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complete coding sequence of the alkhurma virus, a tick-borne flavivirus causing severe hemorrhagic fever in humans in saudi arabia.to date, tick-borne flaviviruses responsible for hemorrhagic fever in humans have been isolated in siberia (omsk hemorrhagic fever virus), india (kyasanur forest disease virus, kfdv), and in saudi arabia (alkhurma virus, alkv). prior to this study, only partial coding sequences of these severe pathogens had been determined. we report here the complete coding sequence of alk virus, which was determined to be 10,248 nucleotides (nt) long, and to encode a single 3,416 amino acid polyprotein. indepe ...200111554750
genetic analysis of viruses associated with emergence of rift valley fever in saudi arabia and yemen, 2000-01.the first confirmed rift valley fever outbreak outside africa was reported in september 2000, in the arabian peninsula. as of february 2001, a total of 884 hospitalized patients were identified in saudi arabia, with 124 deaths. in yemen, 1,087 cases were estimated to have occurred, with 121 deaths. laboratory diagnosis of rift valley fever virus (rvfv) infections included virus genetic detection and characterization of clinical specimens by reverse transcription-polymerase chain reaction, in add ...200212498657
tick-borne encephalitis.tick-borne encephalitis (tbe) is one of the most dangerous human infections occurring in europe and many parts of asia. the etiological agent tick-borne encephalitis virus (tbev), is a member of the virus genus flavivirus, of the family flaviviridae. tbev is believed to cause at least 11,000 human cases of encephalitis in russia and about 3000 cases in the rest of europe annually. related viruses within the same group, louping ill virus (liv), langat virus (lgtv) and powassan virus (powv), also ...200312615309
tick-borne encephalitis with hemorrhagic syndrome, novosibirsk region, russia, 1999.eight fatal cases of tick-borne encephalitis with an unusual hemorrhagic syndrome were identified in 1999 in the novosibirsk region, russia. to study these strains, we sequenced cdna fragments of protein e gene from six archival formalin-fixed brain samples. phylogenetic analysis showed tick-borne encephalitis variants clustered with a far eastern subtype (homology 94.7%) but not with the siberian subtype (82%).200312781020
[the alkhurma virus (family flaviviridae, genus flavivirus): an emerging pathogen responsible for hemorrhage fever in the middle east].to date tick-borne flaviviruses causing hemorrhagic fevers in humans have been isolated in siberia (omsk hemorrhagic fever virus), india (kyasanur forest disease virus), and saudi arabia (akhurma virus). because of their potential use as biological weapons for bioterrorism, these 3 viruses require level 4 biosafety handling facilities and have been listed as hypervirulent pathogens by the center for disease control and prevention. alkhurma virus was isolated in 1995 from patients with hemorrhagi ...200314579470
crimean-congo hemorrhagic fever in turkey.in 2002 and 2003, a total of 19 persons in turkey had suspected cases of crimean-congo hemorrhagic fever (cchf) or a similar viral infection. six serum samples were tested; all six were found positive for immunoglobulin m antibodies against cchf virus. two of the samples yielded cchf virus isolates. genetic analysis of the virus isolates showed them to be closely related to isolates from former yugoslavia and southwestern russia. these cases are the first of cchf reported from turkey. eighteen p ...200415496237
identification and enzymatic characterization of ns2b-ns3 protease of alkhurma virus, a class-4 flavivirus.alkhurma virus (alkv) is a recently discovered class-4 flavivirus that was responsible for several cases of severe haemorrhagic fever in humans in saudi arabia. it has been shown for other flaviviruses that processing of the viral polyprotein is partly due to the virus-encoded ns2b/ns3 trypsin-like serine protease. as the viral proteinase plays a critical role in the virus replication cycle, it represents one of the main targets for antiviral therapy against members of the flavivirus genus. we r ...200515567034
low diversity of alkhurma hemorrhagic fever virus, saudi arabia, 1994-1999.alkhurma hemorrhagic fever virus (genus flavivirus, ahfv) was recently identified as the agent of a viral hemorrhagic fever in saudi arabia and characterized serologically and genetically as a variant genotype of kyasanur forest disease virus (kfdv). since viral diagnosis and vaccine development may be hindered by genetic diversity, this study was intended to address ahfv genetic heterogeneity. eleven strains isolated from hospitalized patients from 1994 to 1999 in saudi arabia were sequenced in ...200515890119
alkhurma hemorrhagic fever virus is an emerging tick-borne flavivirus. 200616216331
the modeled structure of the rna dependent rna polymerase of gbv-c virus suggests a role for motif e in flaviviridae rna polymerases.the flaviviridae virus family includes major human and animal pathogens. the rna dependent rna polymerase (rdrp) plays a central role in the replication process, and thus is a validated target for antiviral drugs. despite the increasing structural and enzymatic characterization of viral rdrps, detailed molecular replication mechanisms remain unclear. the hepatitis c virus (hcv) is a major human pathogen difficult to study in cultured cells. the bovine viral diarrhea virus (bvdv) is often used as ...200516225688
cleavage targets and the d-arginine-based inhibitors of the west nile virus ns3 processing proteinase.mosquito-borne wnv (west nile virus) is an emerging global threat. the ns3 proteinase, which is essential for the proteolytic processing of the viral polyprotein precursor, is a promising drug target. we have isolated and biochemically characterized the recombinant, highly active ns3 proteinase. we have determined that the ns3 proteinase functions in a manner that is distantly similar to furin in cleaving the peptide and protein substrates. we determined that aprotinin and d-arginine-based 9-12- ...200616229682
potential arbovirus emergence and implications for the united kingdom.arboviruses have evolved a number of strategies to survive environmental challenges. this review examines the factors that may determine arbovirus emergence, provides examples of arboviruses that have emerged into new habitats, reviews the arbovirus situation in western europe in detail, discusses potential arthropod vectors, and attempts to predict the risk for arbovirus emergence in the united kingdom. we conclude that climate change is probably the most important requirement for the emergence ...200616704800
