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Molecular Therapy Oncolytics Dec 2022Historically, the clinical utility of oncolytic virotherapy as a treatment for a wide range of cancer types was first demonstrated by three pilot human clinical trials...
Historically, the clinical utility of oncolytic virotherapy as a treatment for a wide range of cancer types was first demonstrated by three pilot human clinical trials conducted in Japan in the 1970s and 1980s using a wild-type Urabe mumps virus (MuV) clinical isolate. Using a sample of the actual original oncolytic Urabe MuV clinical trial virus stock (MuV-U-Japan) used in these Japanese clinical trials, we found that MuV-U-Japan consisted of a wide variety of very closely related Urabe MuVs that differed by an average of only three amino acids. Two MuV-U-Japan isolates, MuV-UA and MuV-UC, potently killed a panel of established human breast cancer cell lines , significantly extended survival of nude mice with human triple-negative breast cancer (TNBC) MDA-MB-231 tumor xenografts , and demonstrated significant killing activity against breast cancer patient-derived xenograft (PDX) cell lines grown as 3D organoids, including PDXs from patients resistant to anthracycline- and taxane-based chemotherapy. We also report success in developing a large-scale MuV-U production and purification process suitable for supporting Investigational New Drug applications for clinical trials. This study demonstrates the suitability of the MuV-UC virus for translation to modern clinical trials for treating patients with TNBC.
PubMed: 36458203
DOI: 10.1016/j.omto.2022.11.002 -
British Medical Journal Feb 1979
Topics: Hearing Loss, Sudden; Humans; Mumps; Mumps virus; Perilymph
PubMed: 421111
DOI: 10.1136/bmj.1.6159.343-b -
Journal of Virology Jun 2003Mumps virus is a common infectious agent of humans, causing parotitis, meningitis, encephalitis, and orchitis. Like other paramyxoviruses in the genus Rubulavirus, mumps...
Mumps virus is a common infectious agent of humans, causing parotitis, meningitis, encephalitis, and orchitis. Like other paramyxoviruses in the genus Rubulavirus, mumps virus catalyzes the proteasomal degradation of cellular STAT1 protein, a means for escaping antiviral responses initiated by alpha/beta and gamma interferons. We demonstrate that mumps virus also eliminates cellular STAT3, a protein that mediates transcriptional responses to cytokines, growth factors, nonreceptor tyrosine kinases, and a variety of oncogenic stimuli. STAT1 and STAT3 are independently targeted by a single mumps virus protein, called V, that assembles STAT-directed ubiquitylation complexes from cellular components, including STAT1, STAT2, STAT3, DDB1, and Cullin4A. Consequently, mumps virus V protein prevents responses to interleukin-6 and v-Src signals and can induce apoptosis in STAT3-dependent multiple myeloma cells and transformed murine fibroblasts. These findings demonstrate a unique cytokine and oncogene evasion property of mumps virus that provides a molecular basis for its observed oncolytic properties.
Topics: 3T3 Cells; Animals; Apoptosis; Cell Line, Transformed; Cytokines; DNA-Binding Proteins; Genes, src; Humans; Interferon-beta; Interleukin-6; Mice; Mumps virus; Oncogenes; STAT1 Transcription Factor; STAT3 Transcription Factor; Signal Transduction; Trans-Activators; Tumor Cells, Cultured; Ubiquitin; Viral Proteins
PubMed: 12743296
DOI: 10.1128/jvi.77.11.6385-6393.2003 -
Journal of Virology Oct 2022The nucleolus is the largest structure in the nucleus, and it plays roles in mediating cellular stress responses and regulating cell proliferation, as well as in...
