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Viruses 2014, 6(2), 683-708; doi:10.3390/v6020683
Abstract
: West Nile (WNV) and Dengue (DENV) viruses are major arboviral human pathogens belonging to the genus Flavivirus. At the current time, there are no approved prophylactics (e.g., vaccines) or specific therapeutics available to prevent or treat human infections by these pathogens. Due to their minimal genome, these viruses require many host molecules for their replication and this offers a therapeutic avenue wherein host factors can be exploited as treatment targets. Since several host factors appear to be shared by many flaviviruses the strategy may result in pan-flaviviral inhibitors and may also attenuate the rapid emergence of drug resistant mutant viruses. The scope of this strategy is greatly enhanced by the recent en masse identification of host factors impacting on WNV and DENV infection. Excellent proof-of-principle experimental demonstrations for host-targeted control of infection and infection-induced pathogenesis have been reported for both WNV and DENV. These include exploiting not only those host factors supporting infection, but also targeting host processes contributing to pathogenesis and innate immune responses. While these early studies validated the host-targeting approach, extensive future investigations spanning a range of aspects are needed for a successful deployment in humans.1. Introduction
West Nile virus (WNV) and the four dengue viruses (DENV1-4) are flaviviruses belonging to the Flaviviridae family [1]. Many mosquito-borne flaviviruses cause a wide range of severe diseases. The mosquito-borne cluster of flaviviruses cause either systemic manifestations (e.g., fever and hemorrhage) or primarily neurological damage (e.g., encephalitis). Yellow fever virus (YFV) and DENVs cause systemic illnesses whose outcomes range from mild to death, and manifestations include high fever, severe headache, retro-orbital pain, and rash [2]. Dengue fever (DF) can progress to dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [3]. The global health impact of the four DENV viruses is staggering: DENVs threaten half of the world’s population, and result in ~400 million infections and 15,000–30,000 deaths per year [4]. Among the neurotropic viruses, WNV and Japanese encephalitis infections can have systemic and also neurological manifestations; as many as 10% of WNV infected patients with neurological symptoms succumb to the disease [2].
All flaviviruses have a ~11 kb positive strand RNA genome and mRNA, which is translated into a single polyprotein that is cleaved into three structural and seven nonstructural (NS) proteins necessary for viral propagation [1]. The flaviviral lifecycle involves complex interactions with many of the host cell cytoplasmic and, very likely, nuclear structures and components. WNV and DENV1-4 enters cells via interactions with one or more receptors and co-receptors at the plasma membrane, delivers its genome to the cytoplasm, and sets up translation-replication-assembly factories in membranous structures associated with the endoplasmic reticulum. The assembled progeny virions will eventually leave the cells through secretory pathways, and initiate subsequent infections
Given their genome’s limited coding capacity and their lifecycle’s complexity, it is not surprising that flaviviruses require scores of host factors [5,6]. These host factors are gene products (RNA or protein) that critically impact viral replication either positively (dependency or proviral factor) or negatively (restriction or antiviral factor). The identification of these host factors and the characterization of their interactions with viral proteins and RNAs are critical for the understanding of flaviviral replication, and should significantly inform our understanding of disease progression and pathogenesis. Moreover, each of these host factors is a candidate for therapeutic intervention.
In this chapter we will provide a review on the current understanding of the host factors that impact replication of WNV and DENV focusing primarily on those factors we deem particularly druggable. As implied by this focus, our review will be emphasizing only those factors in the human (or mammalian) host.
2. Approaches to Identify WNV and DENV Host Factors
En masse approaches have accelerated the discovery of host factors that impact propagation of WNV and DENV by interrogating tens of thousands of gene products or interactions simultaneously. While these methods have important limitations and should be considered hypotheses generating exercises that result in lists of candidate host factors that must be tested carefully, they have generated very important data.