kyasanur forest disease: an epidemiological view in india.kyasanur forest disease (kfd) was first recognised as a febrile illness in the shimoga district of karnataka state of india. the causative agent, kfd virus (kfdv), is a highly pathogenic member in the family flaviviridae, producing a haemorrhagic disease in infected human beings. kfd is a zoonotic disease and has so far been localised only in a southern part of india. the exact cause of its emergence in the mid 1950s is not known. a variant of kfdv, characterised serologically and genetically as ...200616710839
recombination and selection in the evolution of picornaviruses and other mammalian positive-stranded rna viruses.picornaviridae are a large virus family causing widespread, often pathogenic infections in humans and other mammals. picornaviruses are genetically and antigenically highly diverse, with evidence for complex evolutionary histories in which recombination plays a major part. to investigate the nature of recombination and selection processes underlying the evolution of serotypes within different picornavirus genera, large-scale analysis of recombination frequencies and sites, segregation by serotyp ...200616956935
mutagenesis analysis of the ns2b determinants of the alkhurma virus ns2b-ns3 protease activation.alkhurma virus (alkv) is a tick-borne class 4 flavivirus responsible for several human cases of haemorrhagic fever in saudi arabia, with no specific treatment currently available. the viral rna encodes a serine protease (ns2b-ns3), essential for virus replication in infected cells, that constitutes an attractive target for antiviral compounds. in an attempt to identify residues and motifs on ns2b that are necessary for protease activity of the alkv ns2b-ns3 complex, a series of modified ns2b-ns3 ...200617030861
curation of viral genomes: challenges, applications and the way forward.whole genome sequence data is a step towards generating the 'parts list' of life to understand the underlying principles of biocomplexity. genome sequencing initiatives of human and model organisms are targeted efforts towards understanding principles of evolution with an application envisaged to improve human health. these efforts culminated in the development of dedicated resources. whereas a large number of viral genomes have been sequenced by groups or individuals with an interest to study a ...200617254296
alkhurma hemorrhagic fever virus in ornithodoros savignyi ticks.evidence for the tickborne nature of alkhurma hemorrhagic fever virus (ahfv) is indirect because ahfv has not been detected in arthropods. one ornithodoros savignyi tick from saudi arabia contained ahfv rna. this is the first direct evidence that ahfv is a tickborne flavivirus and confirms the association between human ahfv cases and tickbite history.200717370534
novel variant of tickborne encephalitis virus, russia.we isolated a novel strain of tickborne encephalitis virus (tbev), glubinnoe/2004, from a patient with a fatal case in russia. we sequenced the strain, whose landmark features included 57 amino acid substitutions and 5 modified cleavage sites. phylogenetically, glubinnoe/2004 is a novel variant that belongs to the eastern type of tbev.200718258012
emerging pathogens: challenges and successes of molecular diagnostics.more than 50 emerging and reemerging pathogens have been identified during the last 40 years. until 1992 when the institute of medicine issued a report that defined emerging infectious diseases, medicine had been complacent about such infectious diseases despite the alarm bells of infections with human immunodeficiency virus. molecular tools have proven useful in discovering and characterizing emerging viruses and bacteria such as sin nombre virus (hantaviral pulmonary syndrome), hepatitis c vir ...200818403608
tick-borne flaviviruses: dissecting host immune responses and virus countermeasures.the tick-borne encephalitis (tbe) serocomplex of viruses, genus flavivirus, includes a number of important human pathogens that cause serious neurological illnesses and hemorrhagic fevers. these viruses pose a significant public health problem due to high rates of morbidity and mortality, their emergence to new geographic areas, and the recent rise in the incidence of human infections. the most notable member of the tbe serocomplex is tick-borne encephalitis virus (tbev), a neurotropic flaviviru ...200918841330
isolation of kyasanur forest disease virus from febrile patient, yunnan, china.we recently determined that nanjianyin virus, isolated from serum of a patient in yunnan province, china, in 1989, is a type of kyasanur forest disease virus. results of a 1987-1990 seroepidemiologic investigation in yunnan province had shown that residents of the hengduan mountain region had been infected with nanjianyin virus.200919193286
isolation and characterization of selective and potent human fab inhibitors directed to the active-site region of the two-component ns2b-ns3 proteinase of west nile virus.there is a need to develop inhibitors of mosquito-borne flaviviruses, including wnv (west nile virus). in the present paper, we describe a novel and efficient recombinant-antibody technology that led us to the isolation of inhibitory high-affinity human antibodies to the active-site region of a viral proteinase. as a proof-of-principal, we have successfully used this technology and the synthetic naive human combinatorial antibody library hucal gold(r) to isolate selective and potent function-blo ...201020156198
emergence of zoonotic arboviruses by animal trade and migration.abstract: arboviruses are transmitted in nature exclusively or to a major extend by arthropods. they belong to the most important viruses invading new areas in the world and their occurrence is strongly influenced by climatic changes due to the life cycle of the transmitting vectors. several arboviruses have emerged in new regions of the world during the last years, like west nile virus (wnv) in the americas, usutu virus (usuv) in central europe, or rift valley fever virus (rvfv) in the arabian ...201020377873
use of monoclonal antibodies against hendra and nipah viruses in an antigen capture elisa.outbreaks of hendra (hev) and nipah (niv) viruses have been reported starting in 1994 and 1998, respectively. both viruses are capable of causing fatal disease in humans and effecting great economical loss in the livestock industry.201020525276
molecular epidemiology of powassan virus in north america.powassan virus (pow) is a tick-borne flavivirus distributed in canada, the northern usa and the primorsky region of russia. pow is the only tick-borne flavivirus endemic to the western hemisphere, where it is transmitted mainly between ixodes cookei and groundhogs (marmota monax). deer tick virus (dtv), a genotype of pow that has been frequently isolated from deer ticks (ixodes scapularis), appears to be maintained in an enzootic cycle between these ticks and white-footed mice (peromyscus leucop ...201020631087
