern United States where approximately 100 cases are reported annually; TAH virus, indigenous to central Europe, is associated with influenzalike febrile illnesses. La Crosse virus is a NIAID Category B priority pathogen.

    [0263] The orthobunyaviruses are enveloped, negative-stranded RNA viruses with a tripartite genome comprised of large (L), medium (M), and small (S) segments The M segment encodes three proteins in a single open reading frame (ORF): two surface transmembrane glycoproteins, herein referred to as Gn (G2) and Gc (G1), respectively, to delineate their order in the precursor polyprotein, and NSm, a protein of unknown function. Gn and Gc are thought to associate as a heteromultimer after cleavage of the polyprotein.

    [0264] Genus Phlebovirus; type species: Rift Valley fever virus

    [0265] Phlebovirus is one of five genera of the family Bunyaviridae. The Phlebovirus genus currently comprises over 70 antigenically distinct serotypes, only a few of which have been studied. The 68 known serotypes are divided into two groups: the Phlebotomus fever viruses (the sandfly group, transmitted by Phlebotominae sandflies) comprises 55 members and the Uukuniemi group (transmitted by ticks) comprises the remaining 13 members.

    [0266] Of these 68 serotypes, eight of them have been linked to disease in humans. They are: Alenquer virus, Candiru virus, Chagres virus, Naples virus, Punta Toro virus, Rift Valley fever, Sicilian virus, and Toscana virus. Recently identified is another human pathogenic serotype, the SFTS virus.

    [0267] Rift Valley Fever (RVF) is a viral zoonosis (affects primarily domestic livestock, but can be passed to humans) causing fever. It is spread by the bite of infected mosquitoes, typically the Aedes or Culex genera. The disease is caused by the RVF virus, a member of the genus Phlebovirus (family Bunyaviridae). The disease was first reported among livestock in Kenya around 1915, but the virus was not isolated until 1931. RVF outbreaks occur across sub-Saharan Africa, with outbreaks occurring elsewhere infrequently (but sometimes severelyin Egypt in 1977-78, several million people were infected and thousands died during a violent epidemic. In Kenya in 1998, the virus claimed the lives of over 400 Kenyans. In September 2000 an outbreak was confirmed in Saudi Arabia and Yemen).

    [0268] In humans the virus can cause several different syndromes. Usually sufferers have either no symptoms or only a mild illness with fever, headache, myalgia and liver abnormalities. In a small percentage of cases (<2%) the illness can progress to hemorrhagic fever syndrome, meningoencephalitis (inflammation of the brain), or affecting the eye. Patients who become ill usually experience fever, generalized weakness, back pain, dizziness, and weight loss at the onset of the illness. Typically, patients recover within 2-7 days after onset.

    [0269] Approximately 1% of human sufferers die of the disease. Amongst livestock the fatality level is significantly higher. In pregnant livestock infected with RVF there is the abortion of virtually 100% of fetuses. An epizootic (animal disease epidemic) of RVF is usually first indicated by a wave of unexplained abortions.

    Orthomyxoviridae Type I Fusion

    [0270] The Orthomyxoviridae (orthos, Greek for straight; myxa, Greek for mucus).sup.] are a family of RNA viruses that includes five genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus and Thogotovirus. A sixth has recently been described. The first three genera contain viruses that cause influenza in vertebrates, including birds (see also avian influenza), humans, and other mammals. Isaviruses infect salmon; thogotoviruses infect vertebrates and invertebrates, such as mosquitoes and sea lice.

    [0271] The three genera of Influenzavirus, which are identified by antigenic differences in their nucleoprotein and matrix protein infect vertebrates as follows: [0272] Influenzavirus A infects humans, other mammals, and birds, and causes all flu pandemics [0273] Influenzavirus B infects humans and seals [0274] Influenzavirus C infects humans and pigs

    Paramyxoviridae Type I Fusion Mechanism

    [0275] The fusion protein F projects from the envelope surface as a trimer, and mediates cell entry by inducing fusion between the viral envelope and the cell membrane by class I fusion. One of the defining characteristics of members of the paramyxoviridae family is the requirement for a neutral pH for fusogenic activity. A number of important human diseases are caused by paramyxoviruses. These include mumps, measles, which caused 745,000 deaths in 2001 and respiratory syncytial virus (RSV) which is the major cause of bronchiolitis and pneumonia in infants and children. The parainfluenza viruses are the second most common causes of respiratory tract disease in infants and children. They can cause pneumonia, bronchitis and croup in children and the elderly.