The nucleolus is the largest structure in the nucleus, and it plays roles in mediating cellular stress responses and regulating cell proliferation, as well as in ribosome biosynthesis. The nucleolus is composed of a variety of nucleolar factors that interact with each other in a complex manner to enable its function. Many viral proteins interact with nucleolar factors as well, affecting cellular morphology and function. Here, to investigate the association between mumps virus (MuV) infection and the nucleolus, we evaluated the necessity of nucleolar factors for MuV proliferation by performing a knockdown of these factors with small interfering (si)RNAs. Our results reveal that suppressing the expression of Treacle, which is required for ribosome biosynthesis, reduced the proliferative potential of MuV. Additionally, the one-step growth kinetics results indicate that Treacle knockdown did not affect the viral RNA and protein synthesis of MuV, but it did impair the production of infectious virus particles. Viral matrix protein (M) was considered a candidate Treacle interaction partner because it functions in the process of particle formation in the viral life cycle and is partially localized in the nucleolus. Our data confirm that MuV M can interact with Treacle and colocalize with it in the nucleolus. Furthermore, we found that viral infection induces relocalization of Treacle in the nucleus. Together, these findings suggest that interaction with Treacle in the nucleolus is important for the M protein to exert its functions late in the MuV life cycle. The nucleolus, which is the site of ribosome biosynthesis, is a target organelle for many viruses. It is increasingly evident that viruses can favor their own replication and multiplication by interacting with various nucleolar factors. In this study, we found that the nucleolar protein Treacle, known to function in the transcription and processing of pre-rRNA, is required for the efficient propagation of mumps virus (MuV). Specifically, our data indicate that Treacle is not involved in viral RNA or protein synthesis but is important in the processes leading to viral particle production in MuV infection. Additionally, we determined that MuV matrix protein (M), which functions mainly in viral particle assembly and budding, colocalized and interacted with Treacle. Furthermore, we found that Treacle is distributed throughout the nucleus in MuV-infected cells. Our research shows that the interaction between M and Treacle supports efficient viral growth in the late stage of MuV infection.
Topics: Cell Nucleolus; Humans; Mumps; Mumps virus; Nuclear Proteins; Phosphoproteins; RNA Precursors; RNA, Viral; Viral Matrix Proteins
PubMed: 36135364
DOI: 10.1128/jvi.00722-22 -
Infection and Immunity Jan 1982The replication of mumps virus was studied in human continuous lymphoblastoid cell lines (LCLs) with T or B characteristics and in lymphocyte subpopulations derived from... (Comparative Study)
Comparative Study
The replication of mumps virus was studied in human continuous lymphoblastoid cell lines (LCLs) with T or B characteristics and in lymphocyte subpopulations derived from peripheral blood. T-LCLs supported effective virus replication as shown by high titers of free and cell-associated virus over 1 to 4 days after infection. By immunofluorescence analysis, the majority of cells were positive for mumps virus antigens. In contrast, the B-cell lines produced low titers of infectious virus, and only a small percentage expressed viral antigens. This resistance of the B-LCLs was found with several mumps virus strains. Cultures of peripheral blood mononuclear cells also supported mumps virus replication. Very high titers of infectious virus (10(8) PFU/ml) were observed in cultures prestimulated with phytohaemagglutinin. Studies with enriched T and B cells point to the activated T lymphocyte as the major virus-producing cell.
Topics: B-Lymphocytes; Cell Division; Cell Line; Humans; Lymphocyte Activation; Mumps virus; T-Lymphocytes; Virus Replication
PubMed: 6976327
DOI: 10.1128/iai.35.1.25-31.1982 -
Journal of Virology Oct 2018J paramyxovirus (JPV) was first isolated from moribund mice with hemorrhagic lung lesions in Australia in 1972. It is a paramyxovirus classified under the newly proposed...
