Alphavirus
Encyclopedia
In biology
Biology
Biology is a natural science concerned with the study of life and living organisms, including their structure, function, growth, origin, evolution, distribution, and taxonomy. Biology is a vast subject containing many subdivisions, topics, and disciplines...

 and immunology
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...

, an alphavirus belongs to the group IV Togaviridae
Togaviridae
The Togaviridae are a family of viruses, including the following genera:* Genus Alphavirus; type species: Sindbis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Ross River virus, O'nyong'nyong virus, Chikungunya* Genus Rubivirus;...

 family of viruses, according to the system of classification based on viral genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....

 composition introduced by David Baltimore
David Baltimore
David Baltimore is an American biologist, university administrator, and Nobel laureate in Physiology or Medicine. He served as president of the California Institute of Technology from 1997 to 2006, and is currently the Robert A. Millikan Professor of Biology at Caltech...

 in 1971. Alphaviruses, like all other group IV viruses have a positive sense single stranded RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....

 genome. There are 30 alphaviruses, able to infect various vertebrates such as humans, rodents, fish, birds, and larger mammals such as horses as well as invertebrates. Transmission between species and individuals occurs mainly via mosquitoes making the alphaviruses a contributor to the collection of Arboviruses – or Arthropod
Arthropod
An arthropod is an invertebrate animal having an exoskeleton , a segmented body, and jointed appendages. Arthropods are members of the phylum Arthropoda , and include the insects, arachnids, crustaceans, and others...

 Borne Viruses. Alphaviruses particles are enveloped, have a 70 nm diameter, tend to be spherical (although slightly pleomorphic), and have a 40 nm isometric nucleocapsid.

Genome

The alphaviruses are small, spherical, enveloped viruses with a genome of a single positive sense strand RNA. The total genome length ranges between 11,000 and 12,000 nucleotides, and has a 5’ cap, and 3’ poly-A tail. The four non-structural protein genes are encoded in the 5′ two-thirds of the genome, while the three structural proteins are translated from a subgenomic mRNA colinear with the 3′ one-third of the genome.

There are two open reading frames (ORF’s) in the genome, non-structural and structural. The first is non structural and encodes proteins (nsP1–nsP4) necessary for transcription and replication of viral RNA. The second encodes three structural
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...

 proteins: the core nucleocapsid protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 C, and the envelope proteins
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 P62 and E1 that associate as a heterodimer. The viral
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

 membrane-anchored surface glycoproteins are responsible for receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

 recognition and entry into target cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

s through membrane fusion.

Structural proteins

The proteolytic maturation of P62 into E2 and E3 causes a change in the viral surface. Together the E1, E2, and sometimes E3, glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...

 "spikes" form an E1/E2 dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...

 or an E1/E2/E3 trimer, where E2 extends from the centre to the vertices, E1 fills the space between the vertices, and E3, if present, is at the distal end of the spike. Upon exposure of the virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

 to the acidity of the endosome, E1 dissociates from E2 to form an E1 homotrimer, which is necessary for the fusion step to drive the cellular
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

 and viral membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

s together. The alphaviral glycoprotein E1 is a class II viral fusion protein, which is structurally different from the class I fusion proteins found in influenza virus and HIV. The structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...

 of the Semliki Forest virus revealed a structure that is similar to that of flaviviral glycoprotein E, with three structural domains in the same primary sequence arrangement. The E2 glycoprotein functions to interact
Protein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...

 with the nucleocapsid through its cytoplasmic
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

 domain, while its ectodomain is responsible for binding
Binding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...

 a cellular receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

. Most alphaviruses lose the peripheral protein E3, but in Semliki viruses it remains associated with the viral surface.

Virology

The nucleocapsid, 40 nanometers in diameter, contains 240 copies of the capsid protein and has a T = 4 icosahedral symmetry. The E1 and E2 viral glycoproteins are embedded in the lipid bilayer. Single E1 and E2 molecules associate to form heterodimers. The E1-E2 heterodimers form one-to-one contacts between the E2 protein and the nucleocapsid monomers.