2.1. Methods that Identify Changes in Expression of Host RNAs and Proteins
Genome-scale analyses of transcript levels, using one of many approaches (e.g., next generation RNA sequencing), have revealed the identity of host mRNAs that significantly vary after WNV [7,8,9] and DENV infection [8,10,11,12,13,14,15,16,17]. Among the earliest of these studies Fink et al. (2007) identified three pathways containing many component genes with altered expression upon DENV infection of cells in culture and DENV infected blood samples: NF-kappaB initiated immune responses, type I interferon (IFN) and the ubiquitin proteasome pathway [13]. Among studies that examined changes in the transcriptome, Sessions et al. (2013) focused on the expression of mRNA isoforms (products of transcriptional and post-transcriptional events) and concluded that isoforms of genes implicated in the innate immune responses were differentially processed during infection with wild type and attenuated strains of DENV [16]. A few studies have looked at alterations in protein expression in WNV [6] or DENV infection [18,19,20,21]. Proteins associated with the IFN response and the proteasome were upregulated [19], consistent with transcriptomic studies above. A recent study addressed changes in activity of kinases by mass-spectrometry-based chemoproteomic profiling with reactive ATP- and ADP-acyl phosphates as probes, and identified DNA-dependent protein kinase (DNA-PK) as activated early in DENV infection [22].
The logic behind interrogating gene expression differences is the assumption that dependency or restriction factors will be overrepresented among factors with altered expression (or altered modification) and indeed several studies suggest that this is likely true [13,19].
2.2. Methods that Map the Viral Interactome
Many methods look globally for host gene products that physically interact with viral proteins or RNAs. Two-hybrid interaction screens, which identify protein-protein interactions, have been used to define the protein interactome for WNV [23,24,25,26] and DENV viral proteins, [23,27,28,29,30,31,32,33,34,35,36,37]. Khadka et al. screened all 10 DENV proteins (using multiple bait constructs for each) against a human liver cDNA library to identify 105 proteins as potential interactors [32]. The authors found enrichment among proteins in the complement system (also noted in [37]), the coagulation cascade, the centrosome, and the cytoskeleton (Ibid.). Of 12 of these candidates tested for functional significance by RNA interference-mediated knockdown, six (CALR, DDX3X, ERC1, GOLGA2, TRIP11, and UBE2I) inhibited a DENV replicon (Ibid.). Le Breton et al. screened DENV NS3 and NS5 against a cDNA library derived from human liver, spleen, brain and bronchial epithelia, and identified 108 human proteins that interact with NS3 or NS5 or both [34]. Proteins involved in RNA binding, transcription, vesicular transport, and innate immunity were enriched in this group (Ibid.). There was no overlap between the NS3 and NS5 interactomes in the Khadka and Le Breton studies, which suggests caution in interpreting these data.
Affinity chromatography is another commonly used method to determine protein-protein and RNA-protein interactions en masse. Several groups have applied this method to identify host (human and mosquito) proteins that interact with WNV and DENV gene products (both proteins and RNAs) [38,39,40,41,42,43,44,45]. Tandem affinity purification (TAP) was used to discover an interaction between DENV2 NS4A and the human RNA binding protein PTBP1, which was shown to be required for efficient propagation of the virus [38]. Although its precise role in viral replication has not been determined, evidences suggested that PTB was involved in negative strand RNA synthesis [31]. Since WNV and DENV are ribonucleoprotein (RNP) complexes, it follows that many critical interactions take place between host RNA binding proteins (RBPs) and DENV RNAs (genome, antigenome and the sub-genomic flaviviral RNA (sfRNA) [46]. RNA chromatography utilizing biotinylated RNAs, RNAs covalently linked to beads or RNA aptamer affinity matrices have been used for enrichment of viral RNA-protein interactions [41,42,45]. Most of these reports have focused on sequences in the 5' and 3' untranslated regions (UTRs), which control the stability and translation of the viral mRNA, and the formation of the sfRNA [46,47,48,49,50]. One study identified the Y box-binding protein-1 (YB-1) and the heterogeneous nuclear ribonucleoproteins (hnRNPs)—hnRNP A1, hnRNP A2/B1, and hnRNP Q- as 3' UTR interactors and showed that YB-1 has antiviral activity [42]. Using tobramycin aptamer RNA affinity chromatography coupled with quantitative mass spectrometry, Ward et al. (2011) identified scores of proteins that interact with 5' and 3' UTR DENV-2 sequences, including the DEDD-box helicase DDX6, the 3'–5' exonuclease ERI3, which was also identified using functional genomics (see below), and stress granule associated proteins G3BP1, G3BP2 and CAPRIN-1 [45]. HnRNP A1, A2 and U were found in both studies, however, hnRNP proteins are very abundant and the relevance of the interactions requires further study [42,45].
