Novel variant of tickborne encephalitis virus, Russia.We isolated a novel strain of tickborne encephalitis encephalitis (ĕnsĕf'əlī`təs), general term used to describe a diffuse inflammation of the brain and spinal cord, usually of viral origin, often transmitted by mosquitoes, in contrast to a bacterial infection of the meninges virus (TBEV TBEV Tick-Borne Encephalitis Virus ), Glubinnoe/2004, from a patient with a fatal case in Russia. We sequenced the strain, whose landmark features included 57 amino acid amino acid (əmē`nō), any one of a class of simple organic compounds containing carbon, hydrogen, oxygen, nitrogen, and in certain cases sulfur. These compounds are the building blocks of proteins. substitutions and 5 modified cleavage sites. Phylogenetically phy·lo·ge·net·ic adj. 1. Of or relating to phylogeny or phylogenetics. 2. Relating to or based on evolutionary development or history: a phylogenetic classification of species. , Glubinnoe/2004 is a novel variant that belongs to the Eastern type of TBEV. ********** Tickborne encephalitis virus (TBEV) was originally isolated in the Far Eastern region of Russia in 1937 (1). TBEV is defined as a species within the Mammalian tickborne virus group (genus Flavivirus, family Flaviviridae) (2). The TBEV species includes 3 subtypes, Far Eastern (previously RSSE RSSE Reduced-State Sequence Estimation ), Siberian (previously West-Siberian), and Western European (previously Central European encephalitis [CEE cee n. The letter c. ]) viruses. Recently, taxonomic improvements were proposed, and TBEV were divided into 4 types: Western, Eastern, Turkish sheep, and Louping ill louping ill an acute encephalomyelitis affecting mostly sheep and red grouse (Lagopus scoticus), but occasionally other domestic animals and humans, caused by a flavivirus and transmitted by Ixodes ricinus. (3). TBEV has been found in nearly 30 countries in Europe and Asia (4), and [approximately equal to] 700 million persons live in areas (excluding the People's Republic People's Republic n. A political organization founded and controlled by a national Communist party. of China) where TBEV infection is endemic. The annual incidence of TBEV infection is estimated to be as many as 14,000 cases (5). Eleven thousand TBE cases occur annually in Russia, but only [approximately equal to] 150 cases are registered in Primorsky District Primorsky District may refer to:
RNA in full ribonucleic acid One of the two main types of nucleic acid (the other being DNA), which functions in cellular protein synthesis in all living cells and replaces DNA as the carrier of genetic of [approximately equal to] 11,000 nt that encodes 3 structural and 7 nonstructural proteins (9). The differences in nucleotide sequences encoding protein E between subtypes of TBEV may reach 18%-19%; amino acid sequences are considerably more conserved (10). In 2004, a total of 76 confirmed TBE cases occurred in the spring-summer season in Primorsky District; 10 were fatal. We describe 1 case caused by a novel variant of TBEV. The Patient A 15-year-old boy received 2 tick bites near the village of Glubinnoe, in the northern part of Primorsky District, on May 30 and June 1, 2004, respectively. He had not had any vaccinations against TBEV infection. The first prodromal prodromal the stage of premonitory signs presaging the onset of disease or of specific clinical signs such as seizures. symptoms developed on June 8. A high fever with strong headache and paresis paresis /pa·re·sis/ (pah-re´sis) slight or incomplete paralysis. general paresis paralytic dementia; a form of neurosyphilis in which chronic meningoencephalitis causes gradual loss of cortical of cervical muscles developed in the next 2 days. On June 11, the patient was transported by emergency airplane from a local hospital to the