    [0276] Human metapneumovirus, initially described in about 2001, is also implicated in bronchitis, especially in children.

    [0277] genus Paramyxoviruses are also responsible for a range of diseases in other animal species, for example canine distemper virus (dogs), phocine distemper virus (seals), cetacean morbillivirus (dolphins and porpoises) Newcastle disease virus (birds), and rinderpest virus (cattle). Some paramyxoviruses such as the henipaviruses are zoonotic pathogens, occurring naturally in an animal host, but also able to infect humans.

    [0278] Hendra virus (HeV) and Nipah virus (NiV) in the genus Henipavirus have emerged in humans and livestock in Australia and Southeast Asia. Both viruses are contagious, highly virulent, and capable of infecting a number of mammalian species and causing potentially fatal disease. Due to the lack of a licensed vaccine or antiviral therapies, HeV and NiV are designated as biosafety level (BSL) 4 agents. The genomic structure of both viruses is that of a typical paramyxovirus.

    Genus Pneumovirinae

    [0279] Genus Pneumovirus (type species Human respiratory syncytial virus, others include Bovine respiratory syncytial virus) [0280] Human respiratory syncytial virus (RSV) is a virus that causes respiratory tract infections. It is the major cause of lower respiratory tract infections and hospital visits during infancy and childhood. A prophylactic medication (not a vaccine) exists for preterm birth (under 35 weeks gestation) infants and infants with a congenital heart defect (CHD) or bronchopulmonary dysplasia (BPD). Treatment is limited to supportive care, including oxygen therapy. [0281] In temperate climates there is an annual epidemic during the winter months. In tropical climates, infection is most common during the rainy season. [0282] In the United States, 60% of infants are infected during their first RSV season and nearly all children will have been infected with the virus by 2-3 years of age. en.wikipedia.org/wiki/Respiratory_syncytial_viruscite_note-Glezen86-0 Of those infected with RSV, 2-3% will develop bronchiolitis, necessitating hospitalization Natural infection with RSV induces protective immunity which wanes over timepossibly more so than other respiratory viral infectionsand thus people can be infected multiple times. Sometimes an infant can become symptomatically infected more than once, even within a single RSV season. Severe RSV infections have increasingly been found among elderly patients. [0283] RSV is a negative-sense, single-stranded RNA virus of the family Paramyxoviridae, which includes common respiratory viruses such as those causing measles and mumps. RSV is a member of the paramyxovirus subfamily Pneumovirinae. Its name comes from the fact that F proteins on the surface of the virus cause the cell membranes on nearby cells to merge, forming syncytia.

    Coronaviriridae Type I Fusion

    [0284] Coronaviruses primarily infect the upper respiratory and gastrointestinal tract of mammals and birds. Four to five different currently known strains of coronaviruses infect humans. The most publicized human coronavirus, SARS-CoV which causes SARS, has a unique pathogenesis because it causes both upper and lower respiratory tract infections and can also cause gastroenteritis. Coronaviruses are believed to cause a significant percentage of all common colds in human adults. Coronaviruses cause colds in humans primarily in the winter and early spring seasons. The significance and economic impact of coronaviruses as causative agents of the common cold are hard to assess because, unlike rhinoviruses (another common cold virus), human coronaviruses are difficult to grow in the laboratory.

    [0285] Coronaviruses also cause a range of diseases in farm animals and domesticated pets, some of which can be serious and are a threat to the farming industry. Economically significant coronaviruses of farm animals include porcine coronavirus (transmissible gastroenteritis coronavirus, TGE) and bovine coronavirus, which both result in diarrhea in young animals. Feline Coronavirus: 2 forms, Feline enteric coronavirus is a pathogen of minor clinical significance, but spontaneous mutation of this virus can result in feline infectious peritonitis (FIP), a disease associated with high mortality. There are two types of canine coronavirus (CCoV), one that causes mild gastrointestinal disease and one that has been found to cause respiratory disease. Mouse hepatitis virus (MHV) is a coronavirus that causes an epidemic murine illness with high mortality, especially among colonies of laboratory mice. Prior to the discovery of SARS-CoV, MHV had been the best-studied coronavirus both in vivo and in vitro as well as at the molecular level. Some strains of MHV cause a progressive demyelinating encephalitis in mice which has been used as a murine model for multiple sclerosis. Significant research efforts have been focused on elucidating the viral pathogenesis of these animal coronaviruses, especially by virologists interested in veterinary and zoonotic diseases.