2.3. Functional Genomics
Currently the en masse functional analysis in human cells (also true in mosquito cells) involves either gain of function screens accomplished by overexpressing cDNAs, or more commonly, RNAi-mediated loss of function screens (using dsRNA, siRNA or shRNA libraries). There has been one published genome-scale screen for human host factors of WNV [51] and one for dipteran host factors for DENV-2 [52], and several smaller scale screens for DENV human host factors [51,52,53,54]. Krishan et al. (2008) provided the first look at the extensive array of host factors that impacted WNV replication and tested this set of gene products for their impact on DENV [51]. Sessions et al. (2009) adapted DENV-2 for growth in drosophila cells and screened a dsRNA library for insect host factors in insect cells. The human homologs of the identified candidate factors were tested for an effect on DENV-2 replication revealing remarkable conservation for required factors in the human and mosquito hosts [52]. Several groups have carried out more focused screens using DENV replicons to assay replication, avoiding early viral entry and uncoating or viral assembly and release factors, and targeting subsets of gene products [53,54]. The available data suggest that various screening approaches undertaken so far have not revealed the full spectrum of host factors impacting on flaviviruses, and there remains significant room for future focused and genome-scale screens to contribute meaningfully to the database of WNV and DENV host factors.
There is important debate regarding the reproducibility and on-target accuracy of RNAi screens. It should be acknowledged that some genes cannot be knocked down efficiently and that some genes may have redundant functions. Careful experimentation can ensure significant reproducibility, as observed in the case of a human genome-scale RNAi screen for host factors required for replication of yellow fever virus (17D vaccine strain) (YFV-17D) [55,56]. For a careful discussion of these considerations and technical details of running and analyzing these screens we refer the reader to Barrows et al. [55]. The overall accuracy of screens has been difficult to assess and is likely variable depending on how noisy the screens are. Several parameters should be considered: first, primary screens should interrogate each gene product with more than one dsRNA/siRNA/shRNA (or sets of these). Such an approach would reduce the number of potential false positives resulting from the screening. Second, an RNAi independent methodology should be used to support the findings of the screen (e.g., genome editing with RNA guided endonucleases [57]).
2.4. Genome-Wide Associations Studies
Recently, a genome-wide association study (GWAS) coupled with validation of significantly associated markers was performed to identify genes associated with dengue shock syndrome (DSS), by comparing pediatric patients with controls. This study identified association of major histocompatibility complex (MHC) class I polypeptide-related sequence B (MICB), and phospholipase C, epsilon 1 (PLCE1) with DSS [58], and a subsequent study extended the findings to less severe pediatric dengue fever [59]. Another study identified an association between SNPs in JAK1, which is critical for IFN signaling, and DHF [60]. A comprehensive GWAS study in the context of WNV infection is yet to be reported. An early study using 501 human seroconverts revealed that a single nucleotide polymorphism (SNP) in the OAS1 gene increases the susceptibility of humans to WNV [61]. Similarly, another recent study involving 753 WNV seroconverts identified SNPs in IRF3, MX1 and OAS1 that can affect the host susceptibility to WNV [62]. A third study reported that a mutation in chemokine receptor CCR5 is associated with human resistance to WNV infection [63]. It is conceivable that with the availability of large-scale GWAS studies, our understanding of the role of host factors in the susceptibility and effective host response to WNV infection will expand further.