Regional Clinical Hospital No. 1 in Vladivostok, where high fever with pronounced meningeal me·nin·ge·al adj. Of, relating to, or affecting the meninges. meningeal pertaining to the meninges. meningeal hemorrhage symptoms and complete disorientation disorientation /dis·or·i·en·ta·tion/ (-or?e-en-ta´shun) the loss of proper bearings, or a state of mental confusion as to time, place, or identity. in place and time were observed. Coma and acute respiratory dysfunction due to paralysis of respiratory muscles developed the next day, and the patient was put on an automatic respirator respirator /res·pi·ra·tor/ (res´pi-ra?ter) ventilator (2). cuirass respirator see under ventilator. . He died of acute cardiovascular insufficiency and heart failure on June 17. Virus strain Glubinnoe/2004 was isolated from a brain sample from the patient by using pig kidney embryo (PKE PKE - public-key encryption ) cells. One hundred microliters homogenized ho·mog·e·nize v. ho·mog·e·nized, ho·mog·e·niz·ing, ho·mog·e·niz·es v.tr. 1. To make homogeneous. 2. a. To reduce to particles and disperse throughout a fluid. b. brain diluted 1:100 was applied onto PKE cells in minimal essential medium supplemented with 2% fetal calf serum. The cells were incubated at 37[degrees]C for 4 days, and cell culture supernatants were used for second passage on PKE cells. The virus for sequencing and immunologic experiments was purified from infected PKE cells on third passage by centrifugation Centrifugation A mechanical method of separating immiscible liquids or solids from liquids by the application of centrifugal force. This force can be very great, and separations which proceed slowly by gravity can be speeded up enormously in centrifugal on a sucrose gradient (11). The protocol of study was approved by the Institutional Review Board of the Institute of Epidemiology and Microbiology, Vladivostok. Handling of the infectious material was performed under Biosafety Level biosafety level Epidemiology A classification for the degree of caution required when working with specific groups of pathogens. See Maximum containment facility. 3-4 conditions. A panel of monoclonal antibodies This is a list of monoclonal antibodies, antibodies which are clones of a single parent cell. When used as medications, the generic names end in -mab (see "Nomenclature of monoclonal antibodies"). (MAbs) to TBEV was used for ELISA ELISA (e-li´sah) Enzyme-Linked Immuno-Sorbent Assay; any enzyme immunoassay using an enzyme-labeled immunoreactant and an immunosorbent. ELISA n. as described earlier (12). Viral RNA was extracted by using a RIBO-sorb kit (InterLabService Inc., Moscow, Russia); then RNA was transcribed to cDNA and amplified by PCR PCR polymerase chain reaction. PCR abbr. polymerase chain reaction Polymerase chain reaction (PCR) . The purified cDNA fragment was used for sequencing in a Beckman CEQ CEQ Council On Environmental Quality CEQ Course Experience Questionnaire (higher education) CEQ Centrale de l'Enseignement du Québec CEQ Cinema Equalizer 2000XL sequencer See MIDI sequencer. (music) sequencer - Any system for recording and/or playback of music via a programmable memory which stores music not as audio data, but as some representation of notes. (Beckman Coulter This article needs sources or references that appear in reliable, third-party publications. Alone, primary sources and sources affiliated with the subject of this article are not sufficient for an accurate encyclopedia article. , Inc., Fullerton, CA, USA). Fifty primers were designed on the basis of the TBEV sequence (GenBank DQ989336), allowing [approximately equal to] 150-bp overlap between adjacent PCR fragments. Each PCR fragment was independently amplified and sequenced 3x. Sequences were aligned with ClustalX (13). Molecular data were statistically