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International Journal of Molecular... Oct 2023Sindbis alphavirus vectors offer a promising platform for cancer therapy, serving as valuable models for alphavirus-based treatment. This review emphasizes key studies... (Review)
Review
Sindbis alphavirus vectors offer a promising platform for cancer therapy, serving as valuable models for alphavirus-based treatment. This review emphasizes key studies that support the targeted delivery of Sindbis vectors to tumor cells, highlighting their effectiveness in expressing tumor-associated antigens and immunomodulating proteins. Among the various alphavirus vectors developed for cancer therapy, Sindbis-vector-based imaging studies have been particularly extensive. Imaging modalities that enable the in vivo localization of Sindbis vectors within lymph nodes and tumors are discussed. The correlation between laminin receptor expression, tumorigenesis, and Sindbis virus infection is examined. Additionally, we present alternative entry receptors for Sindbis and related alphaviruses, such as Semliki Forest virus and Venezuelan equine encephalitis virus. The review also discusses cancer treatments that are based on the alphavirus vector expression of anti-tumor agents, including tumor-associated antigens, cytokines, checkpoint inhibitors, and costimulatory immune molecules.
Topics: Humans; Alphavirus; Genetic Vectors; Neoplasms; Encephalitis Virus, Venezuelan Equine; Genetic Therapy
PubMed: 37834397
DOI: 10.3390/ijms241914948 -
Microorganisms Dec 2023Vector-borne viral diseases (VBVDs) continue to pose a considerable public health risk to animals and humans globally. Vectors have integral roles in autochthonous... (Review)
Review
Vector-borne viral diseases (VBVDs) continue to pose a considerable public health risk to animals and humans globally. Vectors have integral roles in autochthonous circulation and dissemination of VBVDs worldwide. The interplay of agricultural activities, population expansion, urbanization, host/pathogen evolution, and climate change, all contribute to the continual flux in shaping the epidemiology of VBVDs. In recent decades, VBVDs, once endemic to particular countries, have expanded into new regions such as Iran and its neighbors, increasing the risk of outbreaks and other public health concerns. Both Iran and its neighboring countries are known to host a number of VBVDs that are endemic to these countries or newly circulating. The proximity of Iran to countries hosting regional diseases, along with increased global socioeconomic activities, e.g., international trade and travel, potentially increases the risk for introduction of new VBVDs into Iran. In this review, we examined the epidemiology of numerous VBVDs circulating in Iran, such as Chikungunya virus, Dengue virus, Sindbis virus, West Nile virus, Crimean-Congo hemorrhagic fever virus, Sandfly-borne phleboviruses, and Hantavirus, in relation to their vectors, specifically mosquitoes, ticks, sandflies, and rodents. In addition, we discussed the interplay of factors, e.g., urbanization and climate change on VBVD dissemination patterns and the consequent public health risks in Iran, highlighting the importance of a One Health approach to further surveil and to evolve mitigation strategies.
PubMed: 38138150
DOI: 10.3390/microorganisms11123006 -
International Journal of Molecular... Mar 2024This review article provides a comprehensive overview of a novel Sindbis virus vaccine platform as potential immunotherapy for ovarian cancer patients. Ovarian cancer is... (Review)
Review
This review article provides a comprehensive overview of a novel Sindbis virus vaccine platform as potential immunotherapy for ovarian cancer patients. Ovarian cancer is the most lethal of all gynecological malignancies. The majority of high-grade serous ovarian cancer (HGSOC) patients are diagnosed with advanced disease. Current treatment options are very aggressive and limited, resulting in tumor recurrences and 50-60% patient mortality within 5 years. The unique properties of armed oncolytic Sindbis virus vectors (SV) in vivo have garnered significant interest in recent years to potently target and treat ovarian cancer. We discuss the molecular biology of Sindbis virus, its mechanisms of action against ovarian cancer cells, preclinical in vivo studies, and future perspectives. The potential of Sindbis virus-based therapies for ovarian cancer treatment holds great promise and warrants further investigation. Investigations using other oncolytic viruses in preclinical studies and clinical trials are also presented.
Topics: Humans; Female; Oncolytic Viruses; Sindbis Virus; Oncolytic Virotherapy; Neoplasm Recurrence, Local; Ovarian Neoplasms; Immunotherapy; Vaccines
PubMed: 38474178
DOI: 10.3390/ijms25052925 -
PloS One 2023Meningoencephalitis in children poses a diagnostic challenge, as etiology remains unknown for most of patients. Viral metagenomics by shotgun sequencing represents a...