4. Conclusions and Future Directions
The studies described in this review clearly demonstrated that several host molecules hold the potential to serve as therapeutic targets to treat flaviviral infections. These include both metabolic pathways and non-metabolic targets. While some of these host molecules have already been tested in animal models of infection or humans, most await detailed experimentation and validation. The host-targeting antivirals may not result in rapid formation of drug resistant mutations in the viruses.
Future attempts to develop host-targeted therapeutic approaches to successfully contain the threat of flaviviral infections should take into account at least four general areas of research: (i) Systematic identification and validation of host targets implicated in flaviviral infections. The multitude of flaviviral infection-associated host molecules (proviral and restriction factors) identified through various en masse approaches (e.g., RNAi screens) need to be mined and adequately validated to identify candidates with the potential for modulation by drugs. There is also a need for newer discovery studies to identify essential host factors impacting flavivirus infections in the most appropriate cell types (e.g., primary cellular targets of viruses during in vivo infection). These genetic study-based identifications of the flavivirus host factors should be complemented with more focused screens and validations using drugs that exclusively target known host molecules. Such an approach will provide us with a wider choice of drug targets and drugs against viruses; (ii) In vivo validations. The druggable host target genes that are already identified (as well as the to-be-discovered targets) to regulate viral infection need to be validated using appropriate gene knockout in vivo models of infections. Given the current availability of better animal models for WNV (e.g., mouse), one would anticipate faster progress in the case of WNV than for DENV. Similarly, the drugs targeting the identified host factors should also be evaluated using the most suitable animal model that mimics infection induced disease in humans; (iii) Cross-protection. Because different flaviviruses have a significant degree of conservation in their genome, some of the mechanisms involved in their interaction with host cells are also likely to be conserved. Therefore, any drug or drug target identified as useful against a particular flavivirus should be tested against a wide range of medically relevant flaviviruses of the genus Flavivirus. This will help to identify pan-flaviviral therapeutics; and (iv) Drugs boosting host innate defenses. Particular emphasis should be given to discover drugs that can augment various innate antiviral mechanisms of cells. In addition to enhancing the generic production of interferon, such drugs should ideally activate specific effector mechanisms of cells against viruses. For example, a drug that can enhance the production or antiviral activity of interferon stimulated antiviral genes may offer better protection from infection, and less toxicity to the host. A sub-category of immune response boosting drugs should also have the ability to attenuate viral interference with host immune defenses.
In summary, a multipronged approach integrating both host target and host-directed drug discovery will ultimately facilitate the identification of effective therapeutics against flaviviruses.
Acknowledgements
MNK was funded through DUKE-NUS Graduate Medical School by the Agency for Science, Technology and Research (A*STAR), Singapore, the Ministry of Health, Singapore; the Ministry of Education, Singapore; and the National Research Foundation, Singapore. MGB acknowledges funding from a Duke-NUS Signature Research Program funded by the Agency for Science, Technology and Research (A*STAR), Singapore, the Ministry of Health, Singapore, a grant from the National Medical Research Council, Singapore (NMRC/1267/2010), and grants from NIAID USA (1R01 AI089526 and 1RO1 AI101431).
Author Contributions
M.-N.K. and M.A.G.B. wrote the review.
Conflicts of Interest
The authors declare no conflict of interest.