structural and functional analyses of a conserved hydrophobic pocket of flavivirus methyltransferase.the flavivirus methyltransferase (mtase) sequentially methylates the n7 and 2'-o positions of the viral rna cap (gpppa-rna → m(7)gpppa-rna → m(7)gpppam-rna), using s-adenosyl-l-methionine (adomet) as a methyl donor. we report here that sinefungin (sin), an adomet analog, inhibits several flaviviruses through suppression of viral mtase. the crystal structure of west nile virus mtase in complex with sin inhibitor at 2.0-å resolution revealed a flavivirus-conserved hydrophobic pocket located next t ...201020685660
alkhumra (alkhurma) virus outbreak in najran, saudi arabia: epidemiological, clinical, and laboratory characteristics.after its first appearance in alkhumra district of jeddah in 1994-1995, and then in makkah in 2001-2003, the new hemorrhagic fever virus, known as alkhumra (misnamed as alkhurma) virus (alkv), has subsequently been reported from najran, in the south border of saudi arabia.201020920527
alkhurma hemorrhagic fever in humans, najran, saudi arabia.alkhurma virus is a flavivirus, discovered in 1994 in a person who died of hemorrhagic fever after slaughtering a sheep from the city of alkhurma, saudi arabia. since then, several cases of alkhurma hemorrhagic fever (alkhf), with fatality rates up to 25%, have been documented. from january 1, 2006, through april 1, 2009, active disease surveillance and serologic testing of household contacts identified alkhf in 28 persons in najran, saudi arabia. for epidemiologic comparison, serologic testing ...201021122217
alkhurma hemorrhagic fever in travelers returning from egypt, 2010.two travelers returning to italy from southern egypt were hospitalized with a fever of unknown origin. test results showed infection with alkhurma virus. the geographic distribution of this virus could be broader than previously thought.201021122237
computer-based comparison of structural features of envelope protein of alkhurma hemorrhagic fever virus with the homologous proteins of two closest viruses.the aim of this study was prediction of epitopes and medically important structural properties of protein e of alkhurma hemorrhagic fever virus (ahfv) and comparing these features with two closely relates viruses, i.e. kyasanur forest disease virus (kfdv) and tick-borne encephalitis virus (tbev) by bioinformatics tools. prediction of evolutionary distance, localization, sequence of signal peptides, c, n o glycosylation sites, transmembrane helices (tmhs), cysteine bond positions and b cell and t ...201121235484
kyasanur forest disease virus alkhurma subtype in ticks, najran province, saudi arabia.to the editor: the lineage of kyasanur forest disease virus (kfdv) found in the kingdom of saudi arabia is commonly referred to as alkhurma hemorrhagic fever virus (ahfv). this virus was first isolated from a specimen collected in 1994 from a butcher living in makkah province, who was hospitalized for a hemorrhagic fever from which he died (1). the virus was assigned to the genus flavivirus on the basis of reactivity with genus-specific monoclonal antibodies and sequencing of a fragment of the n ...201121529425
alkhurma hemorrhagic fever in travelers returning from egypt, 2010.to the editor: the report of 2 visitors from italy being infected by alkhurma hemorrhagic fever virus (ahfv) in southeastern egypt near the border with sudan (1) provides useful data to help clarify the evolutionary origin of these tick-borne flaviviruses. ahfv was first isolated in saudi arabia and is associated with camel ticks (2). it is a genetically close relative of kyasanur forest disease virus, which was first isolated in india in 1957. following the original isolation of kyasanur forest ...201121801660
Seroprevalence of alkhurma and other hemorrhagic Fever viruses, saudi arabia.A 2009 deployment of military units from several Saudi Arabian provinces to Jazan Province, Saudi Arabia, enabled us to evaluate exposure to Alkhurma, Crimean-Congo, dengue, and Rift Valley hemorrhagic fever viruses. Seroprevalence to all viruses was low; however, Alkhurma virus seroprevalence was higher (1.3%) and less geographically restricted than previously thought.201122172587
ancient ancestry of kfdv and ahfv revealed by complete genome analyses of viruses isolated from ticks and mammalian hosts.alkhurma hemorrhagic fever virus (ahfv) and kyasanur forest disease virus (kfdv) cause significant human disease and mortality in saudi arabia and india, respectively. despite their distinct geographic ranges, ahfv and kfdv share a remarkably high sequence identity. given its emergence decades after kfdv, ahfv has since been considered a variant of kfdv and thought to have arisen from an introduction of kfdv to saudi arabia from india. to gain a better understanding of the evolutionary history o ...201121991403
Successful propagation of Alkhumra (misnamed as Alkhurma) virus in C6/36 mosquito cells.Epidemiological data suggest that Alkhumra (misnamed as Alkhurma) virus (ALKV) is transmitted from livestock animals to humans by direct contact with animals or by the mosquito bites, but not by ticks. To assess the ability of the virus to replicate in mosquito cells, serum and plasma of seven acutely febrile patients with clinically suspected ALKV infection reported in Najran, Saudi Arabia in 2009 were inoculated onto Aedes albopictus mosquito cells (C6/36) and directly examined with ALKV-RNA-s ...201122154975
flavivirus ns3 and ns5 proteins interaction network: a high-throughput yeast two-hybrid screen.the genus flavivirus encompasses more than 50 distinct species of arthropod-borne viruses, including several major human pathogens, such as west nile virus, yellow fever virus, japanese encephalitis virus and the four serotypes of dengue viruses (denv type 1-4). each year, flaviviruses cause more than 100 million infections worldwide, some of which lead to life-threatening conditions such as encephalitis or haemorrhagic fever. among the viral proteins, ns3 and ns5 proteins constitute the major e ...201122014111
rhabdomyolysis and severe muscular weakness in a traveler diagnosed with alkhurma hemorrhagic fever virus infection.alkhurma hemorrhagic fever virus (ahfv) is a tick-borne flavivirus with high case fatality rates, endemic in the arabian peninsula. recently ahfv was detected in travelers returning from egypt suggesting geographical spreading. we also report ahfv infection in a traveler ex egypt, representing atypical symptoms of rhabdomyolysis and severe muscular weakness.201121889906
revisiting the clinal concept of evolution and dispersal for the tick-borne flaviviruses by using phylogenetic and biogeographic analyses.tick-borne flaviviruses (tbf) are widely dispersed across africa, europe, asia, oceania, and north america, and some present a significant threat to human health. seminal studies on tick-borne encephalitis viruses (tbev), based on partial envelope gene sequences, predicted a westward clinal pattern of evolution and dispersal across northern eurasia, terminating in the british isles. we tested this hypothesis using all available full-length open reading frame (orf) tbf sequences. phylogenetic ana ...201222674986