J paramyxovirus (JPV) was first isolated from moribund mice with hemorrhagic lung lesions in Australia in 1972. It is a paramyxovirus classified under the newly proposed genus JPV has a genome of 18,954 nucleotides, consisting of eight genes in the order 3'-N-P/V/C-M-F-SH-TM-G-L-5'. JPV causes little cytopathic effect (CPE) in tissue culture cells but severe disease in mice. The small hydrophobic (SH) protein is an integral membrane protein encoded by many paramyxoviruses, such as mumps virus (MuV) and respiratory syncytial virus (RSV). However, the function of SH has not been defined in a suitable animal model. In this work, the functions of SH of JPV, MuV, and RSV have been examined by generating recombinant JPV lacking the SH protein (rJPV-ΔSH) or replacing SH of JPV with MuV SH (rJPV-MuVSH) or RSV SH (rJPV-RSVSH). rJPV-ΔSH, rJPV-MuVSH, and rJPV-RSVSH were viable and had no growth defect in tissue culture cells. However, more tumor necrosis factor alpha (TNF-α) was produced during rJPV-ΔSH infection, confirming the role of SH in inhibiting TNF-α production. rJPV-ΔSH induced more apoptosis in tissue culture cells than rJPV, rJPV-MuVSH, and rJPV-RSVSH, suggesting that SH plays a role in blocking apoptosis. Furthermore, rJPV-ΔSH was attenuated in mice compared to rJPV, rJPV-MuVSH, and rJPV-RSVSH, indicating that the SH protein plays an essential role in virulence. The results indicate that the functions of MuV SH and RSV SH are similar to that of JPV SH even though they have no sequence homology. Paramyxoviruses are associated with many devastating diseases in animals and humans. J paramyxovirus (JPV) was isolated from moribund mice in Australia in 1972. Newly isolated viruses, such as Beilong virus (BeiPV) and Tailam virus (TlmPV), have genome structures similar to that of JPV. A new paramyxovirus genus, , which contains JPV, BeiPV, and TlmPV, has been proposed. Small hydrophobic (SH) protein is present in many paramyxoviruses. Our present study investigates the role of SH protein of JPV in pathogenesis in its natural host. Understanding the pathogenic mechanism of is important to control and prevent potential diseases that may emerge from this group of viruses.
Topics: Animals; Apoptosis Regulatory Proteins; Cell Line; Chlorocebus aethiops; Disease Models, Animal; Gene Deletion; Genetic Complementation Test; Humans; Mice; Microbial Viability; Mumps virus; Paramyxoviridae; Paramyxoviridae Infections; Respiratory Syncytial Viruses; Retroviridae Proteins, Oncogenic; Tumor Necrosis Factor-alpha; Virulence; Virulence Factors
PubMed: 30068647
DOI: 10.1128/JVI.00653-18 -
Journal of Virology Apr 2022Mumps virus (MuV) causes a highly contagious human disease characterized by the enlargement of the parotid glands. In severe cases, mumps can lead to neurological...
Mumps virus (MuV) causes a highly contagious human disease characterized by the enlargement of the parotid glands. In severe cases, mumps can lead to neurological complications such as aseptic meningitis and encephalitis. Vaccination with the attenuated Jeryl Lynn (JL) MuV vaccine has dramatically reduced the incidence of MuV infection. Recently, large outbreaks have occurred in vaccinated populations. The vaccine strain JL was generated from genotype A, while most current circulating strains belong to genotype G. In this study, we examined the immunogenicity and longevity of genotype G-based vaccines. We found that our recombinant genotype G-based vaccines provide robust neutralizing titers toward genotype G for up to 1 year in mice. In addition, we demonstrated that a third dose of a genotype G-based vaccine following two doses of JL immunization significantly increases neutralizing titers toward the genotype G strain. Our data suggest that after two doses of JL vaccination, which most people have received, a third dose of a genotype G-based vaccine can generate immunity against a genotype G strain. At present, most individuals have received two doses of the measles, mumps, and rubella (MMR) vaccine, which contains genotype A mumps vaccine. One hurdle in developing a new mumps vaccine against circulating genotype G virus is whether the new genotype G vaccine can generate immunity in humans that are immunized against genotype A virus. This work demonstrates that a novel genotype G-based vaccine can be effective in animals which received two doses of genotype A-based vaccine, suggesting that the lead genotype G vaccine may induce anti-G immunity in humans who have received two doses of the current vaccine, providing support for testing this vaccine in humans.
Topics: Animals; Antibodies, Viral; Genotype; Humans; Infant; Measles; Measles-Mumps-Rubella Vaccine; Mice; Mumps; Mumps Vaccine; Mumps virus
PubMed: 35389265
DOI: 10.1128/jvi.01983-21 -
Journal of Virology Nov 2015The mumps virus (MuV) genome encodes a phosphoprotein (P) that is important for viral RNA synthesis. P forms the viral RNA-dependent RNA polymerase with the large...