References and Notes
- Lindenbach, B.; Thiel, H.J.; Rice, C.M. Flaviviridae: The Viruses and Their Replication, 5th ed.; Lippincott, Williams and Wilkins: Philadelphia, PA, USA, 2007; Volume I. [Google Scholar]
- Gould, E.A.; Solomon, T. Pathogenic flaviviruses. Lancet 2008, 371, 500–509. [Google Scholar] [CrossRef]
- Simmons, C.P.; Farrar, J.J.; van Vinh Chau, N.; Wills, B. Dengue. N. Engl. J. Med. 2012, 366, 1423–1432. [Google Scholar] [CrossRef]
- Bhatt, S.; Gething, P.W.; Brady, O.J.; Messina, J.P.; Farlow, A.W.; Moyes, C.L.; Drake, J.M.; Brownstein, J.S.; Hoen, A.G.; Sankoh, O.; et al. The global distribution and burden of Dengue. Nature 2013, 496, 504–507. [Google Scholar] [CrossRef]
- Fernandez-Garcia, M.D.; Mazzon, M.; Jacobs, M.; Amara, A. Pathogenesis of flavivirus infections: Using and abusing the host cell. Cell Host Microbe 2009, 5, 318–328. [Google Scholar] [CrossRef]
- Pastorino, B.; Nougairede, A.; Wurtz, N.; Gould, E.; de Lamballerie, X. Role of host cell factors in flavivirus infection: Implications for pathogenesis and development of antiviral drugs. Antivir. Res. 2010, 87, 281–294. [Google Scholar] [CrossRef]
- Bourgeois, M.A.; Denslow, N.D.; Seino, K.S.; Barber, D.S.; Long, M.T. Gene expression analysis in the thalamus and cerebrum of horses experimentally infected with West Nile virus. PLoS One 2011, 6, e24371. [Google Scholar]
- Moon, S.L.; Anderson, J.R.; Kumagai, Y.; Wilusz, C.J.; Akira, S.; Khromykh, A.A.; Wilusz, J. A noncoding RNA produced by arthropod-borne flaviviruses inhibits the cellular exoribonuclease XRN1 and alters host mRNA stability. RNA 2012, 18, 2029–2040. [Google Scholar] [CrossRef]
- Munoz-Erazo, L.; Natoli, R.; Provis, J.M.; Madigan, M.C.; King, N.J. Microarray analysis of gene expression in West Nile virus-infected human retinal pigment epithelium. Mol. Vis. 2012, 18, 730–743. [Google Scholar]
- Becerra, A.; Warke, R.V.; Martin, K.; Xhaja, K.; de Bosch, N.; Rothman, A.L.; Bosch, I. Gene expression profiling of Dengue infected human primary cells identifies secreted mediators in vivo. J. Med. Virol. 2009, 81, 1403–1411. [Google Scholar] [CrossRef]
- Conceicao, T.M.; El-Bacha, T.; Villas-Boas, C.S.; Coello, G.; Ramirez, J.; Montero-Lomeli, M.; da Poian, A.T. Gene expression analysis during Dengue virus infection in HepG2 cells reveals virus control of innate immune response. J. Infect. 2010, 60, 65–75. [Google Scholar] [CrossRef]
- Ekkapongpisit, M.; Wannatung, T.; Susantad, T.; Triwitayakorn, K.; Smith, D.R. cDNA-AFLP analysis of differential gene expression in human hepatoma cells (HepG2) upon Dengue virus infection. J. Med. Virol. 2007, 79, 552–561. [Google Scholar] [CrossRef]
- Fink, J.; Gu, F.; Ling, L.; Tolfvenstam, T.; Olfat, F.; Chin, K.C.; Aw, P.; George, J.; Kuznetsov, V.A.; Schreiber, M.; Hibberd, M.L.; et al. Host gene expression profiling of Dengue virus infection in cell lines and patients. PLoS Neglect. Trop. D. 2007, 1, e86. [Google Scholar] [CrossRef]
- Long, H.T.; Hibberd, M.L.; Hien, T.T.; Dung, N.M.; van Ngoc, T.; Farrar, J.; Wills, B.; Simmons, C.P. Patterns of gene transcript abundance in the blood of children with severe or uncomplicated Dengue highlight differences in disease evolution and host response to Dengue virus infection. J. Infect. Dis. 2009, 199, 537–546. [Google Scholar]