experimental transmission of karshi (mammalian tick-borne flavivirus group) virus by ornithodoros ticks >2,900 days after initial virus exposure supports the role of soft ticks as a long-term maintenance mechanism for certain flaviviruses.members of the mammalian tick-borne flavivirus group, including tick-borne encephalitis virus, are responsible for at least 10,000 clinical cases of tick-borne encephalitis each year. to attempt to explain the long-term maintenance of members of this group, we followed ornithodoros parkeri, o. sonrai, and o. tartakovskyi for >2,900 days after they had been exposed to karshi virus, a member of the mammalian tick-borne flavivirus group.201526285211
grp78/dna k is a target for nexavar/stivarga/votrient in the treatment of human malignancies, viral infections and bacterial diseases.prior tumor cell studies have shown that the drugs sorafenib (nexavar) and regorafenib (stivarga) reduce expression of the chaperone grp78. sorafenib/regorafenib and the multi-kinase inhibitor pazopanib (votrient) interacted with sildenafil (viagra) to further rapidly reduce grp78 levels in eukaryotes and as single agents to reduce dna k levels in prokaryotes. similar data were obtained in tumor cells in vitro and in drug-treated mice for: hsp70, mitochondrial hsp70, hsp60, hsp56, hsp40, hsp10, ...201525858032
consensus recommendation for india and bangladesh for the use of pneumococcal vaccine in mass gatherings with special reference to hajj pilgrims.respiratory tract infections are prevalent among hajj pilgrims with pneumonia being a leading cause of hospitalization. streptococcus pneumoniae is a common pathogen isolated from patients with pneumonia and respiratory tract infections during hajj. there is a significant burden of pneumococcal disease in india, which can be prevented. guidelines for preventive measures and adult immunization have been published in india, but the implementation of the guidelines is low. data from bangladesh are ...201627942192
syndromic approach to arboviral diagnostics for global travelers as a basis for infectious disease surveillance.arboviruses have overlapping geographical distributions and can cause symptoms that coincide with more common infections. therefore, arbovirus infections are often neglected by travel diagnostics. here, we assessed the potential of syndrome-based approaches for diagnosis and surveillance of neglected arboviral diseases in returning travelers.201526372010
evolution of mosquito-based arbovirus surveillance systems in australia.control of arboviral disease is dependent on the sensitive and timely detection of elevated virus activity or the identification of emergent or exotic viruses. the emergence of japanese encephalitis virus (jev) in northern australia revealed numerous problems with performing arbovirus surveillance in remote locations. a sentinel pig programme detected jev activity, although there were a number of financial, logistical, diagnostic and ethical limitations. a system was developed which detected vir ...201222505808
biological transmission of arboviruses: reexamination of and new insights into components, mechanisms, and unique traits as well as their evolutionary trends.among animal viruses, arboviruses are unique in that they depend on arthropod vectors for transmission. field research and laboratory investigations related to the three components of this unique mode of transmission, virus, vector, and vertebrate host, have produced an enormous amount of valuable information that may be found in numerous publications. however, despite many reviews on specific viruses, diseases, or interests, a systematic approach to organizing the available information on all f ...016223950
a three-dimensional comparison of tick-borne flavivirus infection in mammalian and tick cell lines.tick-borne flaviviruses (tbfv) are sustained in nature through cycling between mammalian and tick hosts. in this study, we used african green monkey kidney cells (vero) and ixodes scapularis tick cells (ise6) to compare virus-induced changes in mammalian and arthropod cells. using confocal microscopy, transmission electron microscopy (tem), and electron tomography (et), we examined viral protein distribution and the ultrastructural changes that occur during tbfv infection. within host cells, fla ...201223112871
susceptibility of tick cell lines to infection with alkhumra haemorrhagic fever virus.although alkhumra haemorrhagic fever virus (ahfv) has been isolated from ticks, epidemiological data suggest that it is transmitted from livestock to humans by direct contact with animals or by mosquito bites, but not by ticks. this study was carried out to assess the ability of the virus to replicate in tick cells in vitro.201324097806
vaccines for viral hemorrhagic fevers--progress and shortcomings.with a few exceptions, vaccines for viruses that cause hemorrhagic fever remain unavailable or lack well-documented efficacy. in the past decade this has not been due to a lack of the ability to develop vaccine platforms against highly pathogenic viruses, but rather the lack of will/interest to invest in platforms that have the potential to become successful vaccines. the two exceptions to this are vaccines against dengue virus (denv) and rift valley fever virus (rvfv), which recently have seen ...201323773330
ecuador paraiso escondido virus, a new flavivirus isolated from new world sand flies in ecuador, is the first representative of a novel clade in the genus flavivirus.a new flavivirus, ecuador paraiso escondido virus (epev), named after the village where it was discovered, was isolated from sand flies (psathyromyia abonnenci, formerly lutzomyia abonnenci) that are unique to the new world. this represents the first sand fly-borne flavivirus identified in the new world. epev exhibited a typical flavivirus genome organization. nevertheless, the maximum pairwise amino acid sequence identity with currently recognized flaviviruses was 52.8%. phylogenetic analysis o ...201526355096
identification of a flavivirus sequence in a marine arthropod.phylogenetic analysis has yet to uncover the early origins of flaviviruses. in this study, i mined a database of expressed sequence tags in order to discover novel flavivirus sequences. flavivirus sequences were identified in a pool of mrna extracted from the sea spider endeis spinosa (pycnogonida, pantopoda). reconstruction of the translated sequences and blast analysis matched the sequence to the flavivirus ns5 gene. additional sequences corresponding to envelope and the ns5 mtase domain were ...201526717191
characterization of a novel insect-specific flavivirus from brazil: potential for inhibition of infection of arthropod cells with medically important flaviviruses.in the past decade, there has been an upsurge in the number of newly described insect-specific flaviviruses isolated pan-globally. we recently described the isolation of a novel flavivirus (tentatively designated 'nhumirim virus'; nhuv) that represents an example of a unique subset of apparently insect-specific viruses that phylogenetically affiliate with dual-host mosquito-borne flaviviruses despite appearing to be limited to replication in mosquito cells. we characterized the in vitro growth p ...201425146007