Replication occurs within the cytoplasm, and virions mature by budding through the plasma membrane, where virus-encoded surface glycoproteins E2 and E1 are assimilated.

These two glycoproteins are the targets of numerous serologic reactions and tests including neutralization and hemagglutination inhibition. The alphaviruses show various degrees of antigenic cross-reactivity in these reactions and this forms the basis for the seven antigenic complexes, 30 species and many subtypes and varieties. The E2 protein is the site of most neutralizing epitopes, while the E1 protein contains more conserved, cross-reactive epitopes.

Taxonomy

The seven complexs are:
Barmah Forest virus complex
Barmah Forest Virus

Eastern Equine Encephalitis complex
Eastern Equine Encephalitis Virus

Middelburg virus complex
Middelburg Virus

Ndumu virus complex
Ndumu virus

Semliki Forest virus complex
Bebaru virus
Chikungunya Virus
Mayaro Virus
Subtype: Una virus
O’Nyong Nyong Virus
Subtype: Igbo-Ora Virus
Ross River Virus
Subtype: Bebaru virus
Subtype: Getah virus
Subtype: Sagiyama Virus
Semliki Forest Virus
Subtype: Me Tri virus

Venezuelan Equine Encephalitis complex
Cabassou virus
Everglades virus
Mosso das Pedras virus
Mucambo virus
Paramana virus
Pixuna virus
Rio Negro virus
Trocara virus
Subtype: Bijou Bridge virus
Venezuelan Equine Encephalitis Virus

Western Equine Encephalitis complex
Aura Virus
Kyzylagach virus
Sindbis Virus
Ockelbo Virus
Whataroa virus

Recombinants
Buggy Creek Virus
Fort Morgan Virus
Highlands J Virus
Western Equine Encephalitis Virus

Unclassified
Salmon Pancreatic Disease Virus
Sleeping Disease Virus
Southern Elephant Seal Virus
Tonate virus

Pathogenesis and immune response

Medically important alphaviruses
Virus Human Disease Vertebrate Reservoir Distribution
Barmah Forest virus
Barmah Forest virus
Barmah Forest virus is a virus currently found only in Australia. According to a Queensland Public Health Services fact sheet, "there is no specific drug treatment" for the virus, but the disease is non-fatal and relatively mild. The virus is transmitted to humans by bites from infected...

Fever, malaise, rash, joint pain, muscle tenderness Humans Australia
Chikungunya virus Rash, arthritis Primates, humans Africa, India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...

, SE Asia
Mayaro virus Rash, arthritis Primates, humans South America
South America
South America is a continent situated in the Western Hemisphere, mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere. The continent is also considered a subcontinent of the Americas. It is bordered on the west by the Pacific Ocean and on the north and east...

O'nyong'nyong virus
O'nyong'nyong virus
The O'nyong'nyong virus or O'nyong-nyong virus is a virus first isolated by the Uganda Virus Research Institute in Entebbe, Uganda in 1959. It is a togavirus , genus Alphavirus and is closely related to the Chikungunya and Igbo Ora viruses. The name comes from the Nilotic language of Uganda and...

 
Rash, arthritis Primate
Primate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...

s, Humans
Africa
Ross River virus
Ross River virus
Ross River virus is a small encapsulated single-strand RNA alphavirus endemic to Australia, Papua New Guinea and other islands in the South Pacific. It is responsible for a type of mosquito-borne non-lethal but debilitating tropical disease known as Ross River fever, previously termed "epidemic...

Rash, arthritis Mammals, humans Australia, South Pacific
Oceania
Oceania is a region centered on the islands of the tropical Pacific Ocean. Conceptions of what constitutes Oceania range from the coral atolls and volcanic islands of the South Pacific to the entire insular region between Asia and the Americas, including Australasia and the Malay Archipelago...

Semliki Forest Virus
Semliki Forest Virus
The Semliki Forest virus was first isolated from mosquitoes in the Semliki Forest, Uganda by the Uganda Virus Research Institute in 1942. It is known to cause disease in both animals and man...

