Alphavirus

In biology and immunology, an alphavirus (pronounced alph-AV-ir-rus) belongs to the group IV Togaviridae family of viruses, according to the system of classification based on viral genome composition introduced by David Baltimore in 1971. Alphaviruses, like all other group IV viruses have a positive sense single stranded RNA genome. There are 27 alphaviruses, able to infect various vertebrates such as humans, rodents, birds, and larger mammals such as horses as well as invertebrates. Transmission between species and individuals occurs via mosquitoes making the alphaviruses a contributor to the collection of Arboviruses – or Arthropod Borne Viruses. Alphaviruses particles are enveloped have a 70nm diameter, tend to be spherical (although slightly pleomorphic), and have a 40nm isometric nucleocapsid.

Genome
The genome of alphaviruses consists of a single stranded positive sense RNA. The total genome length ranges between 11,000 and 12,000 nucleotides, and has a 5’ cap, and 3’ poly-A tail. There are two open reading frames (ORF’s) in the genome, non-structural and structural. The first is non structural and encodes proteins for transcription and replication of viral RNA, and the second encodes four structural proteins: Capsid protein C, Envelope glycoprotein E1, Envelope glycoprotein E2, and Envelope glycoprotein E3. The expression of these proteins and replication of the viral genome all takes place in the cytoplasm of the host cells.

Alphavirus pathogenesis and the Immune response
The infection is spread by insect vectors such as mosquitoes. Once a human is bit by the infected mosquito, the virus can gain entry into the bloodstream, causing viremia. The alphavirus can also get into the CNS where it is able to grow and multiply within the neurones. This can lead to encephalitis, 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 neutralising antibodies also play an important role to prevent further infection and spread.

Diagnosis, prevention and control
A patient can be diagnosed with the infection based on clinical samples from which the virus can be easily isolated and identified. Although a vaccine exists, it is only used with individuals who are more likely to come into contact with the virus such as those working in the laboratory and in regions where an epidemic is more likely to occur. Control procedures could also be put in place for example using specific sprays against the mosquito and its larvae.

Alphaviruses In Medicine
There are many alphaviruses distributed around the world with the ability to cause human disease. Infectious arthritis, encephalitis, rashes and fever 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.

Alphaviruses In Research
Alphaviruses are of interest to gene therapy researchers, in particular the Ross River virus, Sindbis virus, Semliki Forest virus, 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 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 vectors which efficiently induce humoral and T-cell immune responses. They could therefore be used to vaccinate against viral, bacterial, protozoan, and tumor antigens.