transcriptome analysis reveals a signature profile for tick-borne flavivirus persistence in hek 293t cells.tick-borne flaviviruses (tbfvs) cause febrile illnesses, which may progress to severe encephalitis and/or death in humans globally. most people who recover from severe acute disease suffer from debilitating neurological sequelae, which may be due to viral persistence, infection-induced neurological cell damage, host response, or some combination of these. acute tbfv infection of human embryonic kidney (hek) 293t cells in vitro results in the death of >95% of infected cells by day 5. however, rep ...201627222466
rapid evolutionary dynamics of structural disorder as a potential driving force for biological divergence in flaviviruses.protein structure is commonly regarded to be conserved and to dictate function. most proteins rely on conformational flexibility to some degree. are regions that convey conformational flexibility conserved over evolutionary time? can changes in conformational flexibility alter protein function? here, the evolutionary dynamics of structurally ordered and disordered (flexible) regions are investigated genome-wide in flaviviruses, revealing that the amount and location of structural disorder fluctu ...023418179
ilheus virus isolation in the pantanal, west-central brazil.the wetlands of the brazilian pantanal host large concentrations of diverse wildlife species and hematophagous arthropods, conditions that favor the circulation of zoonotic arboviruses. a recent study from the nhecolândia sub-region of pantanal reported serological evidence of various flaviviruses, including west nile virus and ilheus virus (ilhv). according to the age of seropositive horses, at least three flaviviruses, including ilhv, circulated in the brazilian pantanal between 2005 and 2009. ...201323875051
the flavivirus protease as a target for drug discovery.many flaviviruses are significant human pathogens causing considerable disease burdens, including encephalitis and hemorrhagic fever, in the regions in which they are endemic. a paucity of treatments for flaviviral infections has driven interest in drug development targeting proteins essential to flavivirus replication, such as the viral protease. during viral replication, the flavivirus genome is translated as a single polyprotein precursor, which must be cleaved into individual proteins by a c ...201324242363
flaviviruses in europe: complex circulation patterns and their consequences for the diagnosis and control of west nile disease.in europe, many flaviviruses are endemic (west nile, usutu, tick-borne encephalitis viruses) or occasionally imported (dengue, yellow fever viruses). due to the temporal and geographical co-circulation of flaviviruses in europe, flavivirus differentiation by diagnostic tests is crucial in the adaptation of surveillance and control efforts. serological diagnosis of flavivirus infections is complicated by the antigenic similarities among the flavivirus genus. indeed, most flavivirus antibodies are ...201324225644
nucleoside inhibitors of tick-borne encephalitis virus.tick-borne encephalitis virus (tbev) is a leading cause of human neuroinfections in europe and northeast asia. there are no antiviral therapies for treating tbev infection. a series of nucleoside analogues was tested for the ability to inhibit the replication of tbev in porcine kidney cells and human neuroblastoma cells. the interactions of three nucleoside analogues with viral polymerase were simulated using advanced computational methods. the nucleoside analogues 7-deaza-2'-c-methyladenosine ( ...201526124166
kyasanur forest disease.in the spring of 1957, an outbreak of severe disease was documented in people living near the kyasanur forest in karnataka state, india, which also affected wild nonhuman primates. collection of samples from dead animals and the use of classical virological techniques led to the isolation of a previously unrecognized virus, named kyasanur forest disease virus (kfdv), which was found to be related to the russian spring-summer encephalitis (rsse) complex of tick-borne viruses. further evaluation f ...201223110991
responding to emerging diseases: reducing the risks through understanding the mechanisms of emergence. 201123908876
kyasanur forest disease virus infection in mice is associated with higher morbidity and mortality than infection with the closely related alkhurma hemorrhagic fever virus.kyasanur forest disease virus (kfdv) and alkhurma hemorrhagic fever virus (ahfv) are closely related members of the flavivirus genus and are important causes of human disease in india and the arabian peninsula, respectively. despite high genetic similarity, the viruses have distinctly different host ranges and ecologies. human cases of kfdv or ahfv develop a spectrum of disease syndromes ranging from liver pathology to neurologic disease. case reports suggest kfdv is more commonly associated wit ...201424950196
inhibitors of the tick-borne, hemorrhagic fever-associated flaviviruses.no antiviral therapies are available for the tick-borne flaviviruses associated with hemorrhagic fevers: kyasanur forest disease virus (kfdv), both classical and the alkhurma hemorrhagic fever virus (ahfv) subtype, and omsk hemorrhagic fever virus (ohfv). we tested compounds reported to have antiviral activity against members of the flaviviridae family for their ability to inhibit ahfv replication. 6-azauridine (6-azau), 2'-c-methylcytidine (2'-cmc), and interferon alpha 2a (ifn-α2a) inhibited t ...201424663025
the role of viral persistence in flavivirus biology.in nature, vector-borne flaviviruses are persistently cycled between either the tick or mosquito vector and small mammals such as rodents, skunks, and swine. these viruses account for considerable human morbidity and mortality worldwide. increasing and substantial evidence of viral persistence in humans, which includes the isolation of rna by rt-pcr and infectious virus by culture, continues to be reported. viral persistence can also be established in vitro in various human, animal, arachnid, an ...201424737600
a critical determinant of neurological disease associated with highly pathogenic tick-borne flavivirus in mice.tick-borne encephalitis virus (tbev) and omsk hemorrhagic fever virus (ohfv) are highly pathogenic tick-borne flaviviruses; tbev causes neurological disease in humans, while ohfv causes a disease typically identified with hemorrhagic fever. although tbev and ohfv are closely related genetically, the viral determinants responsible for these distinct disease phenotypes have not been identified. in this study, chimeric viruses incorporating components of tbev and ohfv were generated using infectiou ...201424574402
