Product Code Database
Orthoflavivirus ( Flavivirus prior to 2023; common name orthoflavivirus, orthoflaviviral or orthoflaviviruses) is a genus of positive-strand RNA viruses in the family Flaviviridae. The genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika virus and several other which may cause encephalitis, (2025). 9781904455929, Caister Academic Press. ISBN 9781904455929 as well as insect-specific flaviviruses (ISFs) such as cell fusing agent virus (CFAV), Palm Creek virus (PCV), and Parramatta River virus (PaRV). While dual-host flaviviruses can infect as well as arthropods, insect-specific flaviviruses are restricted to their competent arthropods. The means by which flaviviruses establish persistent infection in their competent vectors and cause disease in humans depends upon several virus-host interactions, including the intricate interplay between flavivirus-encoded immune antagonists and the host antiviral innate immune effector molecules.
Orthoflaviviruses are named for the yellow fever virus; the word flavus means 'yellow' in Latin, and yellow fever in turn is named from its propensity to cause yellow jaundice in victims.The earliest mention of "yellow fever" appears in a manuscript of 1744 by John Mitchell of Virginia; copies of the manuscript were sent to Mr. Cadwallader Colden, a physician in New York, and to Benjamin Rush of Philadelphia; the manuscript was eventually reprinted in 1814. See:
The term "yellow fever" appears on p. 186. On p. 188, Mitchell mentions "... the distemper was what is generally called the yellow fever in America." However, on pages 191–192, he states "... I shall consider the cause of the yellowness which is so remarkable in this distemper, as to have given it the name of the Yellow Fever." Mitchell misdiagnosed the disease that he observed and treated, and the disease was probably Weil's disease or hepatitis. See: Saul Jarcho (1957) "John Mitchell, Benjamin Rush, and Yellow fever". Bulletin of the History of Medicine, 31 (2): 132–6.
Orthoflaviviruses share several common aspects: common size (40–65 nm), symmetry (enveloped, icosahedral nucleocapsid), nucleic acid (positive-sense, single-stranded RNA around 10,000–11,000 bases), and appearance under the electron microscope.
Most of these viruses are primarily transmitted by the bite from an infected arthropod (mosquito or tick), and hence are classified as arboviruses. Human infections with most of these arboviruses are incidental, as humans are unable to replicate the virus to high enough to reinfect the arthropods needed to continue the virus life-cycle – humans are then a dead end host. The exceptions to this are the yellow fever virus, Dengue virus and Zika virus. These three viruses still require mosquito vectors but are well-enough adapted to humans as to not necessarily depend upon animal hosts (although they continue to have important animal transmission routes, as well).
Other virus transmission routes for arboviruses include handling infected animal carcasses, blood transfusion, sex, childbirth and consumption of Pasteurization milk products. Transmission from nonhuman vertebrates to humans without an intermediate vector arthropod however mostly occurs with low probability. For example, early tests with yellow fever showed that the disease is not contagious.
The known non-arboviruses of the flavivirus family reproduce in either arthropods or vertebrates, but not both, with one odd member of the genus affecting a nematode.
Other viruses like West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Zika virus and dengue virus were subsequently discovered in the early 20th century. When the authority on viral classification, the International Committee on Nomenclature of Viruses (ICNV), published it first report in 1971, all the viruses were grouped under the genus Arbovirus group B. In 1974, the ICNV created a more technical name following biological nomenclature, Flavivirus; derived from Latin flavi , as Yellow fever virus was accepted as the type species. ICNV also changed its name to the International Committee on Taxonomy of Viruses (ICTV). The family name Togaviridae was also created for the virus group, which was changed to Flaviviridae in 1984.