Rash, arthritis Birds Africa
Sindbis virus
Sindbis virus
Sindbis Virus is a member of the Togaviridae family, in the alphavirus subfamily. The virus was first isolated in 1952 in Cairo, Egypt. The virus is transmitted by mosquitoes SINV causes sindbis fever in humans and the symptoms include arthralgia, rash and malaise...

Rash, arthritis Birds Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...

, Africa
Africa
Africa is the world's second largest and second most populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...

, Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...

Una virus
Una virus
Una virus is a subtype of the Mayaro virus 4, one of the Semliki Forest Virus complex of the Togaviridae family. According to the Baltimore classification of viruses, it is a class IV virus. It has a linear single-stranded RNA genome...

Rash, arthritis Primates, humans South America
South America
South America is a continent situated in the Western Hemisphere, mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere. The continent is also considered a subcontinent of the Americas. It is bordered on the west by the Pacific Ocean and on the north and east...

Eastern equine encephalitis virus
Eastern equine encephalitis virus
Eastern equine encephalitis virus , commonly called sleeping sickness or Triple E, is a zoonotic alphavirus and arbovirus present in North, Central and South America and the Caribbean. EEE was first recognized in Massachusetts, USA in 1831 when 75 horses died of encephalitic illness...

Encephalitis Birds Americas
Americas
The Americas, or America , are lands in the Western hemisphere, also known as the New World. In English, the plural form the Americas is often used to refer to the landmasses of North America and South America with their associated islands and regions, while the singular form America is primarily...

Tonate virus Encephalitis Humans South America
Venezuelan equine encephalitis virus
Venezuelan equine encephalitis virus
Venezuelan equine encephalitis virus is a mosquito-borne viral pathogen that causes Venezuelan equine encephalitis or encephalomyelitis . VEE can affect all equine species, such as horses, donkeys, and zebras. After infection, equines may suddenly die or show progressive central nervous system...

Encephalitis Rodent
Rodent
Rodentia is an order of mammals also known as rodents, characterised by two continuously growing incisors in the upper and lower jaws which must be kept short by gnawing....

s, horses
Americas
Western equine encephalitis virus
Western equine encephalitis virus
The Western equine encephalomyelitis virus is the causative agent of relatively uncommon viral disease Western equine encephalomyelitis . An Alphavirus of the family Togaviridae, the WEE virus is an arbovirus transmitted by mosquitoes of the genera Culex and Culiseta...

Encephalitis Birds, mammals North America
North America
North America is a continent wholly within the Northern Hemisphere and almost wholly within the Western Hemisphere. It is also considered a northern subcontinent of the Americas...



There are many alphaviruses distributed around the world with the ability to cause human disease. Infectious arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....

, encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...

, rashes and fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

 being the most commonly observed. Larger mammals such as humans and horses are usually dead-end hosts or play a minor role in viral transmission, however in the case of Venezuelan equine encephalitis the virus is mainly amplified in horses. In most other cases the virus is maintained in nature in mosquitoes, rodents and birds.

Alphavirus infections are spread by insect vectors such as mosquitoes. Once a human is bitten by the infected mosquito, the virus can gain entry into the bloodstream, causing viremia
Viremia
Viremia is a medical condition where viruses enter the bloodstream and hence have access to the rest of the body. It is similar to bacteremia, a condition where bacteria enter the bloodstream.- Primary versus Secondary :...

. The alphavirus can also get into the CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 where it is able to grow and multiply within the neurones. This can lead to encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...

, which can be fatal.

When an individual is infected with this particular virus, its immune system can play a role in clearing away the virus particles. Alphaviruses are able to cause the production of interferons. Antibodies and T cells are also involved. The neutralizing antibodies also play an important role to prevent further infection and spread.

Diagnosis, prevention, and control

Diagnoses is based on clinical samples from which the virus can be easily isolated and identified. There are no alphavirus vaccines currently available. Vector control with repellents, protective clothing, breeding site destruction, and spraying are the preventive measures of choice.