flaviviruses as a cause of undifferentiated fever in sindh province, pakistan: a preliminary report.arboviral diseases are expanding worldwide, yet global surveillance is often limited due to diplomatic and cultural barriers between nations. with human encroachment into new habitats, mosquito-borne viruses are also invading new areas. the actual prevalence of expanding arboviruses is unknown in pakistan due to inappropriate diagnosis and poor testing for arboviral diseases. the primary objective of this study was to document evidence of flavivirus infections as the cause of undifferentiated fe ...201626909342
flavidb: a data mining system for knowledge discovery in flaviviruses with direct applications in immunology and vaccinology.the flavivirus genus is unusually large, comprising more than 70 species, of which more than half are known human pathogens. it includes a set of clinically relevant infectious agents such as dengue, west nile, yellow fever, and japanese encephalitis viruses. although these pathogens have been studied extensively, safe and efficient vaccines lack for the majority of the flaviviruses.025544857
limited effects of type i interferons on kyasanur forest disease virus in cell culture.the tick-borne flavivirus, kyasanur forest disease virus (kfdv) causes seasonal infections and periodic outbreaks in south-west india. the current vaccine offers poor protection with reported issues of coverage and immunogenicity. since there are no approved prophylactic therapeutics for kfdv, type i ifn-α/β subtypes were assessed for antiviral potency against kfdv in cell culture.201627479197
flavivirus ns1: a multifaceted enigmatic viral protein.flaviviruses are emerging arthropod-borne viruses representing an immense global health problem. the prominent viruses of this group include dengue virus, yellow fever virus, japanese encephalitis virus, west nile virus tick borne encephalitis virus and zika virus. these are endemic in many parts of the world. they are responsible for the illness ranging from mild flu like symptoms to severe hemorrhagic, neurologic and cognitive manifestations leading to death. ns1 is a highly conserved non-stru ...201627473856
modulation of α-enolase post-translational modifications by dengue virus: increased secretion of the basic isoforms in infected hepatic cells.hepatic cells are major sites of dengue virus (denv) replication and liver injury constitutes a characteristic of severe forms of dengue. the role of hepatic cells in dengue pathogenesis is not well established, but since hepatocytes are the major source of plasma proteins, changes in protein secretion by these cells during infection might contribute to disease progression. previously, we showed that denv infection alters the secretion pattern of hepatic hepg2 cells, with α-enolase appearing as ...201425171719
genetic characterization of an insect-specific flavivirus isolated from culex theileri mosquitoes collected in southern portugal.we describe the full genetic characterization of an insect-specific flavivirus (isf) from culex theileri (theobald) mosquitoes collected in portugal. this represents the first isolation and full characterization of an isf from portuguese mosquitoes. the virus, designated ctfv, for culex theileri flavivirus, was isolated in the c6/36 stegomyia albopicta (=aedes albopictus) cell line, and failed to replicate in vertebrate (vero) cells in common with other isfs. the ctfv genome encodes a single pol ...201222579596
epidemic infections and their relevance to the gulf and other arabian peninsula countries. 024019727
in vitro antiviral activity of adenosine analog nitd008 against tick-borne flaviviruses.there are currently no antiviral therapies available for the tick-borne flaviviruses associated with hemorrhagic fevers: kyasanur forest disease virus (kfdv), both classical and the alkhurma hemorrhagic fever virus (ahfv) subtype, and omsk hemorrhagic fever virus (ohfv). in this brief study, we describe the in vitro antiviral activity of adenosine analog nitd008 against kfdv, ahfv, ohfv, as well as tick-borne encephalitis virus (tbev). alongside the well-established activity of nitd008 against m ...201627016316
analysis of the langat virus genome in persistent infection of an ixodes scapularis cell line.tick-borne flaviviruses (tbfvs) cause a broad spectrum of disease manifestations ranging from asymptomatic to mild febrile illness and life threatening encephalitis. these single-stranded positive-sense (ss(+)) rna viruses are naturally maintained in a persistent infection of ixodid ticks and small-medium sized mammals. the development of cell lines from the ixodid ticks has provided a valuable surrogate system for studying the biology of tbfvs in vitro. when we infected ise6 cells, an ixodes sc ...201627626437
detection of langat virus by taqman real-time one-step qrt-pcr method.langat virus (lgtv), one of the members of the tick-borne encephalitis virus (tbev) complex, was firstly isolated from ixodes granulatus ticks in malaysia. however, the prevalence of lgtv in ticks in the region remains unknown. surveillance for lgtv is therefore important and thus a tool for specific detection of lgtv is needed. in the present study, we developed a real-time quantitative reverse-transcription-polymerase chain reaction (qrt-pcr) for rapid detection of lgtv. our findings showed th ...201526360297
comparative pathogenesis of alkhumra hemorrhagic fever and kyasanur forest disease viruses in a mouse model.kyasanur forest disease virus (kfdv) and alkhumra hemorrhagic fever virus (ahfv) are genetically closely-related, tick-borne flaviviruses that cause severe, often fatal disease in humans. flaviviruses in the tick-borne encephalitis (tbe) complex typically cause neurological disease in humans whereas patients infected with kfdv and ahfv predominately present with hemorrhagic fever. a small animal model for kfdv and ahfv to study the pathogenesis and evaluate countermeasures has been lacking mostl ...201424922308
epidemiology of tick-borne encephalitis (tbe) in europe and its prevention by available vaccines.tick-borne encephalitis (tbe), which is caused by a flavivirus, is the most common tick-transmitted disease in central and eastern europe and russia. today, tbe is endemic in 27 european countries, and has become an international public health problem. the epidemiology of tbe is changing owing to various factors, such as improvements in diagnosis and case reporting, increased recreational activities in areas populated by ticks, and changes in climatic conditions affecting tick habitats. vaccinat ...201323377671
tick-borne encephalitis vaccines.tick-borne encephalitis (tbe) is a disease that is found from western europe across asia and into japan. in recent years the incidence rate has been increasing as has the endemic range of the virus. tick-borne encephalitis is caused by three genetically distinct sutypes of viruses within a single tbe virus (tbev) serocomplex. these three subtypes consist of far-eastern subtype tbev (tbev-fe), siberian subtype (tbev-sib) and european subtype (tbev-eu). each of these subtypes cause clinically dist ...023997980