processed by using the program MEGA (14). The program PHYLIP PHYLIP Phylogeny Inference Package (genetics software) version 3.57 (University of Washington, Seattle, WA, USA) or PUZZLE version 4.0.2 (University of Munich, Munich, Germany) was used for constructing a phylogenetic tree phylogenetic tree Diagram showing the evolutionary interrelations of a group of organisms that usually originated from a shared ancestral form. The ancestor is in the tree trunk; organisms that have arisen from it are placed at the ends of tree branches. . The nucleotide sequences of the viral isolates were compared with published complete polyprotein sequences of TBEV (Table 1). The complete coding sequence cod·ing sequence n. See exon. of Glubinnoe/2004 was 10,886 nt. We found profound differences in the nucleotide sequences between listed TBEV strains and the Glubinnoe/2004 strain. The identity with 2 typical Far Eastern strains, 205 and Sofjin-HO, was 95.2% and 94.9%, respectively (Table 1). The complete Glubinnoe/2004 nucleotide sequence was compared with other TBEV sequences available in GenBank. The conservation of the strain's nucleotide sequences ranged from 82.7% to 95.2%, whereas amino acid sequences' conservation ranged from 91.0% to 98.4%, depending on the type of TBEV (Table 1). To further delineate the genetic variation, we analyzed polyprotein sequences of 37 other flaviviruses in comparison with Glubinnoe/2004 (Table 2). Fifty-three and 57 amino acid (aa) substitutions were found when Glubinnoe/2004 was compared to strains 205 and Sofjin-HO, respectively, and 14 of these were unique substitutions for all studied flaviviruses. Most substitutions were located in the C-terminal hydrophobic hydrophobic /hy·dro·pho·bic/ (-fo´bik) 1. pertaining to hydrophobia (rabies). 2. not readily absorbing water, or being adversely affected by water. 3. domain (CTHD CTHD Crouching Tiger Hidden Dragon (movie) ) of proteins C, NS3, and NS5. The CTHD had 5 substitutions in 20 aa fragment; NS3, 10 substitutions, and NS5,16 substitutions. We also found that 5 putative cleavage sites of polyprotein were modified; the changes were located in viral C/CTHD and anchored C/prM sites. No substitutions were found in well-known features of protein E, such as the 12 cysteine cysteine (sĭs`tēn), organic compound, one of the 20 amino acids commonly found in animal proteins. Only the l-stereoisomer participates in the biosynthesis of mammalian protein. residues, potential N-glycosylation sites, fusion peptide, and DEXH core motif of the NS3 helicase. A cysteine residue in position 4 of NS1 protein was replaced with a glycine glycine (glī`sēn), organic compound, one of the 20 amino acids commonly found in animal proteins. Glycine is the only one of these amino acids that is not optically active, i.e. ; this mutation was described previously only for Sofjin-HO (BAB72162). We also performed phylogenetic phy·lo·ge·net·ic adj. 1. Of or relating to phylogeny or phylogenetics. 2. Relating to or based on evolutionary development or history. analysis of the fully sequenced TBEV strains and Glubinnoe/2004 (Figure 1) and analyzed 100 different protein E gene sequences available in GenBank (data not shown). Both phylogenetic trees clearly demonstrated that Glubinnoe/2004 belonged to the Eastern type and formed a separate clade clade Cladus, subtype Genetics A branch of biological taxa or species that share features inherited from a common ancestor; a single phylogenetic group or line. See Inheritance, Species. (branch or group) within the type. The time of divergence of Glubinnoe/2004 from the Oshima-Sofjin and Senzhang groups was calculated by using the average substitution rate analysis (15). We estimate that Glubinnoe/2004 and Senzhang group diverged 300-470 years ago and Glubinnoe/2004 and Oshima-Sofjin group, 