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Journal of Translational Medicine Jul 2023Viral therapies developed for cancer treatment have classically prioritized direct oncolytic effects over their immune activating properties. However, recent clinical...
BACKGROUND
Viral therapies developed for cancer treatment have classically prioritized direct oncolytic effects over their immune activating properties. However, recent clinical insights have challenged this longstanding prioritization and have shifted the focus to more immune-based mechanisms. Through the potential utilization of novel, inherently immune-stimulating, oncotropic viruses there is a therapeutic opportunity to improve anti-tumor outcomes through virus-mediated immune activation. PV001-DV is an attenuated strain of Dengue virus (DEN-1 #45AZ5) with a favorable clinical safety profile that also maintains the potent immune stimulatory properties characterstic of Dengue virus infection.
METHODS
In this study, we utilized in vitro tumor killing and immune multiplex assays to examine the anti-tumor effects of PV001-DV as a potential novel cancer immunotherapy.
RESULTS
In vitro assays demonstrated that PV001-DV possesses the ability to directly kill human melanoma cells lines as well as patient melanoma tissue ex vivo. Importantly, further work demonstrated that, when patient peripheral blood mononuclear cells (PBMCs) were exposed to PV001-DV, a substantial induction in the production of apoptotic factors and immunostimulatory cytokines was detected. When tumor cells were cultured with the resulting soluble mediators from these PBMCs, rapid cell death of melanoma and breast cancer cell lines was observed. These soluble mediators also increased dengue virus binding ligands and immune checkpoint receptor, PD-L1 expression.
CONCLUSIONS
The direct in vitro tumor-killing and immune-mediated tumor cytotoxicity facilitated by PV001-DV contributes support of its upcoming clinical evaluation in patients with advanced melanoma who have failed prior therapy.
Topics: Humans; Dengue Virus; Leukocytes, Mononuclear; Melanoma; MCF-7 Cells; Dengue; Immunity; Cell Death; Oncolytic Virotherapy; Oncolytic Viruses
PubMed: 37468934
DOI: 10.1186/s12967-023-04344-8 -
RNA (New York, N.Y.) Sep 2022Dengue virus, a single-stranded positive sense RNA virus, is the most prevalent mosquito-borne pathogen in the world. Like all RNA viruses, it uses conserved structural...
Dengue virus, a single-stranded positive sense RNA virus, is the most prevalent mosquito-borne pathogen in the world. Like all RNA viruses, it uses conserved structural elements within its genome to control essential replicative steps. A 70 nt stem-loop RNA structure (called SLA), found at the 5'-end of the genome of all flaviviruses, functions as the promoter for viral replication. This highly conserved structure interacts with the viral polymerase NS5 to initiate RNA synthesis. Here, we report the NMR structure of a monomeric SLA from dengue virus serotype 1, assembled to high-resolution from independently folded structural elements. The DENV1 SLA has an L-shaped structure, where the top and side helices are coaxially stacked, and the bottom helix is roughly perpendicular to them. Because the sequence is highly conserved among different flavivirus genomes, it is very likely that the three-dimensional fold and local structure of SLA are also conserved among flaviviruses and required for efficient replication. This work provides structural insight into the dengue promoter and provides the foundation for the discovery of new antiviral drugs that target this essential replicative step.
Topics: Animals; Dengue Virus; Promoter Regions, Genetic; RNA, Viral; Virus Replication
PubMed: 35750488
DOI: 10.1261/rna.079197.122 -
European Journal of Medicinal Chemistry Aug 2019Dengue is the most important arthropod-borne viral disease of humans, with more than half of the global population living in at-risk areas. Despite the negative impact... (Review)
Review
Dengue is the most important arthropod-borne viral disease of humans, with more than half of the global population living in at-risk areas. Despite the negative impact on public health, there are no antiviral therapies available, and the only licensed vaccine, Dengvaxia, has been contraindicated in children below nine years of age. In an effort to combat dengue, several small molecules have entered into human clinical trials. Here, we review anti-DENV molecules and their drug targets that have been published within the past five years (2014-2018). Further, we discuss their probable mechanisms of action and describe a role for classes of clinically approved drugs and also an unclassified class of anti-DENV agents. This review aims to enhance our understanding of novel agents and their cognate targets in furthering innovations in the use of small molecules for dengue drug therapies.
Topics: Animals; Antiviral Agents; Biological Products; Cell Line, Tumor; Dengue Virus; Drug Discovery; Humans; Serine Proteinase Inhibitors; Viral Nonstructural Proteins; Virus Replication
PubMed: 31128447
DOI: 10.1016/j.ejmech.2019.05.010 -
Archives of Virology Jul 2023Dengue is a viral disease transmitted by mosquitoes that has spread rapidly across all continents in recent years. There are four distinct but closely related serotypes... (Review)
Review
Dengue is a viral disease transmitted by mosquitoes that has spread rapidly across all continents in recent years. There are four distinct but closely related serotypes of the virus that causes dengue (DENV-1, DENV-2, DENV-3, and DENV-4). In the present study, we evaluated temporal spreading and molecular evolution of dengue virus (DENV) serotypes. Bayesian coalescent analysis was performed to study viral evolution, and it was estimated that the most recent common ancestor of DENV-1 was present in 1884 in Southeast Asia, that of DENV-2 was present in 1723 in Europe, that of DENV-3 was present in 1921 in Southeast Asia, and that of DENV-4 was present in 1876 in Southeast Asia. DENV appears to have originated in Spain in approximately 1682, and it was disseminated in Asia and Oceania in approximately 1847. After this period, the virus was introduced into North America in approximately 1890. In South America, it was first disseminated to Ecuador in approximately 1897 and then to Brazil in approximately 1910. Dengue has had a significant impact on global health worldwide, and the present study provides an overview of the molecular evolution of DENV serotypes.