molecular diagnostic and genetic characterization of highly pathogenic viruses: application during crimean-congo haemorrhagic fever virus outbreaks in eastern europe and the middle east.several haemorrhagic fevers are caused by highly pathogenic viruses that must be handled in biosafety level 4 (bsl-4) containment. these zoonotic infections have an important impact on public health and the development of a rapid and differential diagnosis in case of outbreak in risk areas represents a critical priority. we have demonstrated the potential of a dna resequencing microarray (pathogenid v2.0) for this purpose. the microarray was first validated in vitro using supernatants of cells i ...201223240764
virus discovery using tick cell lines.while ticks have been known to harbor and transmit pathogenic arboviruses for over 80 years, the application of high-throughput sequencing technologies has revealed that ticks also appear to harbor a diverse range of endogenous tick-only viruses belonging to many different families. almost nothing is known about these viruses; indeed, it is unclear in most cases whether the identified viral sequences are derived from actual replication-competent viruses or from endogenous virus elements incorpor ...201627679414
establishing protocols for tick containment at biosafety level 4.tick-borne diseases continue to emerge and have a great impact on public health and agriculture. in addition, many of the agents of tick-borne diseases, which are classified as biosafety level 4 (bsl-4) viruses, have the potential to be used as biothreat agents. in spite of the known importance of these pathogens, there is an acute shortage of facilities and trained personnel to study the pathogenesis of tick-borne diseases and to assess vaccine as well as other therapeutic interventions against ...201424838773
animal models of tick-borne hemorrhagic fever viruses.tick-borne hemorrhagic fever viruses (tbhfv) are detected throughout the african and eurasian continents and are an emerging or re-emerging threat to many nations. due to the largely sporadic incidences of these severe diseases, information on human cases and research activities in general have been limited. in the past decade, however, novel tbhfvs have emerged and areas of endemicity have expanded. therefore, the development of countermeasures is of utmost importance in combating tbhfv as elim ...201325437041
the impact of regulations, safety considerations and physical limitations on research progress at maximum biocontainment.we describe herein, limitations on research at biosafety level 4 (bsl-4) containment laboratories, with regard to biosecurity regulations, safety considerations, research space limitations, and physical constraints in executing experimental procedures. these limitations can severely impact the number of collaborations and size of research projects investigating microbial pathogens of biodefense concern. acquisition, use, storage, and transfer of biological select agents and toxins (bsat) are hig ...023342380
metagenomic profile of the viral communities in rhipicephalus spp. ticks from yunnan, china.besides mosquitoes, ticks are regarded as the primary source of vector-borne infectious diseases. indeed, a wide variety of severe infectious human diseases, including those involving viruses, are transmitted by ticks in many parts of the world. to date, there are no published reports on the use of next-generation sequencing for studying viral diversity in ticks or discovering new viruses in these arthropods from china. here, ion-torrent sequencing was used to investigate the presence of viruses ...201525799057
is the epidemiology of alkhurma hemorrhagic fever changing?: a three-year overview in saudi arabia.the epidemiology of alkhurma hemorrhagic fever disease is yet to be fully understood since the virus was isolated in 1994 in the kingdom of saudi arabia.201424516520
phylogenetic characterization of circulating dengue and alkhumra hemorrhagic fever viruses in western saudi arabia and lack of evidence of zika virus in the region: a retrospective study, 2010-2015.flaviviruses represent a global public health concern. they consist of ∼70 viruses with almost half of them causing human diseases with unspecified febrile illnesses. cities in western saudi arabia are endemic for viruses (denv) with sporadic infections due to alkhumra hemorrhagic fever virus (ahfv). they also represent a major destination for travelers coming for annual religious pilgrimages (hajj and umrah) from all over the world. however, whether other flaviviruses are circulating is not kno ...201728198548
electron microscopy of alkhumra hemorrhagic fever virus.alkhumra hemorrhagic fever virus (ahfv) is a newly described zoonotic flavivirus that was first isolated during 1994-1995 from the alkhumra district south of jeddah, saudi arabia. subsequently, the virus was also isolated from makkah city (2001-2003) and najran (2008-2009), saudi arabia. the virus causes acute febrile illness with hepatitis, hemorrhagic manifestations, and encephalitis. a case fatality rate of 25% was reported among hospitalized patients. although several biological and molecula ...201728051359
growth characteristics of alkhumra hemorrhagic fever virus in mammalian cell lines.alkhumra hemorrhagic fever virus (ahfv) is a flavivirus that was discovered in 1995 in saudi arabia. clinical manifestations of ahfv infection include hemorrhagic fever, hepatitis, and encephalitis with a reported mortality rate as high as 25%. there are no published data on the growth characteristics of ahfv in mammalian cell lines. the objective of this study was to examine the ability of ahfv to grow and propagate in four of the commonly used mammalian cell culture lines and to determine the ...201627710208
homology modeling and conformational epitope prediction of envelope protein of alkhumra haemorrhagic fever virus.the aim of this study was to generate in silico 3d-structure of the envelope protein of ahfv using homology modeling method to further predict its conformational epitopes and help other studies to investigate its structural features using the model.201526114149
complete genome sequencing and genetic characterization of alkhumra hemorrhagic fever virus isolated from najran, saudi arabia.alkhumra hemorrhagic fever virus (ahfv) is a newly described flavivirus first isolated in 1994-1995 from the alkhumra district south of jeddah, saudi arabia. subsequently, the virus was also isolated from makkah (2001-2003) and najran (2008-2009), saudi arabia.201425096447
