Semliki Forest virus (SFV) is an RNA virus of the Togaviridae family, Alphavirus genus. It was first isolated from mosquitoes in Semliki Frost, Uganda, in 1942. It causes infection and diseases in humans and animals, including wild birds, rodents, domestic animals, and non-human primates. Semliki Forest virus is found in central and west Africa, parts of Asia, and possibly in central and southern Europe, where it is mainly transmitted by forest Aedes mosquitoes. When infected with humans, Semliki Forest virus can cause a mild febrile disease. In mice, however, certain strains of the Semliki Forest virus are neuroinvasive and cause demyelinating disease once they enter the central nervous system. Semliki Forest virus also directly infects oligodendrocytes.
Antiviral research and development for Semliki Forest virus shall be conducted in a biosafety level 3 facility. Laboratory personnel must receive specialized training in handling pathogenic, potentially lethal agents, and must be supervised by scientists competent in handling infectious agents. Since clinical signs and symptoms are similar to those of many infections, the diagnosis of Semliki Forest virus infection depends on a positive laboratory test result. Blood should be collected as soon as possible after a fever for inoculation of serum intracerebrally into suckling mice. Saline or buffered borate suspensions obtained from sick or moribund inoculated mouse brain tissue can be used as antigens for preliminary identification by complement fixation test. Instead of isolating virus from acute blood, paired sera can be used for complement fixation and hemagglutination assays to detect significant rises in titer against group or homologous serum antigens.
Figure 1. Models of the alphavirus life cycle and the virus-induced structures in mammalian.
Each SFV particle contains 240 copies of 4 structural proteins: capsid proteins (package single plus-stranded RNA into a nucleocapsid), 3 envelope proteins (i.e., type I transmembrane polypeptides E1 and E2 and peripheral E3 polypeptides). The envelope protein assembles into 80 spikes, each consisting of a trimer (E1/E2/E3). Both the S protein and the viral nucleocapsid have a T=4 icosahedral structure, and they are connected to each other through the one-to-one interaction between the E2 internal domain and the capsid protein. The viral lipid bilayer is derived from the host cell plasma membrane during budding. The life cycle of SFV and other alphaviruses has been studied in detail. SFV enters host cells through receptor-mediated endocytosis, whereas viral membrane fusion is mediated by Spike proteins and triggered by the low pH present in endosomes. In addition to the low pH requirement, fusion of alphaviruses, such as SFV, is also strongly dependent on the presence of cholesterol and sphingolipid in the target membrane. After fusion of the viral and endosomal membranes, the nucleocapsid is released into the cytoplasm and viral replication is initiated. Progeny RNA molecules bind to capsid proteins in the cytoplasm to form new nucleocapsids. The Spike protein E1 subunit and the E2 precursor (p62) are translated and translocated into the rough endoplasmic reticulum, where they are glycosylated to form stable non-covalently bound heterodimers. The dimer is transported via the secretory pathway, and p62 is processed into mature E2 and E3 by furin, a cellular protease, in the late secretory pathway. Then, E1, E2, and E3 are transported to the plasma membrane, where virus budding occurs (Figure 1).
There is currently no known antiviral treatment for SFV infection and no vaccine against SFV. However, due to its broad host range and efficient viral replication, SFV has been developed as a vaccine vector for anticancer treatment agents and a gene therapy tool against glioblastoma brain tumors. Personal protective measures (e.g., bed nets, mosquito repellants, protective clothing) against malaria and mosquito-borne arbovirus infection should be effective in preventing SFV infection during travel to endemic areas. Creative Diagnostics supports clients in Semliki Forest virus antiviral research and development with extensive knowledge.
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