Topics: Animals; Humans; Bayes Theorem; Brazil; Dengue; Dengue Virus; Evolution, Molecular; Phylogeny
PubMed: 37410187
DOI: 10.1007/s00705-023-05833-3 -
Viruses May 2023Dengue virus (DENV) infections have unpredictable clinical outcomes, ranging from asymptomatic or minor febrile illness to severe and fatal disease. The severity of...
Dengue virus (DENV) infections have unpredictable clinical outcomes, ranging from asymptomatic or minor febrile illness to severe and fatal disease. The severity of dengue infection is at least partly related to the replacement of circulating DENV serotypes and/or genotypes. To describe clinical profiles of patients and the viral sequence diversity corresponding to non-severe and severe cases, we collected patient samples from 2018 to 2022 at Evercare Hospital Dhaka, Bangladesh. Serotyping of 495 cases and sequencing of 179 cases showed that the dominant serotype of DENV shifted from DENV2 in 2017 and 2018 to DENV3 in 2019. DENV3 persisted as the only representative serotype until 2022. Co-circulation of clades B and C of the DENV2 cosmopolitan genotype in 2017 was replaced by circulation of clade C alone in 2018 with all clones disappearing thereafter. DENV3 genotype I was first detected in 2017 and was the only genotype in circulation until 2022. We observed a high incidence of severe cases in 2019 when the DENV3 genotype I became the only virus in circulation. Phylogenetic analysis revealed clusters of severe cases in several different subclades of DENV3 genotype I. Thus, these serotype and genotype changes in DENV may explain the large dengue outbreaks and increased severity of the disease in 2019.
Topics: Humans; Dengue Virus; Dengue; Phylogeny; Bangladesh; Serogroup; Genotype
PubMed: 37243230
DOI: 10.3390/v15051144 -
Frontiers in Cellular and Infection... 2023Among many medically important pathogens, arboviruses like dengue, Zika and chikungunya cause severe health and economic burdens especially in developing countries.... (Review)
Review
Among many medically important pathogens, arboviruses like dengue, Zika and chikungunya cause severe health and economic burdens especially in developing countries. These viruses are primarily vectored by mosquitoes. Having surmounted geographical barriers and threat of control strategies, these vectors continue to conquer many areas of the globe exposing more than half of the world's population to these viruses. Unfortunately, no medical interventions have been capable so far to produce successful vaccines or antivirals against many of these viruses. Thus, vector control remains the fundamental strategy to prevent disease transmission. The long-established understanding regarding the replication of these viruses is that they reshape both human and mosquito host cellular membranes upon infection for their replicative benefit. This leads to or is a result of significant alterations in lipid metabolism. Metabolism involves complex chemical reactions in the body that are essential for general physiological functions and survival of an organism. Finely tuned metabolic homeostases are maintained in healthy organisms. However, a simple stimulus like a viral infection can alter this homeostatic landscape driving considerable phenotypic change. Better comprehension of these mechanisms can serve as innovative control strategies against these vectors and viruses. Here, we review the metabolic basis of fundamental mosquito biology and virus-vector interactions. The cited work provides compelling evidence that targeting metabolism can be a paradigm shift and provide potent tools for vector control as well as tools to answer many unresolved questions and gaps in the field of arbovirology.
Topics: Animals; Humans; Dengue Virus; Aedes; Arboviruses; Zika Virus; Zika Virus Infection
PubMed: 37360524
DOI: 10.3389/fcimb.2023.1128577 -
Emerging Infectious Diseases Jun 2022We investigated the effects of dengue virus (DENV) on semen using samples collected 7, 15, 30, 60, and 90 days after symptom onset from 10 infected volunteers on...
We investigated the effects of dengue virus (DENV) on semen using samples collected 7, 15, 30, 60, and 90 days after symptom onset from 10 infected volunteers on Réunion Island. We assessed characteristics of semen and reproductive hormones and isolated motile spermatozoa from semen. We assayed semen for DENV using reverse transcription PCR and searched for DENV RNA by virus isolation in Vero E6 cell cultures. Four volunteers had >1 DENV RNA-positive semen samples; 2 volunteers had DENV RNA-positive semen at day 15 and 1 at day 30. No motile sperm were DENV positive. After exposure to positive semen, few Vero E6 cells stained positive for DENV antigens, indicating low levels of replicative virus. We found DENV had shorter duration in semen than in blood. These findings support the possibilities that DENV is sexually transmissible for a short period after acute dengue illness and that acute dengue induces reversible alterations in sperm.