320-490 years ago. Our findings suggest that parallel evolution of different genetic groups of TBEV occurred in the relatively small Far Eastern region of Russia. The growth curves for Glubinnoe/2004 and 205 viruses in PKE cells at 37[degrees]C are shown in Figure 2. The virus yield rapidly increased 9-18 h after infection and then stabilized. The maximum difference in virus yields (in 50% tissue culture infective doses [[TCID TCID tissue culture infective dose; that amount of a pathogenic agent that will produce pathological change when inoculated on tissue cultures. .sub.50]/mL) between Glubinnoe/2004 and 205 viruses was 2.1 [TCID.sub.50]/mL at 12 h postinfection and nearly 10x from 15 to 36 h. By 72 h postinfection, PKE cells infected by Glubinnoe/2004 and 205 were completely lysed. We also evaluated the replication of viruses by directly measuring viral E protein levels by using 2 MAbs. E protein level rapidly increased 15-24 h postinfection and was similar for both strains. This finding correlated with a production rate of infectious virions with delay close to 6 h, which demonstrates that the Glubinnoe/2004 strain may produce more infectious virions in the early stage of infection of a PKE cell. The discovered mutations in 4 of 5 cleavage sites in viral polyprotein are required for cleavage of structural viral proteins. This finding may explain the more robust formation of infectious virions in the early stages of infection. Serologic se·rol·o·gy n. pl. se·rol·o·gies 1. The science that deals with the properties and reactions of serums, especially blood serum. 2. data demonstrate that strain Glubinnoe/2004 has epitopes well recognized by 14 anti-TBEV MAbs (data not shown). Based on these data, we concluded that all protein E epitopes of strain 205 virus are also present on Glubinnoe/2004 virions and are not affected by 4 aa substitutions found in protein E. This would suggest that modern vaccines against TBE and diagnostic immunologic kits will be effective against this novel variant. Conclusions We have genetically characterized TBEV isolate Glubinnoe/2004 by determining its complete coding nucleotide sequence and comparing it with most of the available TBEV sequences. We found 53 and 57 aa substitutions in comparison with strains 205 and Sofjin-HO, respectively, and 14 of these were unique for 37 flaviviruses. Most substitutions were located in the CTHD of proteins C, NS3, and NS5. Phylogenetic analysis showed that Glubinnoe/2004 appears to be a separate lineage within the Eastern type of TBEV. We estimate that strain Glubinnoe/2004 diverged from Eastern TBEV in Senzhang group [approximately equal to] 300-470 years ago and from viruses in the Oshima-Sofjin group [approximately equal to] 320-490 years ago. Five putative cleavage sites of the viral polyprotein were changed, including 4 sites responsible for processing of structural proteins. Strain Glubinnoe/2004 replicated more effectively in PKE cells than did strain 205. These data suggest that Glubinnoe/2004 could be used for production of vaccines, instead of strains 205 and Sofjin, and for development of diagnostic kits. This conclusion is supported by immunologic data with anti-TBEV MAbs, which demonstrated that viral glycoprotein glycoprotein (glī'kōprō`tēn), organic compound composed of both a protein and a carbohydrate joined together in covalent chemical linkage. E has a conserved antigenic structure typical of the Eastern type of TBEV. [FIGURE 1 OMITTED] [FIGURE 2 OMITTED] Acknowledgments We thank the medical personnel of the Neurology and Pathology Divisions of the Regional Clinical Hospital No. 1, Vladivostok, for collaboration in studying the tickborne encephalitis cases, and Tatyana Bondarenko for technical assistance in our experiments. References (1.) Pogodina VV. Expedition's book