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Journal of Biomedical Science Apr 2024Dengue viruses (DENV) are positive-stranded RNA viruses belonging to the Flaviviridae family. DENV is the causative agent of dengue, the most rapidly spreading viral... (Review)
Review
Dengue viruses (DENV) are positive-stranded RNA viruses belonging to the Flaviviridae family. DENV is the causative agent of dengue, the most rapidly spreading viral disease transmitted by mosquitoes. Each year, millions of people contract the virus through bites from infected female mosquitoes of the Aedes species. In the majority of individuals, the infection is asymptomatic, and the immune system successfully manages to control virus replication within a few days. Symptomatic individuals may present with a mild fever (Dengue fever or DF) that may or may not progress to a more critical disease termed Dengue hemorrhagic fever (DHF) or the fatal Dengue shock syndrome (DSS). In the absence of a universally accepted prophylactic vaccine or therapeutic drug, treatment is mostly restricted to supportive measures. Similar to many other viruses that induce acute illness, DENV has developed several ways to modulate host metabolism to create an environment conducive to genome replication and the dissemination of viral progeny. To search for new therapeutic options, understanding the underlying host-virus regulatory system involved in various biological processes of the viral life cycle is essential. This review aims to summarize the complex interaction between DENV and the host cellular machinery, comprising regulatory mechanisms at various molecular levels such as epigenetic modulation of the host genome, transcription of host genes, translation of viral and host mRNAs, post-transcriptional regulation of the host transcriptome, post-translational regulation of viral proteins, and pathways involved in protein degradation.
Topics: Dengue Virus; Humans; Dengue; Animals; Host-Pathogen Interactions; Virus Replication
PubMed: 38649998
DOI: 10.1186/s12929-024-01030-9 -
Viruses Nov 2023Subgenomic flaviviral RNAs (sfRNAs) are produced during flavivirus infections in both arthropod and vertebrate cells. They are undegraded products originating from the... (Review)
Review
Subgenomic flaviviral RNAs (sfRNAs) are produced during flavivirus infections in both arthropod and vertebrate cells. They are undegraded products originating from the viral 3' untranslated region (3' UTR), a result of the action of the host 5'-3' exoribonuclease, Xrn1, when it encounters specific RNA structures known as Xrn1-resistant RNAs (xrRNAs) within the viral 3' UTR. Dengue viruses generate three to four distinct species of sfRNAs through the presence of two xrRNAs and two dumbbell structures (DBs). The tertiary structures of xrRNAs have been characterized to form a ringlike structure around the 5' end of the viral RNA, effectively inhibiting the activity of Xrn1. The most important role of DENV sfRNAs is to inhibit host antiviral responses by interacting with viral and host proteins, thereby influencing viral pathogenicity, replicative fitness, epidemiological fitness, and transmission. In this review, we aimed to summarize the biogenesis, structures, and functions of DENV sfRNAs, exploring their implications for viral interference.
Topics: Humans; Flavivirus; Dengue Virus; Subgenomic RNA; 3' Untranslated Regions; Nucleic Acid Conformation; RNA, Viral; Dengue
PubMed: 38140548
DOI: 10.3390/v15122306 -
Biochemical Pharmacology Aug 2018Despite the ever-increasing global incidence of dengue fever, there are no specific chemotherapy regimens for its treatment. Structural studies on dengue virus (DENV)... (Review)
Review
Despite the ever-increasing global incidence of dengue fever, there are no specific chemotherapy regimens for its treatment. Structural studies on dengue virus (DENV) proteins have revealed potential drug targets. Major DENV proteins such as the envelope protein and non-structural (NS) proteins 3 and 5 have been extensively investigated in antiviral studies, but with limited success in vitro. However, the minor NS proteins NS2 and NS4 have remained relatively underreported. Emerging evidence indicating their indispensable roles in virus propagation and host immunomodulation should encourage us to target these proteins for drug discovery. This review covers current knowledge on DENV NS2 and NS4 proteins from structural and functional perspectives and assesses their potential as targets for antiviral design. Antiviral targets in NS2A include surface-exposed transmembrane regions involved in pathogenesis, while those in NS2B include protease-binding sites in a conserved hydrophilic domain. Ideal drug targets in NS4A include helix α4 and the PEPEKQR sequence, which are essential for NS4A-2K cleavage and NS4A-NS4B association, respectively. In NS4B, the cytoplasmic loop connecting helices α5 and α7 is an attractive target for antiviral design owing to its role in dimerization and NS4B-NS3 interaction. Findings implicating NS2A, NS2B, and NS4A in membrane-modulation and viroporin-like activities indicate an opportunity to target these proteins by disrupting their association with membrane lipids. Despite the lack of 3D structural data, recent topological findings and progress in structure-prediction methods should be sufficient impetus for targeting NS2 and NS4 for drug design.