Topics: Aedes; Animals; Body Fluids; DNA Viruses; Dengue; Dengue Virus; Humans; Male; RNA; Spermatozoa
PubMed: 35608553
DOI: 10.3201/eid2806.212317 -
International Journal of Infectious... Jun 2021Dengue fever was included in the top 10 global health threats announced by the World Health Organization (WHO) in early 2019. In some southern provinces of China,...
Dengue fever was included in the top 10 global health threats announced by the World Health Organization (WHO) in early 2019. In some southern provinces of China, autochthonous outbreaks have also been reported over the last decade. An unexpected large outbreak of dengue fever was reported in Xishuangbanna, a border area of China, Myanmar, and Laos, in 2019. Among the 226 hospitalized cases, 90 were diagnosed as severe dengue according to the 2009 WHO guidelines. Serotyping and phylogenetic analyses of envelope gene sequences from 246 randomly selected samples showed that three serotypes of dengue virus were co-circulating in this outbreak, which is very rare in this area. Dengue virus serotype 1 (DENV-1, genotype I) and serotype 2 (DENV-2, Cosmopolitan genotype and Asian genotype) were the main pathogenic agents of this outbreak. Dengue virus serotype 3 (DENV-3) epidemic strains were classified as genotype III and formed a close cluster with the Thailand 2015 epidemic strain. The co-circulation may have led to more serious clinical symptoms and a larger scale epidemic. This finding is of great importance in understanding the circulation of DENV and to strengthen the detection and management of dengue fever in border areas.
Topics: Adolescent; Adult; China; Dengue Virus; Disease Outbreaks; Epidemics; Female; Genotype; Humans; Laos; Male; Middle Aged; Myanmar; Phylogeny; Serogroup; Serotyping; Severe Dengue; Thailand; Young Adult
PubMed: 33857610
DOI: 10.1016/j.ijid.2021.04.010 -
Current Opinion in Virology Aug 2020Endothelial dysfunction leading to vascular permeability and plasma leakage are characteristic features of severe dengue and sepsis. However, the mechanisms underlying... (Review)
Review
Endothelial dysfunction leading to vascular permeability and plasma leakage are characteristic features of severe dengue and sepsis. However, the mechanisms underlying these immune-pathologies remain unclear. The risk of severe dengue and sepsis development depend on patient-related and pathogen-related factors. Additionally, comorbidities increase the risk of severe disease and their incidence hampers correct diagnosis and treatments. To date, there is no efficient therapy to combat severe dengue and sepsis. Here, we discuss the differences and similarities between the pathogenesis of severe dengue and that of bacterial sepsis. We identify gaps in knowledge that need to be better understood in order to move towards the rational development and/or usage of therapeutic strategies to ameliorate severe dengue disease.
Topics: Animals; Capillary Permeability; Dengue Virus; Humans; Sepsis; Severe Dengue
PubMed: 32896675
DOI: 10.1016/j.coviro.2020.07.010 -
Epidemiological survey and screening strategy for dengue virus in blood donors from Yunnan Province.BMC Infectious Diseases Jan 2021Dengue virus (DENV) infection is increasingly common in southern China and can be transmitted through blood transfusion but is not currently part of donor screening...
BACKGROUND
Dengue virus (DENV) infection is increasingly common in southern China and can be transmitted through blood transfusion but is not currently part of donor screening throughout the region. We assessed DENV prevalence among donors at the Xishuangbanna Blood Center, Yunnan, to support development of DENV screening strategies.
METHODS
Blood samples were collected randomly between June 2019 and August 2019. These were screened for anti-DENV IgG and IgM using enzyme-linked immunosorbent assay (ELISA). Then, all reactive samples and some randomly-chosen non-reactive samples were used to detect DENV RNAs using real-time polymerase-chain-reaction (RT-PCR) assays. After RT-PCR, samples were further tested for soluble nonstructural protein 1 (NS1) using the colloidal gold method. Donors demographics were also collected and assessed.
RESULTS
Over the study period, 2254 donor samples were collected and tested for anti-DENV IgG and IgM by ELISA. This revealed 598 anti-DENV IgG and/or IgM reactive samples, a serological prevalence of 26.53%. Of these, 26 were RT-PCR positive and/or NS1 positive. Significant differences in DENV prevalence were noted by occupation (P = 0.001), education (P < 0.001), and ethnicity (P = 0.026).
CONCLUSION
The prevalence of DENV in Xishuangbanna Blood Center was higher than most other blood centers that have implemented DENV donor screening. Our study provides first-hand data about the prevalence of DENV and allows the development of a screening strategy for clinical use.
Topics: Adult; Antibodies, Viral; Blood Donors; China; Dengue; Dengue Virus; Female; Humans; Male; Mass Screening; Middle Aged; Prevalence; RNA, Viral; Viral Nonstructural Proteins; Young Adult
PubMed: 33482756
DOI: 10.1186/s12879-021-05810-8