    SARS-Coronavirus

    [0286] SARS is most closely related to group 2 coronaviruses, but it does not segregate into any of the other three groups of coronaviruses. SARS was determined to be an early split off from the group 2 coronaviruses based on a set of conserved domains that it shares with group 2. A main difference between group 2 coronovirus and SARS is the nsp3 replicase subunit encoded by ORF1a. SARS does not have a papain-like proteinase 1.

    Arenaviridae: Glycoprotein G2 is a Type I Fusion

    [0287] Arenavirus is a genus of virus that infects rodents and occasionally humans. At least eight Arenaviruses are known to cause human disease. The diseases derived from Arenaviruses range in severity. Aseptic meningitis, a severe human disease that causes inflammation covering the brain and spinal cord, can arise from the Lymphocytic choriomeningitis virus (LCMV) infection. Hemorrhagic fever syndromes are derived from infections such Guanarito virus (GTOV), Junin virus (JUNV), Lassa virus (LASV) causing Lassa fever, Machupo virus (MACV), Sabia virus (SABV), or Whitewater Arroyo virus (WWAV)..sup.[1] Arenaviruses are divided into two groups; the Old World or New World. The differences between these groups are distinguished geographically and genetically. Because of the epidemiological association with rodents, some arenaviruses and bunyaviruses are designated as Roboviruses. [0288] LCMV-Lassa virus (Old World) complex: [0289] Ippy virus [0290] Lassa virus [0291] Lujo virus [0292] Lymphocytic choriomeningitis virus

    [0293] LCMV infection manifests itself in a wide range of clinical symptoms, and may even be asymptomatic for immunocompetent individuals. Onset typically occurs between one or two weeks after exposure to the virus and is followed by a biphasic febrile illness. During the initial or prodromal phase, which may last up to a week, common symptoms include fever, lack of appetite, headache, muscle aches, malaise, nausea, and/or vomiting. Less frequent symptoms include a sore throat and cough, as well as joint, chest, and parotid pain. The onset of the second phase occurs several days after recovery, and consists of symptoms of meningitis or encephalitis. Pathological findings during the first stage consist of leukopenia and thrombocytopenia. During the second phase, typical findings include elevated protein levels, increased leukocyte count, or a decrease in glucose levels of the cerebrospinal fluid).

    Congenital Infection

    [0294] Lymphocytic choriomeningitis is a particular concern in obstetrics, as vertical transmission is known to occur. For immunocompetent mothers, there is no significant threat, but the virus has damaging effects upon the fetus. If infection occurs during the first trimester, LCMV results in an increased risk of spontaneous abortion. Later congenital infection may lead to malformations such as chorioretinitis, intracranial calcifications, hydrocephalus, microcephaly or macrocephaly, mental retardation, and seizures. Other findings include chorioretinal scars, optic atrophy, and cataracts. Mortality among infants is approximately 30%. Among the survivors, two thirds have lasting neurologic abnormalities. If a woman has come into contact with a rodent during pregnancy and LCM symptoms are manifested, a blood test is available to determine previous or current infection. A history of infection does not pose a risk for future pregnancies.

    Human-to-Human Transmission Through Organ Donation

    [0295] In May 2005, four solid-organ transplant recipients contracted an illness that was later diagnosed as lymphocytic choriomeningitis. All received organs from a common donor, and within a month of transplantation, three of the four recipients had died as a result of the viral infection. Epidemiologic investigation traced the source to a pet hamster that the organ donor had recently purchased from a Rhode Island pet store. A similar case occurred in Massachusetts in 2008. Currently, there is not a LCMV infection test that is approved by the Food and Drug Administration for organ donor screening. The Morbidity and Mortality Weekly Report advises health-care providers to consider LCMV infection in patients with aseptic meningitis and encephalitis and in organ transplant recipients with unexplained fever, hepatitis, or multisystem organ failure.

    Hepadnaviridae: Fusion Mechanism Neither Type I nor Type II

    [0296] Hepadnaviruses are a family of viruses which can cause liver infections in humans and animals. There are two recognized genera

    [0297] Hepadnaviruses have very small genomes of partially double-stranded, partially single stranded circular DNA. The genome consists of two uneven strands of DNA. One has a negative-sense orientation, and the other, shorter, strand has a positive-sense orientation.

    [0298] As it is a group 7 virus, replication involves an RNA intermediate. Three main open reading frames are encoded (ORFs) and the virus has four known genes which encode the core protein, the virus polymerase, surface antigens (preS1, preS2, and S) and the X protein. The X protein is thought to be non-structural; however, its function and significance are poorly understood.