Research

Alphaviruses are of interest to gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...

 researchers, in particular the Ross River virus, Sindbis virus
Sindbis virus
Sindbis Virus is a member of the Togaviridae family, in the alphavirus subfamily. The virus was first isolated in 1952 in Cairo, Egypt. The virus is transmitted by mosquitoes SINV causes sindbis fever in humans and the symptoms include arthralgia, rash and malaise...

, Semliki Forest virus
Semliki Forest Virus
The Semliki Forest virus was first isolated from mosquitoes in the Semliki Forest, Uganda by the Uganda Virus Research Institute in 1942. It is known to cause disease in both animals and man...

, and Venezuelan equine encephalitis virus have all been used to develop viral vectors for gene delivery. Of particular interest are the chimeric viruses that may be formed with alphaviral envelopes and retroviral capsids. Such chimeras are termed pseudotyped viruses. Alphaviral envelope pseudotypes of retroviruses or lentiviruses are able to integrate the genes that they carry into the expansive range of potential host cells that are recognized and infected by the alphaviral envelope proteins E2 and E1. The stable integration of viral genes is mediated by the retroviral interiors of these vectors. There are limitations to the use of alphaviruses in the field of gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...

 due to their lack of targeting, however, through the introduction of variable antibody domains in a non-conserved loop in the structure of E2, specific populations of cells have been targeted. Furthermore, the use of whole alphaviruses for gene therapy is of limited efficacy both because several internal alphaviral proteins are involved in the induction of apoptosis upon infection and also because the alphaviral capsid mediates only the transient introduction of mRNA into host cells. Neither of these limitations extend to alphaviral envelope pseudotypes of retroviruses or lentiviruses. However, the expression of Sindbis virus envelopes may lead to apoptosis, and their introduction into host cells upon infection by Sindbis virus envelope pseudotyped retroviruses may also lead to cell death. The toxicity of Sindbis viral envelopes may be the cause of the very low production titers realized from packaging cells constructed to produce Sindbis pseudotypes. Another branch of research involving alphaviruses is in vaccination. Alphaviruses are apt to be engineered to create replicon
Replicon
*A Replicon in genetics is a region of DNA or RNA, that replicates from a single origin of replication.*Replicon is a software company providing timesheet and expense management software....

 vectors which efficiently induce humoral and T-cell immune responses. They could therefore be used to vaccinate against viral, bacterial, protozoan, and tumor antigens.

See also

  • Alphavirus infection
    Alphavirus infection
    Alphavirus infection may be caused by a Sindbis virus infection, and result in a cutaneous eruption of multiple, erythematous, 4- to 4-mm papules....

  • Chikungunya
    Chikungunya
    Chikungunya virus is an insect-borne virus, of the genus Alphavirus, that is transmitted to humans by virus-carrying Aedes mosquitoes. There have been recent breakouts of CHIKV associated with severe illness...

  • Semliki forest virus
    Semliki Forest Virus
    The Semliki Forest virus was first isolated from mosquitoes in the Semliki Forest, Uganda by the Uganda Virus Research Institute in 1942. It is known to cause disease in both animals and man...

  • Sindbis virus
    Sindbis virus
    Sindbis Virus is a member of the Togaviridae family, in the alphavirus subfamily. The virus was first isolated in 1952 in Cairo, Egypt. The virus is transmitted by mosquitoes SINV causes sindbis fever in humans and the symptoms include arthralgia, rash and malaise...


Sources

  • http://virology-online.com/viruses/Arboviruses2.htm
  • http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/73010000.htm
  • Alphavirus vectors: from protein production to gene therapy, C Smerdou & P Liljestrom, Gene Therapy and Regulation Vol 1 No 1 2000 pp. 33–63
  • Alphavirus vectors and vaccination, J O Rayner et al., Reviews in Medical Virology vol 12 issue 5 pp 279–296
  • http://ep.physoc.org/cgi/content/full/90/1/45
  • http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.chapter.2894
  • http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.section.2918

External links

The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
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