tick-borne viruses: a review from the perspective of therapeutic approaches.several important human diseases worldwide are caused by tick-borne viruses. these diseases have become important public health concerns in recent years. the tick-borne viruses that cause diseases in humans mainly belong to 3 families: bunyaviridae, flaviviridae, and reoviridae. in this review, we focus on therapeutic approaches for several of the more important tick-borne viruses from these 3 families. these viruses are crimean-congo hemorrhagic fever virus (cchf) and the newly discovered tick- ...201424907187
thermal inactivation of alkhumra hemorrhagic fever virus.the physico-chemical and biological characteristics of alkhumra hemorrhagic fever virus (ahfv) are not yet known. the present study describes the thermal stability of this virus at different temperatures for different periods. the kinetics of thermal inactivation were studied, linear regressions were plotted, the arrhenius equation was applied, and the activation energy was calculated accordingly. titers of the residual virus were determined in median tissue culture infective dose (tcid50), and ...201424906524
propagation and titration of alkhumra hemorrhagic fever virus in the brains of newborn wistar rats.alkhumra hemorrhagic fever virus (ahfv) is a novel flavivirus identified first in saudi arabia. in this study, successful propagation of ahfv in the brains of newborn wistar rats is described and the median rat lethal dose (rld50) is determined. ahfv-rna-positive human sera diluted 1:10 were injected intracerebrally into 16, ≤24h old rats. post-inoculation, the rats were observed daily for 30 days. brains of moribund rats were tested for ahfv-rna using rt-pcr and cultured in llc-mk2 cells. the t ...201424445058
comparison of rt-pcr assay and virus isolation in cell culture for the detection of alkhumra hemorrhagic fever virus.alkhumra hemorrhagic fever virus (ahfv) is an emerging flavivirus that was isolated originally from saudi arabia in 1994-1995. the main tests used for the detection of ahfv are the real time (rt) rt-pcr and virus isolation in cell culture. in the present study the detection of ahfv by rtrt-pcr was compared with virus isolation in bhk-21, hep-2, and llc-mk2 cell lines. ahfv suspensions grown in bhk-21, hep-2, and llc-mk2 cell lines were serially diluted 10-fold from 10(-1) to 10(-11) . samples fr ...201424249525
trypsin-dependent hemagglutination of erythrocytes of a variety of mammalian and avian species by alkhumra hemorrhagic fever virus.alkhumra hemorrhagic fever virus (ahfv) is an emerging flavivirus that was discovered in 1994-1995 in saudi arabia. clinical manifestations of ahfv infection include hemorrhagic fever, hepatitis, and encephalitis, with a reported mortality rate as high as 25 %. biological characteristics of this virus have not been well defined. agglutination of erythrocytes (hemagglutination) is a laboratory tool for studying the attachment of viruses to cellular receptors. the envelope protein contains sites f ...201322983112
alkhurma hemorrhagic fever virus.alkhurma hemorrhagic fever virus (ahfv) was first isolated in jeddah, saudi arabia, in the 1990s from the blood of a butcher. subsequently, the virus was recognized in many patients in saudi arabia and rarely from egypt and djibouti. in this review, we summarize the current literature on ahfv globally with special focus on saudi arabia.201728456648
comment on: successful propagation of alkhumra (misnamed as alkhurma) virus in c6/36 mosquito cells. 201222579559
ultrastructural features of alkhumra hemorrhagic fever virus infection of cells under in vivo and in vitro conditions.alkhumra hemorrhagic fever virus (ahfv) is an emerging novel flavivirus that was discovered in saudi arabia in 1995. the virus has since caused several outbreaks in the country that resulted in case fatality rates ranging from 1% to 25%. meager information has been published on the ultrastructural features of the virus on cells under in vitro or in vivo conditions. the present electron microscopic study examined and compared the intracellular growth of the ahfv on the llc-mk2 cells and brain cel ...201829298405
comparative genome analysis of alkhumra hemorrhagic fever virus with kyasanur forest disease and tick-borne encephalitis viruses by the in silico approach.alkhumra hemorrhagic fever virus (ahfv), a relatively new member of the flaviviruses, was discovered in saudi arabia 23 years ago. ahfv is classified in the tick-borne encephalitis virus serocomplex, along with the kyasanur forest disease virus (kfdv) and tick-borne encephalitis virus (tbev). currently, very little is known about the pathologies of ahfv. in this study, using the available genome information of ahfv, kfdv and tbev, we have predicted and compared the following aspects of these vir ...201829745301
genetic diversity of alkhurma hemorrhagic fever virus in western asia.alkhurma hemorrhagic fever, caused by alkhurma hemorrhagic fever virus (alkv), is an arboviral infection which is further expanding in tropical and subtropical regions of the western asia. a number of alkhurma hemorrhagic fever virus (alkv) strains have been isolated from clinical cases representing saudi arabia and egypt; however, the phylogenetic relationship of these particular isolates to those reported previously elsewhere in the world remains elusive. based on the analysis of the envelope ...201930779959
epidemiology, pathogenesis, and control of a tick-borne disease- kyasanur forest disease: current status and future directions.in south asia, haemaphysalis spinigera tick transmits kyasanur forest disease virus (kfdv), a flavivirus that causes severe hemorrhagic fever with neurological manifestations such as mental disturbances, severe headache, tremors, and vision deficits in infected human beings with a fatality rate of 3-10%. the disease was first reported in march 1957 from kyasanur forest of karnataka (india) from sick and dying monkeys. since then, between 400 and 500 humans cases per year have been recorded; monk ...201829868505
alkhurma hemorrhagic fever virus rna in hyalomma rufipes ticks infesting migratory birds, europe and asia minor.alkhurma hemorrhagic fever virus rna was detected in immature hyalomma rufipes ticks infesting northward migratory birds caught in the north mediterranean basin. this finding suggests a role for birds in the ecology of the alkhurma hemorrhagic fever virus and a potential mechanism for dissemination to novel regions. increased surveillance is warranted.201829664386
in silico analysis for development of epitopes-based peptide vaccine against alkhurma hemorrhagic fever virus.alkhurma hemorrhagic fever virus (alkv) causes a fatal clinical disease in human beings of different tropical and sub-tropical regions. recently, the alkv epidemics have raised a great public health concern with the room for improvement in the essential therapeutic interventions. despite increased realistic clinical cases of alkv infection, the efficient vaccine or immunotherapy is not yet available to-date. therefore, the current study aimed to analyze the envelope glycoprotein of alkv for the ...201931370756
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