INTRODUCTION
Meningoencephalitis in children poses a diagnostic challenge, as etiology remains unknown for most of patients. Viral metagenomics by shotgun sequencing represents a powerful tool for investigating unknown viral infections related to these cases.
PATIENTS AND METHODS
In a two-year, reference-centre, retrospective study, we investigated the usefulness of viral metagenomics of cerebrospinal fluid (CSF) for the diagnosis of viral infectious meningoencephalitis in forty seven pediatric patients, forty of them previously tested negative with a routine neurologic panel of viral targets that included herpesvirus 1-3 and enterovirus. We enhanced the detection by targeting viral sequences by hybrid capture. Raw sequence data was analysed using three bioinformatics pipelines.
RESULTS
Out of forty remaining children with meningoencephalitis of unknown viral etiology, a significant detection of viral nucleic acid by shotgun sequencing was found in twenty one, which was confirmed in ten of them by specific PCR: seven human endogenous retrovirus K113 (HER K113), one parechovirus 3, one human herpesvirus 5 (HHV5); one enterovirus B (Echovirus 9). The remaining eleven CSF were not confirmed by PCR: three rotavirus, one human herpesvirus 7 (HHV7), one influenza A, one mastadenovirus C, one sindbis virus, one torque teno virus, one human immunodeficiency virus 1 (HIV-1), one human alphaherpesvirus 3 (HHV3), one human alphaherpesvirus 2 (HHV2).
CONCLUSIONS
Underutilization of currently available meningitis-encephalitis diagnostic techniques such as BioFire® FilmArray® is the main cause of undiagnosed cases of meningoencephalitis. However, in this study we detected uncommon viruses that should be considered, including virus, rotavirus, sindbis virus, influenza A virus and HHV7. No other viral sequences that could be readily linked to CNS inflammation were detected. Some findings may stem from reagent or sample contamination, as seen with papillomavirus; for others, the clinical relevance of the virus remains uncertain and should be substantiated by further studies, as is the case with endogenous retrovirus K113 virus. Online bioinformatics pipeline CZID represents a valuable tool for analysing shotgun sequencing data in cases of neurological conditions with unknown etiology. Altogether, this study highlights the potential of shotgun sequencing in identifying previously unknown viral neuropathogens and sheds light on the interpretation issues related to its application in clinical microbiology.
Topics: Humans; Child; Retrospective Studies; Meningoencephalitis; Viruses; Virus Diseases; Inflammation; Herpesvirus 3, Human; Metagenomics
PubMed: 38127927
DOI: 10.1371/journal.pone.0296036 -
CDKL5 regulates p62-mediated selective autophagy and confers protection against neurotropic viruses.The Journal of Clinical Investigation Jan 2024Virophagy, the selective autophagosomal engulfment and lysosomal degradation of viral components, is crucial for neuronal cell survival and antiviral immunity. However,...
Virophagy, the selective autophagosomal engulfment and lysosomal degradation of viral components, is crucial for neuronal cell survival and antiviral immunity. However, the mechanisms leading to viral antigen recognition and capture by autophagic machinery remain poorly understood. Here, we identified cyclin-dependent kinase-like 5 (CDKL5), known to function in neurodevelopment, as an essential regulator of virophagy. Loss-of-function mutations in CDKL5 are associated with a severe neurodevelopmental encephalopathy. We found that deletion of CDKL5 or expression of a clinically relevant pathogenic mutant of CDKL5 reduced virophagy of Sindbis virus (SINV), a neurotropic RNA virus, and increased intracellular accumulation of SINV capsid protein aggregates and cellular cytotoxicity. Cdkl5-knockout mice displayed increased viral antigen accumulation and neuronal cell death after SINV infection and enhanced lethality after infection with several neurotropic viruses. Mechanistic studies demonstrated that CDKL5 directly binds the canonical selective autophagy receptor p62 and phosphorylates p62 at T269/S272 to promote its interaction with viral capsid aggregates. We found that CDKL5-mediated phosphorylation of p62 facilitated the formation of large p62 inclusion bodies that captured viral capsids to initiate capsid targeting to autophagic machinery. Overall, these findings identify a cell-autonomous innate immune mechanism for autophagy activation to clear intracellular toxic viral protein aggregates during infection.