of M.P. Chumakov. In: Drozdov S, Nuvakhov B, Pogodina V, editors. Reminiscences on Michail Petrovich Chumakov [in Russian]. Moscow: Nauka; 1999. p. 20-23. (2.) Heinz FX, Collett MS, Purcell RH, Gould EA, Howard CR, Houghton M, et al. 2000. Family Flaviviridae. In: van Regenmortel MHV MHV mouse hepatitis virus. , Fauquet CM, Bishop DHL DHL abbr. 1. Doctor of Hebrew Letters 2. Doctor of Hebrew Literature , Carstens E, Estes MK, Lemon S, Maniloff J, et al., editors. Virus taxonomy: classification and nomenclature of viruses. Seventh report of the International Committee on Taxonomy of Viruses The International Committee on Taxonomy of Viruses (ICTV) is a committee which authorizes and organizes the taxonomic classification of viruses. They have developed a universal taxonomic scheme for viruses and aim to describe all the viruses of living organisms. . San Diego San Diego (săn dēā`gō), city (1990 pop. 1,110,549), seat of San Diego co., S Calif., on San Diego Bay; inc. 1850. San Diego includes the unincorporated communities of La Jolla and Spring Valley. Coronado is across the bay. (CA): Academic Press; 2000. p. 859-78. (3.) Grard G, Moureau G, Charrel RN, Lemasson JJ, Gonzalez JP, Gallian P, et al. Genetic characterization of tickborne ftaviviruses: new insights into evolution, pathogenetic determinants and taxonomy. Virology virology, study of viruses and their role in disease. Many viruses, such as animal RNA viruses and viruses that infect bacteria, or bacteriophages, have become useful laboratory tools in genetic studies and in work on the cellular metabolic control of gene expression . 2007;361:80-92. (4.) Suss J. Epidemiology and ecology of TBE relevant to the production of effective vaccines. Vaccine. 2003;21(Suppl):S19-35. (5.) Gritsun TS, Lashkevich VA, Gould EA. Tickborne encephalitis. Antiviral antiviral /an·ti·vi·ral/ (-vi´ral) destroying viruses or suppressing their replication, or an agent that so acts. an·ti·vi·ral adj. Res. 2003;57:129-46. (6.) Leonova GN, Pavlenko EV, Krylova NV. Prophylactic of the tickborne encephalitis with vaccines [in Russian]. Vladivostok: Dal'nauka; 2006. (7.) Leonova GN. Tickborne encephalitis in Primorsky district [in Russian]. Vladivostok: Dal'nauka; 1997. (8.) Heinz FX, Kunz C. Tick-borne encephalitis and impact of vaccination. Arch Virol Suppl. 18 2004;18:201-5. (9.) Chambers TJ, Hahn CS, Galler R, Rice CM. Flavivirus genome organization, expression, and replication. Annu Rev Microbiol. 1990;44:649-88. (10.) Ternovoi VA, Kurzhukov GP, Sokolov YV, Ivanov GY, Ivanisenko VA, Loktev AV, et al. Tickborne encephalitis with hemorrhagic Hemorrhagic A condition resulting in massive, difficult-to-control bleeding. Mentioned in: Hantavirus Infections hemorrhagic pertaining to or characterized by hemorrhage. syndrome, Novosibirsk Region, Russia, 1999. Emerg Infect Dis. 2003;9:743-6. (11.) Protopopova EV, Khusainova AD, Konovalova SN, Loktev VB. Preparation and study of properties of anti-idiotypic antibodies, carrying hemagglutinating paratopes of tickborne encephalitis virus on their surface [in Russian]. Vopr Virusol. 1996;41:50-3. (12.) Gaidamovich SI, Loktev VB, Lavrova NA, Maksutov AZ. Melnikova EE, Pereboev AV, et al. Monoclonal antibodies cross-reacting with the tickborne encephalitis virus and with the Venezuelan equine encephalomyelitis Venezuelan equine encephalomyelitis an encephalomyelitis with clinical signs similar to those of western and eastern encephalomyelitis; abbreviated VEE. See also equine viral encephalomyelitis. virus [in Russian]. Vopr Virusol. 1990:35:221-5. (13.) Higgins D, Bleasby A, Fuchs R. CLUSTAL V: improved software for multiple sequence aligmnent. CABIOS CABIOS Computer Applications in the Biosciences (journal) . 