- Nasirudeen, A.M.; Wong, H.H.; Thien, P.; Xu, S.; Lam, K.P.; Liu, D.X. RIG-I, MDA5 and TLR3 synergistically play an important role in restriction of Dengue virus infection. PLoS Neglect. Trop. D. 2011, 5, e926. [Google Scholar] [CrossRef]
- Sessions, O.M.; Tan, Y.; Goh, K.C.; Liu, Y.; Tan, P.; Rozen, S.; Ooi, E.E. Host cell transcriptome profile during wild-type and attenuated Dengue virus infection. PLoS Neglect. Trop. D. 2013, 7, e2107. [Google Scholar] [CrossRef]
- Ubol, S.; Masrinoul, P.; Chaijaruwanich, J.; Kalayanarooj, S.; Charoensirisuthikul, T.; Kasisith, J. Differences in global gene expression in peripheral blood mononuclear cells indicate a significant role of the innate responses in progression of Dengue fever but not Dengue hemorrhagic fever. J. Infect. Dis. 2008, 197, 1459–1467. [Google Scholar] [CrossRef]
- Kanlaya, R.; Pattanakitsakul, S.N.; Sinchaikul, S.; Chen, S.T.; Thongboonkerd, V. Alterations in actin cytoskeletal assembly and junctional protein complexes in human endothelial cells induced by Dengue virus infection and mimicry of leukocyte transendothelial migration. J. Proteome Res. 2009, 8, 2551–2562. [Google Scholar] [CrossRef]
- Kanlaya, R.; Pattanakitsakul, S.N.; Sinchaikul, S.; Chen, S.T.; Thongboonkerd, V. The ubiquitin-proteasome pathway is important for Dengue virus infection in primary human endothelial cells. J. Proteome Res. 2010, 9, 4960–4971. [Google Scholar] [CrossRef]
- Pattanakitsakul, S.N.; Poungsawai, J.; Kanlaya, R.; Sinchaikul, S.; Chen, S.T.; Thongboonkerd, V. Association of Alix with late endosomal lysobisphosphatidic acid is important for Dengue virus infection in human endothelial cells. J. Proteome Res. 2010, 9, 4640–4648. [Google Scholar] [CrossRef]
- Pattanakitsakul, S.N.; Rungrojcharoenkit, K.; Kanlaya, R.; Sinchaikul, S.; Noisakran, S.; Chen, S.T.; Malasit, P.; Thongboonkerd, V. Proteomic analysis of host responses in HepG2 cells during Dengue virus infection. J. Proteome Res. 2007, 6, 4592–4600. [Google Scholar] [CrossRef]
- Vetter, M.L.; Rodgers, M.A.; Patricelli, M.P.; Yang, P.L. Chemoproteomic profiling identifies changes in DNA-PK as markers of early Dengue virus infection. ACS Chem. Biol. 2012, 7, 2019–2026. [Google Scholar] [CrossRef]
- Bhuvanakantham, R.; Cheong, Y.K.; Ng, M.L. West nile virus capsid protein interaction with importin and HDM2 protein is regulated by protein kinase C-mediated phosphorylation. Microb. Infect. 2010, 12, 615–625. [Google Scholar] [CrossRef]
- Oh, W.; Yang, M.R.; Lee, E.W.; Park, K.M.; Pyo, S.; Yang, J.S.; Lee, H.W.; Song, J. Jab1 mediates cytoplasmic localization and degradation of West Nile virus capsid protein. J. Biol. Chem. 2006, 281, 30166–30174. [Google Scholar]
- Oh, W.K.; Song, J. Hsp70 functions as a negative regulator of West Nile virus capsid protein through direct interaction. Biochem. Biophys. Res. Comm. 2006, 347, 994–1000. [Google Scholar] [CrossRef]
- Xu, Z.; Anderson, R.; Hobman, T.C. The capsid-binding nucleolar helicase DDX56 is important for infectivity of West Nile virus. J. Virol. 2011, 85, 5571–5580. [Google Scholar] [CrossRef]
- Brault, J.B.; Kudelko, M.; Vidalain, P.O.; Tangy, F.; Despres, P.; Pardigon, N. The interaction of flavivirus M protein with light chain Tctex-1 of human dynein plays a role in late stages of virus replication. Virology 2011, 417, 369–378. [Google Scholar] [CrossRef]