Topics: Mice; Animals; Protein Aggregates; Viruses; Autophagy; Phosphorylation; Mice, Knockout; Capsid Proteins; Antigens, Viral; Protein Serine-Threonine Kinases
PubMed: 37917202
DOI: 10.1172/JCI168544 -
Viruses Dec 2023Sindbis virus (SINV) is a widely dispersed mosquito-borne alphavirus. Reports of Sindbis disease are largely restricted to northern Europe and South Africa. SINV is...
Sindbis virus (SINV) is a widely dispersed mosquito-borne alphavirus. Reports of Sindbis disease are largely restricted to northern Europe and South Africa. SINV is frequently sampled in Australian mosquito-based arbovirus surveillance programs, but human disease has rarely been reported. Molecular epidemiological studies have characterized six SINV genotypes (G1-G6) based on E2 gene phylogenies, mostly comprising viruses derived from the African-European zoogeographical region and with limited representation of Australasian SINV. In this study, we conducted whole genome sequencing of 66 SINV isolates sampled between 1960 and 2014 from countries of the Australasian region: Australia, Malaysia, and Papua New Guinea. G2 viruses were the most frequently and widely sampled, with three distinct sub-lineages defined. No new G6 SINV were identified, confirming geographic restriction of these viruses to south-western Australia. Comparison with global SINV characterized large-scale nucleotide and amino acid sequence divergence between African-European G1 viruses and viruses that circulate in Australasia (G2 and G3) of up to 26.83% and 14.55%, respectively, divergence that is sufficient for G2/G3 species demarcation. We propose G2 and G3 are collectively a single distinct alphavirus species that we name Argyle virus, supported by the inapparent or mild disease phenotype and the higher evolutionary rate compared with G1. Similarly, we propose G6, with 24.7% and 12.61% nucleotide and amino acid sequence divergence, is a distinct alphavirus species that we name Thomson's Lake virus.
Topics: Animals; Humans; Sindbis Virus; Australia; Culicidae; Genomics; Nucleotides
PubMed: 38275942
DOI: 10.3390/v16010007 -
Proceedings of the National Academy of... Sep 2023Multiple viruses, including pathogenic viruses, bacteriophages, and even plant viruses, cause a phenomenon termed superinfection exclusion whereby a currently infected...
Multiple viruses, including pathogenic viruses, bacteriophages, and even plant viruses, cause a phenomenon termed superinfection exclusion whereby a currently infected cell is resistant to secondary infection by the same or a closely related virus. In alphaviruses, this process is thought to be mediated, at least in part, by the viral protease (nsP2) which is responsible for processing the nonstructural polyproteins (P123 and P1234) into individual proteins (nsP1-nsP4), forming the viral replication complex. Taking a synthetic biology approach, we mimicked this naturally occurring phenomenon by generating a superinfection exclusion-like state in mosquitoes, rendering them refractory to alphavirus infection. By artificially expressing Sindbis virus (SINV) and chikungunya virus (CHIKV) nsP2 in mosquito cells and transgenic mosquitoes, we demonstrated a reduction in both SINV and CHIKV viral replication rates in cells following viral infection as well as reduced infection prevalence, viral titers, and transmission potential in mosquitoes.
Topics: Animals; Aedes; Yellow Fever; Superinfection; Alphavirus Infections; Chikungunya virus; Sindbis Virus
PubMed: 37669371
DOI: 10.1073/pnas.2303080120 -
Trends in Parasitology Apr 2024Parasites can manipulate host behavior to enhance transmission, but our understanding of arbovirus-induced changes in mosquito behavior is limited. Here, we explore... (Review)
Review
Parasites can manipulate host behavior to enhance transmission, but our understanding of arbovirus-induced changes in mosquito behavior is limited. Here, we explore current knowledge on such behavioral alterations in mosquito vectors, focusing on host-seeking and blood-feeding behaviors. Reviewing studies on dengue, Zika, La Crosse, Sindbis, and West Nile viruses in Aedes or Culex mosquitoes reveals subtle yet potentially significant effects. However, assay heterogeneity and limited sample sizes challenge definitive conclusions. To enhance robustness, we propose using deep-learning tools for automated behavior quantification and stress the need for standardized assays. Additionally, conducting longitudinal studies across the extrinsic incubation period and integrating diverse traits into modeling frameworks are crucial for understanding the nuanced implications of arbovirus-induced behavioral changes for virus transmission dynamics.
