Sendai Virus (SeV) as Vaccine-vectors
The ability to manipulate the genome of the negative-strand RNA virus, including the insertion of additional non-viral genes, has led to the development of a new class of viral vectors for gene transfer. Since its isolation in Japan in 1953, SeV has been widely used as a research tool in cell biology and industry. Recombinant SeV vectors have a variety of unique properties, such as low pathogenicity, a powerful capacity for gene expression and a wide range of hosts. Due to these advantages, SeV has important application value in gene therapy as a vaccine vector.
Introduction of Sendai Virus Structure
Sendai virus (SeV, also named as mouse parainfluenza virus type 1, hemagglutinating virus of Japan (HVJ) is a nonsegmented negative-strand RNA virus belonging to the Paramyxovirus family with a large spherical shape and an average diameter of 260 nm. The SeV virion consists of a nucleocapsid (genomic RNA complexed with NP, P and L proteins), an envelope (a lipid bilayer with F and HN proteins) and a matrix (M protein) linked to the nucleocapsid and envelope. In addition to the six structural proteins, accessory C and V proteins are expressed from the P gene by overlapping reading frames and by RNA editing, which leads to a pseudotemplated insertion of nucleotides into the mRNA, respectively. This simple genome structure encouraged us to develop a recombinant SeV vector by replacing the genes dispensable for gene expression (F, HN and M genes) with therapeutic genes.
Fig.1 The structure of Sendai virus.
Sendai Virus as Vaccine-vectors
The SeV vector has several merits for delivering foreign genes to host cells. First, each gene expression cassette of SeV has a transcriptional initiation and termination signal to be transcribed to mRNA encoding each protein. Therefore, constructing a recombinant virus is simple, and the foreign gene is expressed in the viral genome by replacing or inserting an additional gene expression cassette. Second, SEV has a negative single-stranded RNA genome that replicates only in the cytoplasm with viral RNA and ribonucleoprotein (RNP) complexes. Therefore, there is no risk of disrupting the host chromosome, suggesting the safety of the vector in terms of genotoxicity. Third, SEV has the potential to enter a variety of species and cell types by utilizing sialic acid on the surface of host cells. Finally, the natural host of SEV is mice, and the SeV vector is non-pathogenic in primates including humans. Thus, the preferred route for SeV vector administration is intranasal, which may be beneficial in inducing a mucosal immune response. SeV vector with some modifications has been constructed by deleting some genes such as F, M, and HN from the genomic backbone of the SeV vector. These replication-defective (non-transmissible) SeV vectors showed reduced cytopathic and are expected to become novel vaccine vectors.
The Design for Sendai Virus Vectors
The use of full-length genomic vectors is greatly limited for reasons such as safety, and so new vector generations must be developed that are devoid of as many viral proteins as possible. In addition, deletion of viral genes will result in increased coding capacity for vector generation in the future, and deletion of immunogenic viral proteins will significantly reduce anti-vector responses in vivo. Defective and persistent Sendai virus (SeVdp) vectors are now also considered to be a superior tool for iPSC generation thanks to their remarkably high potential and simplicity (Figure 2). Creative Biolabs has established a replication-defective viral vector by deleting or replacing some genes of the viral genome (such as fusion protein F), providing new strategies for the treatment and control of some diseases.
Fig.2 The genomic structure of the defective and persistent Sendai virus (SeVdp) vector. SeVdp has mutations in the L and P genes that result in low cytotoxicity and defective induction of IFN-β. The M, F and HN genes are deleted and replaced with the gene of interest (A-D). (Nakanishi and Otsu. 2012)
The replication-deficient SeV vector represents an efficient platform that can be used for vaccine developments against various viral pathogens. Creative Biolabs has modified the Sendai virus genome by reverse genetics technology to produce recombinant SeV vectors that can induce virus-specific T-cell responses in a variety of animal models. If you are interested in our services, please feel free to contact us.
Reference
- Nakanishi M and Otsu M. (2012). Development of Sendai virus vectors and their potential applications in gene therapy and regenerative medicine. Current Gene Therapy, 12(5):410-6.
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