Topics: Amino Acid Sequence; Animals; Dengue; Dengue Virus; Humans; Protein Structure, Secondary; Viral Nonstructural Proteins
PubMed: 29674002
DOI: 10.1016/j.bcp.2018.04.008 -
Viruses Jul 2021The four serotypes of the mature dengue virus can display different morphologies, including the compact spherical, the bumpy spherical and the non-spherical clubshape... (Review)
Review
The four serotypes of the mature dengue virus can display different morphologies, including the compact spherical, the bumpy spherical and the non-spherical clubshape morphologies. In addition, the maturation process of dengue virus is inefficient and therefore some partially immature dengue virus particles have been observed and they are infectious. All these viral particles have different antigenicity profiles and thus may affect the type of the elicited antibodies during an immune response. Understanding the molecular determinants and environmental conditions (e.g., temperature) in inducing morphological changes in the virus and how potent antibodies interact with these particles is important for designing effective therapeutics or vaccines. Several techniques, including cryoEM, site-directed mutagenesis, hydrogen-deuterium exchange mass spectrometry, time-resolve fluorescence resonance energy transfer, and molecular dynamic simulation, have been performed to investigate the structural changes. This review describes all known morphological variants of DENV discovered thus far, their surface protein dynamics and the key residues or interactions that play important roles in the structural changes.
Topics: Antibodies, Neutralizing; Antibodies, Viral; Antibody-Dependent Enhancement; Antigenic Variation; Antigens, Viral; Dengue; Dengue Vaccines; Dengue Virus; Humans; Serogroup; Viral Envelope Proteins
PubMed: 34452312
DOI: 10.3390/v13081446 -
Current Medicinal Chemistry 2020To date, there is still no approved anti-dengue agent to treat dengue infection in the market. Although the only licensed dengue vaccine, Dengvaxia is available, its...
To date, there is still no approved anti-dengue agent to treat dengue infection in the market. Although the only licensed dengue vaccine, Dengvaxia is available, its protective efficacy against serotypes 1 and 2 of dengue virus was reported to be lower than serotypes 3 and 4. Moreover, according to WHO, the risk of being hospitalized and having severe dengue increased in seronegative individuals after they received Dengvaxia vaccination. Nevertheless, various studies had been carried out in search of dengue virus inhibitors. These studies focused on the structural (C, prM, E) and non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) of dengue virus as well as host factors as drug targets. Hence, this article provides an overall up-to-date review of the discovery of dengue virus inhibitors that are only targeting the structural and non-structural viral proteins as drug targets.
Topics: Dengue; Dengue Virus; Humans; Viral Nonstructural Proteins
PubMed: 30514185
DOI: 10.2174/0929867326666181204155336 -
Viral Immunology 2017Dengue virus infection is a self-limited condition, which is of particular importance in tropical and subtropical regions and for which no specific treatment or... (Review)
Review
Dengue virus infection is a self-limited condition, which is of particular importance in tropical and subtropical regions and for which no specific treatment or effective vaccine is available. There are several hypotheses explaining dengue pathogenesis. These usually refer to host immune responses, including antibody-dependent enhancement, cytokine expression, and dengue virus particles including NS1 protein, which lead to cell death by both apoptosis and pyroptosis. A clear understanding of the pathogenesis should facilitate the development of vaccines and therapies. This review focuses on the immunopathogenesis in relation to clinical manifestations and patterns of cell death, focusing on the pathogenesis of severe dengue.
Topics: Apoptosis; Dengue; Dengue Virus; Host-Pathogen Interactions; Humans
PubMed: 27860556
DOI: 10.1089/vim.2016.0092 -
Current Medicinal Chemistry 2021Dengue, the oldest and the most prevalent mosquito-borne illness, is caused by the dengue virus (DENV), from the family of Flaviviridae. It infects approximately 400... (Review)
Review
Dengue, the oldest and the most prevalent mosquito-borne illness, is caused by the dengue virus (DENV), from the family of Flaviviridae. It infects approximately 400 million individuals per annum, with approximately half of the global population residing in high-risk areas. The factors attributed to the geographic expansion of dengue, include urbanization, population density, modern means of transportation, international travels, habit modification, climate change, virus genetics, vector capacity, and poor vector control. Despite the significant progress made in the past against dengue, no effective antiviral therapy is currently available. Among the structural and non-structural proteins encoded by DENV genome, the NS2B-NS3 protease complex is amongst the extensively studied targets for the development of antiviral therapeutics owing to its multiple roles in virus life cycle. Furthermore, protease inhibitors were found to be successful in Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). Likewise, several peptidic, peptide derived/peptidomimetic, and small molecules inhibitors have been identified as DENV protease inhibitors. Unfortunately, none of them have resulted in a clinically approved drug. Considering all the abovementioned facts, this review descriptively explains the molecular mechanism and therapeutic potential of DENV protease along with an up to date information on various competitive inhibitors reported against DENV protease. This review might be helpful for the researchers working in this area to understand the critical aspects of DENV protease that will help them develop effective and novel inhibitors against DENV to protect lives of millions of people worldwide.