Topics: Animals; Arboviruses; Zika Virus; Zika Virus Infection; Aedes; Mosquito Vectors
PubMed: 38423938
DOI: 10.1016/j.pt.2024.02.004 -
Cancers Sep 2023The characteristics of glioblastoma, such as drug resistance during treatment, short patient survival, and high recurrence rates, have made patients with glioblastoma...
BACKGROUND
The characteristics of glioblastoma, such as drug resistance during treatment, short patient survival, and high recurrence rates, have made patients with glioblastoma more likely to benefit from oncolytic therapy.
METHODS
In this study, we investigated the safety of the sindbis virus by injecting virus intravenously and intracranially in mice and evaluated the therapeutic effect of the virus carrying different combinations of IL-12, IL-7, and GM-CSF on glioma in a glioma-bearing mouse model.
RESULTS
SINV was autologously eliminated from the serum and organs as well as from neural networks after entering mice. Furthermore, SINV was restricted to the injection site in the tree shrew brain and did not spread throughout the whole brain. In addition, we found that SINV-induced apoptosis in conjunction with the stimulation of the immune system by tumor-killing cytokines substantially suppressed tumor development. It is worth mentioning that SINV carrying IL-7 and IL-12 had the most notable glioma-killing effect. Furthermore, in an intracranial glioma model, SINV containing IL-7 and IL-12 effectively prolonged the survival time of mice and inhibited glioma progression.
CONCLUSIONS
These results suggest that SINV has a significant safety profile as an oncolytic virus and that combining SINV with cytokines is an efficient treatment option for malignant gliomas.
PubMed: 37835433
DOI: 10.3390/cancers15194738 -
Journal of Virology Jun 2023Viral oncolytic immunotherapy is a nascent field that is developing tools to direct the immune system to find and eliminate cancer cells. Safety is improved by using...
Viral oncolytic immunotherapy is a nascent field that is developing tools to direct the immune system to find and eliminate cancer cells. Safety is improved by using cancer-targeted viruses that infect or grow poorly on normal cells. The recent discovery of the low-density lipoprotein (LDL) receptor as the major vesicular stomatitis virus (VSV) binding site allowed for the creation of a Her2/neu-targeted replicating recombinant VSV (rrVSV-G) by eliminating the LDL receptor binding site in the VSV-G glycoprotein (gp) and adding a sequence coding for a single chain antibody (SCA) to the Her2/neu receptor. The virus was adapted by serial passage on Her2/neu-expressing cancer cells resulting in a virus that yielded a 15- to 25-fold higher titer following infection of Her2/neu-expressing cell lines than that of Her2/neu-negative cells (~1 × 10/mL versus 4 × 10 to 8 × 10/mL). An essential mutation resulting in a higher titer virus was a threonine-to-arginine change that produced an N-glycosylation site in the SCA. Infection of Her2/neu subcutaneous tumors yielded >10-fold more virus on days 1 and 2 than Her2/neu tumors, and virus production continued for 5 days in Her2/neu tumors compared with 3 days that of 3 days in Her2/neu tumors. rrVSV-G cured 70% of large 5-day peritoneal tumors compared with a 10% cure by a previously targeted rrVSV with a modified Sindbis gp. rrVSV-G also cured 33% of very large 7-day tumors. rrVSV-G is a new targeted oncolytic virus that has potent antitumor capabilities and allows for heterologous combination with other targeted oncolytic viruses. A new form of vesicular stomatitis virus (VSV) was created that specifically targets and destroys cancer cells that express the Her2/neu receptor. This receptor is commonly found in human breast cancer and is associated with a poor prognosis. In laboratory tests using mouse models, the virus was highly effective at eliminating implanted tumors and creating a strong immune response against cancer. VSV has many advantages as a cancer treatment, including high levels of safety and efficacy and the ability to be combined with other oncolytic viruses to enhance treatment results or to create an effective cancer vaccine. This new virus can also be easily modified to target other cancer cell surface molecules and to add immune-modifying genes. Overall, this new VSV is a promising candidate for further development as an immune-based cancer therapy.
Topics: Animals; Female; Humans; Mice; Breast Neoplasms; Cell Line, Tumor; Glycoproteins; Oncolytic Virotherapy; Oncolytic Viruses; Receptor, ErbB-2; Vesiculovirus; Virus Replication; Survival Analysis
PubMed: 37199666
DOI: 10.1128/jvi.00372-23