Murine respirovirus

SeV has several features that are important in a vector for a successful vaccine: the virus does not integrate into the host genome, it does not undergo genetic recombination, it replicates only in the cytoplasm without DNA intermediates or a nuclear phase and it does not cause any disease in humans or domestic animals.

Imported animals should be vaccinated with SeV and placed in quarantine, while, in the laboratory environment, breeding programs should be discontinued, and the non-breeding adults isolated for two months.

[59] Currently, there is no scientific data obtained using modern detection methods that would identify SeV as an infectious - disease causing agent for humans or domestic animals.

After experimental SeV infection the virus can replicate and shed from the upper and lower respiratory tract of African green monkeys and chimpanzees, but it is not causing any disease.

[114] In addition, SeV triggers the expression of the chemokine interferon-γ inducible protein 10 kDa (CXCL10), which is involved in chemotaxis, induction of apoptosis, regulation of cell growth and mediation of angiostatic effects.

[124] In response to SeV infection, the production of hBD-1 mRNA and protein increases 2 hours after exposure to the virus in purified plasmacytoid dendritic cells or in PBMC.

Moreover, even the animals that are unresponsive to type I IFN develop long-term anti-SeV immunity in a form of memory response that includes generation of CD8+ T cells and neutralizing antibodies.

Evaluation of the safety and immunogenicity of an intranasally administered replication-competent Sendai Virus–vectored HIV Type 1 gag vaccine demonstrated: induction of potent T-Cell and antibody responses in prime-boost regimens.

[9] Short-term remission after an intravenous injection of SeV was described in a patient with acute leukemia treated in the Clinical Research Center of University Hospitals of Cleveland (USA) by multiple viruses in 1964.

[145] It is also reported[8][146] that the Moscow strain of SeV[147] was tested by Dr. V. Senin[148] and his team as an anticancer agent in a few dozen patients affected by various malignancies with metastatic growth in Russia in the 1990s.

[149] Intratumoral injection of UV irradiated and inactivated SeV resulted in an antitumor effect in a few melanoma patients with stage IIIC or IV progressive disease with skin or lymph metastasis.

[159][160] Among other receptors represented by gangliosides GT1b is highly expressed on the outer membranes of brain metastases cells that originate from an extremely broad range of cancer,[161] while GD1a,[156] GT1b[162] and GQ1b[163] can be detected in human gliosarcomas.

[251] NA also promotes cell fusion, which helps the nascent virions to avoid contact with host antibodies and thus enables the virus to spread within tissues.

Therefore, the ability of SeV sialidase (NA) to remove sialic acid from the surface of malignant cells most likely helps to ensure the availability of tumor antigens for recognition by cytotoxic T lymphocytes.

This was shown in a mouse model of renal cancer, in which the anti-tumor effect of SeV was suppressed by reducing the number of NK cells by co-injection of specific antibodies.

First, the functional hemagglutinin-neuraminidase protein of the oncolytic Newcastle disease virus (NDV), which is a relative of SeV, has been shown to enhance the tumor-specific cytotoxic response of CD8+ T-cells and to increase the activity of CD4+ T-helper cells.

[108] SeV has been known to the research community since the late 1950s and has been widely used to create numerous variants of genetically engineered constructs, including vectors for transgene delivery.

Due to SeV genetic stability, multiple serial passages of the virus construct in cell cultures or embryonated chicken eggs without drastic genomic changes are possible.

The recovery and amplification of SeV/ΔF vectors proceed as follows: Researchers have developed an innovative method to efficiently produce substantial quantities of heterologous viral glycoproteins within the allantoic cavity of embryonated chicken eggs.

[308] SeV has several features that are important in a vector for a successful vaccine: the virus does not integrate into the host genome, it does not undergo genetic recombination, it replicates only in the cytoplasm without DNA intermediates or a nuclear phase.

The study that was published in 2011 demonstrated that SeV neutralizing antibodies (which were formed due to HPIV-1 past infection) can be detected in 92.5% subjects worldwide with a median EC50 titer of 60.6 and values ranging from 5.9–11,324.

Evaluation of the safety and immunogenicity of an intranasally administered replication-competent Sendai Virus–vectored HIV Type 1 gag vaccine demonstrated: induction of potent T-Cell and antibody responses in prime-boost regimens.

[15][312][313] For effective prevention of infections caused by SARS-CoV-2, the ability of the vaccine to stimulate the mucosal immunity of the upper respiratory tract, including the nasal cavity, might be highly important.

One design utilizes a modified Sendai virus (SeV) as a vector to deliver the SARS-CoV-2 spike protein's receptor binding domain (RBD) directly to the respiratory tract.

Mice demonstrated elevated levels of antibodies specific to the SARS-CoV-2 S-RBD (IgM, IgG, IgA) in both their blood serum and bronchoalveolar lavage fluid, lasting up to 12 weeks.

[159][160] Among other receptors represented by gangliosides GT1b is highly expressed on the outer membranes of brain metastases cells that originate from an extremely broad range of cancer,[161] while GD1a,[156] GT1b[162] and GQ1b[163] can be detected in human gliosarcomas.