    Rhabdoviridae Fusion Mechanism Neither Type I nor Type II

    [0299] Rhabdoviruses carry their genetic material in the form of negative-sense single-stranded RNA. They typically carry genes for five proteins: large protein (L), glycoprotein (G), nucleoprotein (N), phosphoprotein (P), and matrix protein (M). Rhabdoviruses that infect vertebrates are bullet-shaped. The prototypical and best studied rhabdovirus is vesicular stomatitis virus.

    [0300] Rhabdoviruses are important pathogens of animals and plants. Rhabdoviruses include RaV (Rabies virus), VSV (Vesicular stomatitis virus). Rhabdoviruses are transmitted to hosts by arthropods, such as aphids, planthoppers, leafhoppers, black flies, sandflies, and mosquitoes.

    [0301] The content of the XML file of the sequence listing named Sequence-Listing-ST26-12397-0504.xml, having a size of 355 kb and a creation date of 8 Jan. 2024, and electronically submitted via Patent Center on 8 Jan. 2024, is incorporated herein by reference in its entirety.

    ADDITIONAL REFERENCES

    [0302] 1. Sapir, A., et al., Viral and developmental cell fusion mechanisms: conservation and divergence. Dev Cell, 2008. 14(1): p. 11-21. [0303] 2. Cianciolo, G.J., et al., Murine malignant cells synthesize a 19,000-dalton protein that is physicochemically and antigenically related to the immunosuppressive retroviral protein, P15E. J Exp Med, 1983. 158(3): p. 885-900. [0304] 3. Hebebrand, L.C., et al., Inhibition of human lymphocyte mitogen and antigen response by a 15,000-dalton protein from feline leukemia virus. Cancer Res, 1979. 39(2 Pt 1): p. 443-7. [0305] 4. Cianciolo, G.J., et al., Macrophage accumulation in mice is inhibited by low molecular weight products from murine leukemia viruses. J Immunol, 1980. 124(6): p. 2900-5. [0306] 5. Mangeney, M. and T. Heidmann, Tumor cells expressing a retroviral envelope escape immune rejection in vivo. Proc Natl Acad Sci USA, 1998. 95(25): p. 14920-5. [0307] 6. Mangeney, M., et al., Placental syncytins: Genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins. Proc Natl Acad Sci USA, 2007. 104(51): p. 20534-9. [0308] 7. Cianciolo, G.J., et al., Inhibition of lymphocyte proliferation by a synthetic peptide homologous to retroviral envelope proteins. Science, 1985. 230(4724): p. 453-5. [0309] 8. Cianciolo, G.J., H. Bogerd, and R. Snyderman, Human retrovirus-related synthetic peptides inhibit T lymphocyte proliferation. Immunol Lett, 1988. 19(1): p. 7-13. [0310] 9. Yaddanapudi, K., et al., Implication of a retrovirus-like glycoprotein peptide in the immunopathogenesis of Ebola and Marburg viruses. Faseb J, 2006. 20(14): p. 2519-30. [0311] 10. Haraguchi, S., et al. Differential modulation of Th1-and Th2-related cytokine mRNA expression by a synthetic peptide homologous to a conserved domain within retroviral envelope protein. Proc Natl Acad Sci USA, 1995. 92, 3611-15. [0312] 11. Harrell, R.A., et al Cianciolo. Suppression of the respiratoryburst of human monocytes by a synthetic peptide homologous to envelope proteins of human and animal retroviruses. J Immunol, 1986. 136, 3517-520. [0313] 12. Kleinerman, E.S., et al. Lachman. A synthetic peptide homologous to the envelope proteins of retroviruses inhibits monocyte-mediated killing by inactivating interleukin 1. J Immunol, 1987. 139, 2329-337. [0314] 13. Schlecht-Louf G,. et al. Retro viral infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses. Proc Natl Acad Sci USA. 2010 Feb. 23; 107(8):3782-7. [0315] 14. Volchkov VE et al. The envelope glycoprotein of Ebola virus contains an 25 immunosuppressive-like domain similar to oncogenic retroviruses. FEBS Lett. 1992 Jul. 6; 305(3):181-4. [0316] 15. Cross KJ, Wharton SA, Skehel JJ, Wiley DC, Steinhauer DA. Studies on influenza haemagglutinin fusion peptide mutants generated by reverse genetics. EMBO J. 2001 Aug. 15; 20(16):4432-42.