1991:8:189-91. (14.) Kumar S, Tamura K, Nei M. MEGA: Molecular Evolution Genetic Analysis version 1.0. University Park (PA): Pennsylvania State University Pennsylvania State University, main campus at University Park, State College; land-grant and state supported; coeducational; chartered 1855, opened 1859 as Farmers' High School. ; 1993. (15.) Li WH, Tanimura M, Sharp PM. Rates and dates of divergence between AIDS virus AIDS virus n. See HIV. nucleotide sequences. Mol Biol Evol. 1988;5: 313-30. Vladimir A. Ternovoi, * Elena V. Protopopova, * Eugene V. Chausov, * Dmitry V. Novikov, ([dagger]) Galina N. Leonova, ([double dagger]) Sergey V. Netesov, * and Valery B. Loktev * * State Research Center of Virology and Biotechnology "VECTOR," Koltsovo, Novosibirsk Region, Russia; ([dagger]) Regional Clinical Hospital No. 1, Vladivostok, Russia; and ([double dagger]) Institute of Epidemiology and Microbiology, Vladivostok, Russia Address for correspondence: Valery B. Loktev, State Research Center of Virology and Biotechnology "VECTOR," Koltsovo, Novosibirsk Oblast Koltsovo was founded in 1979 as a settlement near Novosibirsk for employees of the State Research Center of Virology and Biotechnology VECTOR. In 2003, Koltsovo was granted a new status of a naukograd, or scientific city. The population of Koltsovo is 10,700. , 630559, Russia; email: loktev@vector.nsc.ru Dr Ternovoi is head of the Section for Molecular Diagnostic, Department Molecular Virology for Flaviviruses and Viral Hepatitis viral hepatitis n. Any of various forms of hepatitis caused by a virus. viral hepatitis, n an inflammatory condition of the liver, caused by the hepatitis viruses: A, B, C, delta, E, F, G, or H. , State Research Center of Virology and Biotechnology "VECTOR," Koltsovo, Russia. His current research interests are associated with genetic diagnosis of viral infection viral infection, n an infection by a pathogenic virus. A virus acts on the cell nucleus, taking over the genetic material within the nucleus and replicating itself. , mechanisms of gene expression, and the role of viral polypeptides in the development of immune response immune response n. An integrated bodily response to an antigen, especially one mediated by lymphocytes and involving recognition of antigens by specific antibodies or previously sensitized lymphocytes. for the prevention of viral infection.
Table 1. Tickborne encephalitis virus (TBEV) strains used in
the study and comparison of identify for full-length polyprotein
sequences with strains Glubinnoe/2004 of TBEV *
Virus, subtype, strain Place of origin
TBEV, Eastern type
Glubinnoe/2004 Glubinnoe, Primorsky district, Russia
205 Khabarovsk district, Russia
Sofjin-HO Khabarovsk district, Russia
Oshima 5-10 Oshima, Japan
Senzhang China
MDJ-01 China
Vasilchenko Novosibirsk, Russia
Zausaev Tomsk, Russia
EK-328 Estonia
TBEV, Western type
Neudoerfl Neudoerfl, Austria
263 Temelin, Czech Republic
Hypr Brno, Czech Republic
TBEV, Turkish sheep type
Turkish sheep encephalitis Turkey
TBEV, Louping ill type
Louping ill, strain 369/T2 Selkirkshire, Scotland
Spanish sheep encephalitis Spain
Glubinnoe/2004
% Identity % Identity
Yearof of nt of aa
Virus, subtype, strain isolation sequence sequence
TBEV, Eastern type
Glubinnoe/2004 2004 100.0 100.0
205 1973 95.2 98.4
Sofjin-HO 1937 94.9 98.3
Oshima 5-10 1995 94.7 98.2
Senzhang 1953 94.8 98.4
MDJ-01 2003 94.6 98.0
([double
dagger])
Vasilchenko 1969 85.9 94.9
Zausaev 1985 85.9 94.9
([double
dagger])
EK-328 1972 85.7 94.9
TBEV, Western type
Neudoerfl 1971 84.3 93.4
263 1987 84.5 93.3
Hypr 1953 84.1 93.0
TBEV, Turkish sheep type
Turkish sheep encephalitis 1969 82.9 91.0
TBEV, Louping ill type
Louping ill, strain 369/T2 1929 83.2 91.0
Spanish sheep encephalitis 1987 82.7 91.0
* TBEV type classification described previously (3).
nt, nucleotide; aa, amino acid.
([dagger]) Time of submission of the sequence to GenBank.