[380] Two of SeV proteins: HA and F, after their binding directly to a cellular membrane, promote a cell-cell fusion, which leads to a large multinuclear cell formation (syncytium).

Thus, a SeV infection in a form of genetic material in partially assembled virions can spread without any exposure to host neutralizing antibodies (see the section "Directed cells fusion (syncytium formation)" for details and references).

[389] One recognized feature of the Sendai virus, shared with members of its genus, is the ability to induce syncytia formation in vivo and in vitro in eukaryotic cell cultures.

[411][412] A single amino acid substitution in a nucleoprotein (NP) causes an increased production rate of DI genomes in the SeV Cantell strain, which is known for its particularly strong induction of interferon beta (IFN-β) during viral infection.

Phylogenetic tree of paramyxoviruses with Sendai virus
Phylogenetic tree
Non-invasive bioluminescence imaging of infection in the respiratory tracts of living mice
electron microscopy of murine respirovirus virus
Electron microscopy of virus
Viral stimulation of RIG-1 and MDA-5 mediated IFN production
Canine mast cell tumors treated with oncolytic Sendai virus.
Case 1. Male dog of 7 years old developed cutaneous, ulcerated, and poorly differentiated mastocytoma (35 mm diameter) located close to his anus. (1) Primary tumor; (2) 2 weeks after the first virus treatment; (3) 4 weeks after the first virus treatment.
Case 2. Male German shorthaired pointer of 9 years old developed subcutaneous, regional (stage 2) intermediately differentiated mastocytoma. The primary tumor was removed without clean margins. (1) secondary growth 1 week after the surgical procedure; (2) 2 weeks after the first virus treatment; (3) 5 weeks after the first virus treatment.
Intrinsic anti-tumor and anti- angiogenic functions of type I interferons
Schematic diagram of Sendai Virus genome with Green Fluorescent Protein (GFP). (A) The recombinant virus genome expresses eGFP (239 residues) fused to the C-terminus of the L protein (2,228 residues). (B) Western blot analysis of GFP expressed in infected cells. Lysates of mock- (lane 1), recombinant virus genomes (lane 2 and lane 3) infected cells were reacted with anti-GFP antibody. (C) Analysis of construct localization in live cells. HeLa cells were infected with recombinant genomes and images of the cells were captured at the indicated hours post infection.
SeV construct with a modified protease cleavage site in its fusion protein (F) gene was created. The image shows intratumoral and intra-organ spread of recombinant virions in vivo in a murine model of hepatoma which has been xenografted .
Sendai virus constructs that express luciferase. Upstream insertion of luciferase in rSeV-luc (P-M) resulted in greater luciferase activity than downstream insertion in rSeV-luc (F-HN).
Non-invasive bioluminescence imaging of Sendai virus infection in the respiratory tracts of living mice
Trafficking of nucleocapsids is mediated by intracellular vesicles
Sendai Virus minigenome with emerald-green protein
Large scale production of foreign soluble glycoproteins in allantoic fluid using Sendai Virus minigenome eхpression system
Sendai viral vector platform for reprogramming somatic cells into induced pluripotent stem cells (iPSCs)
Schematic representation of virion
Schematic representation of virion
Genome structure of the Sendai virus. Transcription of capped mRNAs starts from the transcription initiation signal with RNA-dependent RNA polymerase (L protein). Transcription ends at the transcription termination signal, followed by a poly-A signal.
Genome structure
The positions of translation initiation sites for products of the alternative reading frame of the P-coding mRNA
SeV cell entry receptors. The names of receptors with known high binding affinity to the virus are marked with stars. The names of receptors that are overexpressed in some malignancies are in bold and underlined.
Sendai virus life cycle
Hypothetical fusion mechanism of viral and cell plasma membrane
The process of fusion of the virus envelope with the cell membrane.
Possible model depicting formation of the viral assembly complex
The top panel shows one-step kinetics of viral replication in seven cell lines. Cells were infected with SeV-GFP at MOI of 3 CIU/cell (1 h absorption), washed 3 times with PBS, and kept in SFM. The media containing newly generated virions was collected at the indicated time points and viral titrations were performed on Vero cells. The bottom panel shows photographs of seven cell lines infected with SeV-GFP at MOI 3 CIU/cell 48 hours post infection. Fluorescence microscopy images were captured at 10× magnification.
Variable sensitivity of different cell lines to infection
Infection spreads with variable efficiency. The virus was visualized with green fluorescent antibodies, and cell nuclei were stained with DAPI blue fluorescent dye. Photographs were taken immediately after the addition of virus to the cells and 26 hours later.
Virus partially or completely loses oncolytic activity after adapting to growth in cell cultures
Sendai virus green fluorescent protein infection of ovine cells. Fluorescence microscopy images of alveolar macrophages (A), blood-derived macrophages (B), and ovine skin fibroblasts (C) infected with Sendai virus vector expressing the GFP (right panel) at a multiplicity of infection (MOI) of 10. Bright-field images are shown in the left panel. The three cell types and all cells in the three cultures are GFP-positive. Ovine fibroblasts remained GFP-positive after 13 in vitro culture passages ((C), third image).