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Review
. 2020 Dec 5;12(12):3659.
doi: 10.3390/cancers12123659.

Prospects for Using Expression Patterns of Paramyxovirus Receptors as Biomarkers for Oncolytic Virotherapy

Olga V Matveeva  1 , Svetlana A Shabalina  2
Affiliations
Review

Prospects for Using Expression Patterns of Paramyxovirus Receptors as Biomarkers for Oncolytic Virotherapy

Olga V Matveeva et al. Cancers (Basel). .

Abstract

The effectiveness of oncolytic virotherapy in cancer treatment depends on several factors, including successful virus delivery to the tumor, ability of the virus to enter the target malignant cell, virus replication, and the release of progeny virions from infected cells. The multi-stage process is influenced by the efficiency with which the virus enters host cells via specific receptors. This review describes natural and artificial receptors for two oncolytic paramyxoviruses, nonpathogenic measles, and Sendai viruses. Cell entry receptors are proteins for measles virus (MV) and sialylated glycans (sialylated glycoproteins or glycolipids/gangliosides) for Sendai virus (SeV). Accumulated published data reviewed here show different levels of expression of cell surface receptors for both viruses in different malignancies. Patients whose tumor cells have low or no expression of receptors for a specific oncolytic virus cannot be successfully treated with the virus. Recent published studies have revealed that an expression signature for immune genes is another important factor that determines the vulnerability of tumor cells to viral infection. In the future, a combination of expression signatures of immune and receptor genes could be used to find a set of oncolytic viruses that are more effective for specific malignancies.

Keywords: Sendai virus; biomarkers; gangliosides; glycosphingolipid receptors; measles virus; oncolytic virotherapy; oncolytic viruses; protein receptors; receptor retargeting; viral oncolysis; virus receptor expression; virus receptors.

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Conflict of interest statement

The authors declare no conflict of interest. Olga V. Matveeva belong to a company (Sendai Viralytics LLC). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Factors influencing cells’ vulnerability to paramyxovirus infection. The host cell needs to (1) express virus receptors (2) have a malfunctioning IFN pathway, (3) express proteases responsible for proteolytic activation of virus fusion rotein, and (4) have other genes that require further identification.
Figure 2
Figure 2
A visual representation of the cell cycle of measles virus (MV) and Sendai virus (SeV). Both viruses belong to the Paramyxoviridae family, but MV belongs to the Morbillivirus genus and SeV to the Respirovirus genus. The life cycles of MV and SeV are very similar, but there are several important differences. Their attachment to host cells occurs through different cell entry receptors and different viral cell attachment proteins. The MV virus uses an H protein with hemagglutinin activity, while SeV uses the HN protein with hemagglutinin (H) and neuraminidase (N) activities. In addition to these proteins, the genomes of these viruses encode 5 structural proteins and accessary proteins. The main structural proteins for both viruses are: Nucleoprotein (N), Phosphoprotein (P), Matrix protein (M), Fusion protein (F), and Large Protein (L). The MV genome encodes two non-structural proteins, C and V, [20], while the SeV genome encodes a set of non-structural proteins, collectively referred as C-proteins (C’, C, Y1, Y2, V, W) [21]. Viral replication for MV and SeV follows a negative-stranded RNA virus replication model in which genomic RNA (minus strand) is used as a template to create a copy of positive sense RNA, employing the RNA-dependent RNA polymerase embedded in the virion. The plus RNA is further used as a template for making multiple copies of the minus RNA. The plus RNA is also translated by the host’s ribosomes, producing all viral proteins. Viruses are then assembled from these proteins along with genomic RNA and budded from the host cell. Both MV and SeV can form syncytia by fusing neighboring infected and non-infected cells into a polykayion.
Figure 3
Figure 3
Schematic representation of the MV genome (A), virion (B) and host cell entry receptors (C). The RNA genome (gRNA) contains six transcription units that codes 6 main structural proteins: nucleoprotein (N), phosphoprotein (P), matrix protein (M), fusion protein (F), hemagglutinin (H), and large protein (L) RNA dependent RNA polymerase (RdRp). The viral genome also codes the nonstructural V and C proteins, which are antagonists of host innate immunity. The transcription units for each structural gene are separated by non-transcribed trinucleotide intergenic sequences and together are flanked by short leader and trailer sequences containing the genomic promoter (on the minus strand) and the antigenomic promoter (on the plus strand). Inside the virion, genomic RNA forms a complex with N, L, and P proteins. The virus is enveloped by a lipid membrane that has glycoproteins H and F associated with it as virion surface proteins. These proteins coordinate how the virus finds cells and enters them. For H protein, three receptors have been identified: Complement regulatory molecule CD46, the cell adhesion molecule nectin-4 and the signaling lymphocyte activation molecule (SLAM). MV wild-type strains use SLAM and nectin-4 as cell entry receptors. Vaccine strains and a small fraction of wild type strains, in addition, use CD46 as a cell entry receptor.
Figure 4
Figure 4
SeV 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.
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