([double dagger]) Virus was isolated from a patient with
chronic form of TBEV infection, a patient was infected in
1973 in Tomsk; the virus was isolated in Moscow in 1985
from brain.
Table 2. Individual amino acid substitutions of Glubinnoe/2004 and
205/Sofjin-HO viruses and unique substitutions in comparison with
37 flaviviruses, determined by polyprotein alignment * ([dagger])
Amino acid substitutions Glubinnoe/2004 205
or Sofjin-HO
Gene 205
Viral C No
CTHD [A.sub.99] ([double dagger]) V; [I.sub.108] V;
[M.sub.111] [right arrow] I; [M.sub.113]
([double dagger]) [right arrow] V; [F.sub.115]
([double dagger]) [right arrow] L
prM No
M [R.sub.210] ([double dagger]) [right arrow] P
E [K.sub.508] [right arrow] R; [I.sub.597] [right arrow] T;
[T.sub.646] [right arrow] N; [V.sub.743] A
NS1 [G.sub.780] ([double dagger]) [right arrow] C; [K.sub.883]
[right arrow] R, [S.sub.951] [right arrow] P; [I.sub.1053]
[right arrow] T
NS2A [R.sub.1180] [right arrow] K; [R.sub.1227] [right arrow] S;
[G.sub.1250] [right arrow] S; [G.sub.1277] [right arrow] E;
[C.sub.1311] [right arrow] Y
NS2B [V.sub.1423] [right arrow] M
NS3 [E.sub.1563] [right arrow] D; [G.sub.1650] [right arrow] E;
[I.sub.1673] [right arrow] S; [I.sub.1707] [right arrow] T;
[T.sub.1828] [right arrow] S; [A.sub.1861] [right arrow] V;
[P.sub.1948] [right arrow] Q; [V.sub.1975] [right arrow] G;
[D.sub.1988] [right arrow] N; [A.sub.2062] [right arrow] T
NS4A [D.sub.2143] [right arrow] E; [V.sub.2165] [right arrow] A
NS4B [M.sub.2283] [right arrow] L; [I.sub.2314] [right arrow] M;
[A.sub.2331] [right arrow] V; [V.sub.2349] [right arrow] I;
[A.sub.2472] [right arrow] V
NS5 [K.sub.2625] [right arrow] R; [A.sub.2757] [right arrow] G;
[G.sub.2758] [right arrow] D; [E.sub.3013] [right arrow] G;
[S.sub.3014] [right arrow] F; [G.sub.3033] [right arrow] E;
[K.sub.3074] [right arrow] R, [V.sub.3080] [right arrow] I;
[S.sub.3187] [right arrow] G; P3251 [right arrow] R;
[V.sub.3260] [right arrow] I; [K.sub.3297] [right arrow] V;
[V.sub.3342] [right arrow] I; [K.sub.3389] [right arrow] E;
[Y.sub.3402] [right arrow] D; [N.sub.3406] [right arrow] E
Total
Amino acid substitutions Glubinnoe/2004 205
or Sofjin-HO
Gene Sofjin-HO
Viral C [M.sub.43] [right arrow] L; [A.sub.54] [right arrow] V;
[N.sub.64] [right arrow] K
CTHD [A.sub.99] ([double dagger]) [right arrow] V; [I.sub.108]
[right arrow] V; [M.sub.111] [right arrow] L; [M.sub.113]
([double dagger]) [right arrow] V; [F.sub.115] ([double
dagger]) [right arrow] L
prM No
M [R.sub.210] ([double dagger]) [right arrow] P; [I.sub.246]
[right arrow] M; [I.sub.266] [right arrow] V
E [A.sub.433] [right arrow] V; [T.sub.646] [right arrow] N;
[M.sub.740] [right arrow] V; [G.sub.759] [right arrow] S