It was the customary to call members of Flaviviridae and its genus Flavivirus by common names like flavivirus, flaviviral, and flaviviruses. However, the confusion arose when other viruses of the family but different genera were described such as Hepacivirus, Pegivirus, and Pestivirus. To resolve the issue, ICTV decided in 2022 to change the genus name to Orthoflavivirus, which was adopted in 2023. By the new name, the genus Orthoflavivirus should be known by vernacular names like orthoflavivirus, orthoflaviviral or orthoflaviviruses . According to ICTV resolution:
To preclude this potential confusion, a taxonomic proposal (TaxoProp 2022.007S.A.Flaviviridae_1genren_sprenamed) was submitted to the ICTV in 2022. It proposed that the genus Flavivirus be renamed Orthoflavivirus, which roughly translates to "true flaviviruses" or "flaviviruses sensu stricto". This proposal was approved by the ICTV Executive Committee in late 2022 and ratified by the ICTV in April 2023 . Consequently, the terms "flaviviral", "flavivirus", and "flaviviruses" should be used to refer to the collective members of the family Flaviviridae, whereas the terms "orthoflaviviral", "orthoflavivirus", and "orthoflaviviruses" should be used for viruses of the genus Orthoflavivirus (all orthoflaviviruses are flaviviruses, but not all flaviviruses are orthoflaviviruses).
Cellular RNA cap structures are formed via the action of an RNA triphosphatase, with guanylyltransferase, N7-methyltransferase and 2′-O methyltransferase. The virus encodes these activities in its non-structural proteins. The NS3 protein encodes a RNA triphosphatase within its helicase domain. It uses the helicase ATP hydrolysis site to remove the γ-phosphate from the 5′ end of the RNA. The N-terminal domain of the non-structural protein 5 (NS5) has both the N7-methyltransferase and guanylyltransferase activities necessary for forming mature RNA cap structures. RNA binding affinity is reduced by the presence of ATP or GTP and enhanced by S-adenosyl methionine. This protein also encodes a 2′-O methyltransferase. Once translated, the polyprotein is cleaved by a combination of viral and host to release mature polypeptide products. Nevertheless, cellular post-translational modification is dependent on the presence of a poly-A tail; therefore this process is not host-dependent. Instead, the poly-protein contains an autocatalytic feature which automatically releases the first peptide, a virus specific enzyme. This enzyme is then able to bond cleavage the remaining poly-protein into the individual products. One of the products cleaved is a RNA-dependent RNA polymerase, responsible for the synthesis of a negative-sense RNA molecule. Consequently, this molecule acts as the template for the synthesis of the genomic offspring RNA.
Flavivirus genomic RNA replication occurs on rough endoplasmic reticulum membranes in membranous compartments. New viral particles are subsequently assembled. This occurs during the budding process which is also responsible for the accumulation of the envelope and cell lysis.
A G protein-coupled receptor kinase 2 (also known as ADRBK1) appears to be important in entry and replication for several viruses in Flaviviridae.
Humans, mammals, mosquitoes, and ticks serve as the natural host. Transmission routes are zoonosis and bite.
| Zoonosis; arthropod bite |
Currently 8 secondary structures have been identified within the 3'UTR of WNV and are (in the order in which they are found with the 3'UTR) SL-I, SL-II, SL-III, SL-IV, DB1, DB2 and CRE. Some of these secondary structures have been characterised and are important in facilitating viral replication and protecting the 3'UTR from 5' endonuclease digestion. Nuclease resistance protects the downstream 3' UTR RNA fragment from degradation and is essential for virus-induced cytopathicity and pathogenicity.
SL-II has been suggested to contribute to nuclease resistance. It may be related to another hairpin loop identified in the 5'UTR of the Japanese encephalitis virus (JEV) genome. The JEV hairpin is significantly over-represented upon host cell infection and it has been suggested that the hairpin structure may play a role in regulating RNA synthesis.
This secondary structure is located within the 3'UTR of the genome of Flavivirus upstream of the DB elements. The function of this conserved structure is unknown but is thought to contribute to ribonuclease resistance.
CRE is the Cis-acting replication element, also known as the 3'SL RNA elements, and is thought to be essential in viral replication by facilitating the formation of a "replication complex". Although evidence has been presented for an existence of a pseudoknot structure in this RNA, it does not appear to be well conserved across orthoflaviviruses. Deletions of the 3' UTR of orthoflaviviruses have been shown to be lethal for infectious clones.