Topics: Animals; Antiviral Agents; Dengue Virus; Humans; Peptide Hydrolases; Protease Inhibitors; Serine Endopeptidases; Viral Nonstructural Proteins
PubMed: 34212826
DOI: 10.2174/0929867328666210629152929 -
Journal of Biomedical Science Jul 2018Dengue virus (DENV) infection is the most common mosquito-transmitted viral infection. DENV infection can cause mild dengue fever or severe dengue hemorrhagic fever... (Review)
Review
Dengue virus (DENV) infection is the most common mosquito-transmitted viral infection. DENV infection can cause mild dengue fever or severe dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS). Hemorrhage and vascular leakage are two characteristic symptoms of DHF/DSS. However, due to the limited understanding of dengue pathogenesis, no satisfactory therapies to treat nor vaccine to prevent dengue infection are available, and the mortality of DHF/DSS is still high. DENV nonstructural protein 1 (NS1), which can be secreted in patients' sera, has been used as an early diagnostic marker for dengue infection for many years. However, the roles of NS1 in dengue-induced vascular leakage were described only recently. In this article, the pathogenic roles of DENV NS1 in hemorrhage and vascular leakage are reviewed, and the possibility of using NS1 as a therapeutic target and vaccine candidate is discussed.
Topics: Antibodies, Viral; Dengue Virus; Humans; Severe Dengue; Vaccines; Viral Nonstructural Proteins
PubMed: 30037331
DOI: 10.1186/s12929-018-0462-0 -
Reviews in Medical Virology Jan 2015Dengue virus (DENV) is a leading cause of illness and death, mainly in the (sub)tropics, where it causes dengue fever and/or the more serious diseases dengue hemorrhagic... (Review)
Review
Dengue virus (DENV) is a leading cause of illness and death, mainly in the (sub)tropics, where it causes dengue fever and/or the more serious diseases dengue hemorrhagic fever and dengue shock syndrome that are associated with changes in vascular permeability. Despite extensive research, the pathogenesis of DENV is still poorly understood and, although endothelial cells represent the primary fluid barrier of the blood vessels, the extent to which these cells contribute to DENV pathology is still under debate. The primary target cells for DENV are dendritic cells and monocytes/macrophages that release various chemokines and cytokines upon infection, which can activate the endothelium and are thought to play a major role in DENV-induced vascular permeability. However, recent studies indicate that DENV also replicates in endothelial cells and that DENV-infected endothelial cells may directly contribute to viremia, immune activation, vascular permeability and immune targeting of the endothelium. Also, the viral non-structural protein-1 and antibodies directed against this secreted protein have been reported to be involved in endothelial cell dysfunction. This review provides an extensive overview of the effects of DENV infection on endothelial cell physiology and barrier function.
Topics: Animals; Dengue; Dengue Virus; Endothelial Cells; Humans
PubMed: 25430853
DOI: 10.1002/rmv.1818 -
International Journal of Molecular... May 2023Dengue virus (DENV) is a single-stranded (+)-sense RNA virus that infects humans and mosquitoes, posing a significant health risk in tropical and subtropical regions....
Dengue virus (DENV) is a single-stranded (+)-sense RNA virus that infects humans and mosquitoes, posing a significant health risk in tropical and subtropical regions. Mature virions are composed of an icosahedral shell of envelope (E) and membrane (M) proteins circumscribing a lipid bilayer, which in turn contains a complex of the approximately 11 kb genomic RNA with capsid (C) proteins. Whereas the structure of the envelope is clearly defined, the structure of the packaged genome in complex with C proteins remains elusive. Here, we investigated the interactions of C proteins with viral RNA, in solution and inside mature virions, via footprinting and cross-linking experiments. We demonstrated that C protein interaction with DENV genomes saturates at an RNA:C protein ratio below 1:250. Moreover, we also showed that the length of the RNA genome interaction sites varies, in a multimodal distribution, consistent with the C protein binding to each RNA site mostly in singlets or pairs (and, in some instances, higher numbers). We showed that interaction sites are preferentially sites with low base pairing, as previously measured by 2'-acetylation analyzed by primer extension (SHAPE) reactivity indicating structuredness. We found a clear association pattern emerged: RNA-C protein binding sites are strongly associated with long-range RNA-RNA interaction sites, particularly inside virions. This, in turn, explains the need for C protein in viral genome packaging: the protein has a chief role in coordinating these key interactions, promoting proper packaging of viral RNA. Such sites are, thus, highly consequential for viral assembly, and, as such, may be targeted in future drug development strategies against these and related viruses.
Topics: Animals; Humans; Capsid Proteins; Dengue Virus; Genome, Viral; Capsid; RNA, Viral
PubMed: 37175867
DOI: 10.3390/ijms24098158