UNLABELLED
The mumps virus (MuV) genome encodes a phosphoprotein (P) that is important for viral RNA synthesis. P forms the viral RNA-dependent RNA polymerase with the large protein (L). P also interacts with the viral nucleoprotein (NP) and self-associates to form a homotetramer. The P protein consists of three domains, the N-terminal domain (P(N)), the oligomerization domain (P(O)), and the C-terminal domain (P(C)). While P(N) is known to relax the NP-bound RNA genome, the roles of P(O) and P(C) are not clear. In this study, we investigated the roles of P(O) and P(C) in viral RNA synthesis using mutational analysis and a minigenome system. We found that P(N) and P(C) functions can be trans-complemented. However, this complementation requires P(O), indicating that P(O) is essential for P function. Using this trans-complementation system, we found that P forms parallel dimers (P(N) to P(N) and P(C) to P(C)). Furthermore, we found that residues R231, K238, K253, and K260 in P(O) are critical for P's functions. We identified P(C) to be the domain that interacts with L. These results provide structure-function insights into the role of MuV P.
IMPORTANCE
MuV, a paramyxovirus, is an important human pathogen. The P protein of MuV is critical for viral RNA synthesis. In this work, we established a novel minigenome system that allows the domains of P to be complemented in trans. Using this system, we confirmed that MuV P forms parallel dimers. An understanding of viral RNA synthesis will allow the design of better vaccines and the development of antivirals.
Topics: Cloning, Molecular; DNA Mutational Analysis; HEK293 Cells; Humans; Immunoblotting; Immunoprecipitation; Luciferases; Mumps virus; N-Acetylglucosaminyltransferases; Phosphoproteins; Polymerization; RNA, Viral; Viral Proteins
PubMed: 26311887
DOI: 10.1128/JVI.01719-15 -
Virology Mar 2007Mumps is an acute infectious disease caused by mumps virus, a member of the family Paramyxoviridae. With the implementation of vaccination programs, mumps infection is...
Mumps is an acute infectious disease caused by mumps virus, a member of the family Paramyxoviridae. With the implementation of vaccination programs, mumps infection is under control. However, due to resurgence of mumps epidemics, there is a renewed interest in understanding the antigenic diversity of mumps virus. Hemagglutinin-neuraminidase (HN) is the major surface antigen and is known to elicit neutralizing antibodies. Mutational analysis of HN of wild-type and vaccine strains revealed that the hypervariable positions are distributed over the entire length with no detectable pattern. In the absence of experimentally derived 3D structure data, the structure of HN protein of mumps virus was predicted using homology modeling. Mutations mapped on the predicted structures were found to cluster on one of the surfaces. A predicted conformational epitope encompasses experimentally characterized epitopes suggesting that it is a major site for neutralization. These analyses provide rationale for strain specificity, antigenic diversity and varying efficacy of mumps vaccines.
Topics: Antigenic Variation; Antigens, Viral; Computational Biology; Genetic Speciation; Models, Molecular; Mumps virus; Protein Conformation; Species Specificity; Viral Proteins
PubMed: 17081582
DOI: 10.1016/j.virol.2006.09.040 -
Journal of Virology Jul 2013In recent years, many mumps outbreaks have occurred in vaccinated populations worldwide. The reasons for these outbreaks are not clear. Animal models are needed to... (Comparative Study)
Comparative Study
In recent years, many mumps outbreaks have occurred in vaccinated populations worldwide. The reasons for these outbreaks are not clear. Animal models are needed to investigate the causes of outbreaks and to understand the pathogenesis of mumps virus (MuV). In this study, we have examined the infection of three animal models with an isolate of mumps virus from a recent outbreak (MuV-IA). We have found that while both ferrets and mice generated humoral and cellular immune responses to MuV-IA infection, no obvious signs of illness were observed in these animals; rhesus macaques were the most susceptible to MuV-IA infection. Infection of rhesus macaques via both intranasal and intratracheal routes with MuV-IA led to the typical clinical signs of mumps 2 weeks to 4 weeks postinfection. However, none of the infected macaques showed any fever or neurologic signs during the experimental period. Mumps viral antigen was detected in parotid glands by immunohistochemistry (IHC). Rhesus macaques represent the best animal model for the study of mumps virus pathogenesis.
Topics: Animals; Chlorocebus aethiops; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Ferrets; Immunohistochemistry; Macaca mulatta; Mice; Mice, Inbred BALB C; Mumps; Mumps virus; Neutralization Tests; Parotid Gland; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Species Specificity; Vero Cells
PubMed: 23678169
DOI: 10.1128/JVI.01028-13