The mosquito group can be divided into two branches: one branch contains neurotropic viruses, often associated with encephalitic disease in humans or livestock. This branch tends to be spread by Culex species and to have bird reservoirs. The second branch is the non-neurotropic viruses associated with human haemorrhagic disease. These tend to have Aedes species as vectors and primate hosts.
The tick-borne viruses also form two distinct groups: one is associated with and the other – the tick-borne encephalitis complex viruses – is associated primarily with .
The viruses that lack a known vector can be divided into three groups: one closely related to the mosquito-borne viruses, which is associated with ; a second, genetically more distant, is also associated with bats; and a third group is associated with rodents.
Evolutionary relationships between endogenised viral elements of orthoflaviviruses and contemporary flaviviruses using maximum likelihood approaches have identified that arthropod-vectored flaviviruses likely emerged from an arachnid source. This contradicts earlier work with a smaller number of extant viruses showing that the tick-borne viruses emerged from a mosquito-borne group.
Several partial and complete genomes of orthoflaviviruses have been found in aquatic invertebrates such as the sea spider Endeis spinosa and several crustaceans and cephalopods. These sequences appear to be related to those in the insect-specific orthoflaviviruses and also the Tamana bat virus groupings. While it is not presently clear how aquatic orthoflaviviruses fit into the evolution of this group of viruses, there is some evidence that one of these viruses, Wenzhou shark flavivirus, infects both a crustacean ( Portunus trituberculatus) Pacific spadenose shark ( Scoliodon macrorhynchos) shark host, indicating an aquatic arbovirus life cycle. Estimates of divergence times have been made for several of these viruses. The origin of these viruses appears to be at least 9400 to 14,000 years ago. The Old World and New World dengue strains diverged between 150 and 450 years ago. The European and Far Eastern tick-borne encephalitis strains diverged about 1087 (1610–649) years ago. European tick-borne encephalitis and louping ill viruses diverged about 572 (844–328) years ago. This latter estimate is consistent with historical records. Kunjin virus diverged from West Nile virus approximately 277 (475–137) years ago. This time corresponds to the settlement of Australia from Europe. The Japanese encephalitis group appears to have evolved in Africa 2000–3000 years ago and then spread initially to South East Asia before migrating to the rest of Asia.
Phylogeny studies of the West Nile virus has shown that it emerged as a distinct virus around 1000 years ago. This initial virus developed into two distinct lineages, lineage 1 and its multiple profiles is the source of the epidemic transmission in Africa and throughout the world. Lineage 2 was considered an Africa zoonosis. However, in 2008, lineage 2, previously only seen in horses in sub-Saharan Africa and Madagascar, began to appear in horses in Europe, where the first known outbreak affected 18 animals in Hungary in 2008. From statements by Orsolya Kutasi, DVM, of the Szent Istvan University, Hungary at the 2009 American Association of Equine Practitioners Convention, December 5–9, 2009. Lineage 1 West Nile virus was detected in South Africa in 2010 in a mare and her aborted fetus; previously, only lineage 2 West Nile virus had been detected in horses and humans in South Africa. A 2007 fatal case in a killer whale in Texas broadened the known host range of West Nile virus to include .
Omsk haemorrhagic fever virus appears to have evolved within the last 1000 years. The viral genomes can be divided into 2 clades — A and B. Clade A has five genotypes, and clade B has one. These clades separated about 700 years ago. This separation appears to have occurred in the Kurgan province. Clade A subsequently underwent division into clade C, D and E 230 years ago. Clade C and E appear to have originated in the Novosibirsk and Omsk Provinces, respectively. The muskrat Ondatra zibethicus, which is highly susceptible to this virus, was introduced into this area in the 1930s.
Effective inactivated 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 inactivated 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 Asia—North, 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 are in varying stages of development. CYD-TDV, sold under the trade name Dengvaxia, is a tetravalent chimeric vaccine that splices structural genes of the four dengue viruses onto a 17D yellow fever backbone. Dengvaxia is approved in five countries.
|
|