NS1 [I.sub.1053] [right arrow] T, [V.sub.1122] [right arrow] I
NS2A [R.sub.1180] [right arrow] K; [R.sub.1227] [right arrow] S;
[G.sub.1250] [right arrow] S; [G.sub.1277] [right arrow] E;
[I.sub.1296] [right arrow] T; [A.sub.1297] [right arrow] V
NS2B [V.sub.1423] [right arrow] M
NS3 [D.sub.1491] ([double dagger]) [right arrow] G; [S.sub.1551]
[right arrow] Y; [E.sub.1563] [right arrow] D; [G.sub.1650]
[right arrow] E; [I.sub.1673] [right arrow] T; [N.sub.1731]
[right arrow] S; [T.sub.1828] [right arrow] S; [T.sub.1869]
[right arrow] A; [P.sub.1948] [right arrow] Q; [V.sub.1975]
[right arrow] G; [D.sub.1988] [right arrow] N; [A.sub.2062]
[right arrow] T
NS4A [D.sub.2143] [right arrow] E: [A.sub.2173] [right arrow] G
NS4B [M.sub.2283] [right arrow] V; [F.sub.2347] [right arrow] L;
[S.sub.2457] [right arrow] A
NS5 [K.sub.2526] [right arrow] R, [M.sub.2641] [right arrow] V;
[A.sub.2757] [right arrow] G; [G.sub.2758] [right arrow] D;
[E.sub.3013] [right arrow] G; [Y.sub.3030] [right arrow] H;
[V.sub.3080] [right arrow] I; [R.sub.3188] [right arrow] G;
[P.sub.3251] [right arrow] R; [I.sub.3297] [right arrow] V;
[V.sub.3342] [right arrow] I; [V.sub.3343] [right arrow] A;
[R.sub.3384] [right arrow] K; [K.sub.3389] [right arrow] E;
[Y.sub.3402] [right arrow] D; [N.sub.3406] [right arrow] E
Total
Summary of
Unique Changed putative substitutions
Gene substitutions cleavage sites 205/Sofjin-HO
Viral C No No 0/3
CTHD No Viral C/CTHD 5/5
(RGKRR/SAA ([dagger])
DW) anchored C/prM
(GM ([double dagger])
TF ([double dagger])
A/ATVRK)
prM No No 0/0
M [R.sub.210] * prM/M (SRTRR/SVLIR 1/3
([double dagger]))
E No No 4/4
NS1 No E/NS1 4/2
(LGVGA/DVGG
([double dagger]) A)
NS2A No No 5/6
NS2B No No 1/1
NS3 [E.sub.1563]; NS2B/NS3 10/12
[G.sub.1650]; (RTARR/SD
[P.sub.1948]; ([double dagger]) LVF)
[V.sub.1975];
[D.sub.1988]
NS4A [D.sub.2143] No 2/2
NS4B [M.sub.2283] No 5/3
NS5 [A.sub.2757]; No 16/16
[G.sub.2758];
[P.sub.3251];
[K.sub.3389];
[Y.sub.3402];
[N.sub.3406]
Total 14 5 53/57
* Position number corresponds to the polyprotein sequence
Glubinnoe/2004 of tickborne encephalitis virus (TBEV).
CTHID, C-terminal hydrophobic domain.
([dagger]) The following polyproten sequences were used for
polyprotein alignment: DQ862460 (TBEV, Glubinnoe/2004): ABJ74160
AAN73266 BAB71943 BAB72162 AF 069066 AAD34205 ABF46836 AAO43537
NP_043135 Neudoerfl AAZ80455 AAA86739 (TBEV, 263); Q01299 Hypr
ABB90676 BB90675 AAQ91606 Bogolubovka NP 878909 Bogoluvovska
AAR98531 Kubrin ABB90677 NP_044677 NP_620108 AAF75260E5 P29837
(AAQ91607 NP_722551 NP_620099 AAL32169 ABB90669 ABB90671
YP_224133 ABE73208 ABB90673 ABB90670 ABB90674 ABB90668 ABB90672
NP_689391).
([double dagger]) For substitution in cleavage sites.
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