- Chiu, M.W.; Shih, H.M.; Yang, T.H.; Yang, Y.L. The type 2 Dengue virus envelope protein interacts with small ubiquitin-like modifier-1 (SUMO-1) conjugating enzyme 9 (Ubc9). J. Biomed. Sci. 2007, 14, 429–444. [Google Scholar] [CrossRef]
- Chua, J.J.; Bhuvanakantham, R.; Chow, V.T.; Ng, M.L. Recombinant non-structural 1 (NS1) protein of Dengue-2 virus interacts with human STAT3beta protein. Virus Res. 2005, 112, 85–94. [Google Scholar] [CrossRef]
- Folly, B.B.; Weffort-Santos, A.M.; Fathman, C.G.; Soares, L.R. Dengue-2 structural proteins associate with human proteins to produce a coagulation and innate immune response biased interactome. BMC Infect. Dis. 2011, 11, 34. [Google Scholar] [CrossRef]
- Jiang, L.; Yao, H.; Duan, X.; Lu, X.; Liu, Y. Polypyrimidine tract-binding protein influences negative strand RNA synthesis of Dengue virus. Biochem. Biophys. Res. Comm. 2009, 385, 187–192. [Google Scholar] [CrossRef]
- Khadka, S.; Vangeloff, A.D.; Zhang, C.; Siddavatam, P.; Heaton, N.S.; Wang, L.; Sengupta, R.; Sahasrabudhe, S.; Randall, G.; Gribskov, M.; et al. A physical interaction network of Dengue virus and human proteins. Mol. Cell. Proteomics 2011, 10, M111.012187. [Google Scholar] [CrossRef]
- Khunchai, S.; Junking, M.; Suttitheptumrong, A.; Yasamut, U.; Sawasdee, N.; Netsawang, J.; Morchang, A.; Chaowalit, P.; Noisakran, S.; Yenchitsomanus, P.T.; et al. Interaction of Dengue virus nonstructural protein 5 with Daxx modulates RANTES production. Biochem. Biophys. Res. Comm. 2012, 423, 398–403. [Google Scholar] [CrossRef]
- Le Breton, M.; Meyniel-Schicklin, L.; Deloire, A.; Coutard, B.; Canard, B.; de Lamballerie, X.; Andre, P.; Rabourdin-Combe, C.; Lotteau, V.; Davoust, N. Flavivirus NS3 and NS5 proteins interaction network: A high-throughput yeast two-hybrid screen. BMC Microbiol. 2011, 11, 234. [Google Scholar] [CrossRef]
- Li, J.; Huang, R.; Liao, W.; Chen, Z.; Zhang, S.; Huang, R. Dengue virus utilizes calcium modulating cyclophilin-binding ligand to subvert apoptosis. Biochem. Biophys. Res. Comm. 2012, 418, 622–627. [Google Scholar] [CrossRef]
- Mairiang, D.; Zhang, H.; Sodja, A.; Murali, T.; Suriyaphol, P.; Malasit, P.; Limjindaporn, T.; Finley, R.L., Jr. Identification of new protein interactions between Dengue fever virus and its hosts, human and mosquito. PLoS One 2013, 8, e53535. [Google Scholar]
- Silva, E.M.; Conde, J.N.; Allonso, D.; Nogueira, M.L.; Mohana-Borges, R. Mapping the interactions of Dengue virus NS1 protein with human liver proteins using a yeast two-hybrid system: Identification of C1q as an interacting partner. PLoS One 2013, 8, e57514. [Google Scholar]
- Anwar, A.; Leong, K.M.; Ng, M.L.; Chu, J.J.; Garcia-Blanco, M.A. The polypyrimidine tract-binding protein is required for efficient Dengue virus propagation and associates with the viral replication machinery. J. Biol. Chem. 2009, 284, 17021–17029. [Google Scholar] [CrossRef]
- Colpitts, T.M.; Barthel, S.; Wang, P.; Fikrig, E. Dengue virus capsid protein binds core histones and inhibits nucleosome formation in human liver cells. PLoS One 2011, 6, e24365. [Google Scholar]
- Colpitts, T.M.; Cox, J.; Nguyen, A.; Feitosa, F.; Krishnan, M.N.; Fikrig, E. Use of a tandem affinity purification assay to detect interactions between West Nile and Dengue viral proteins and proteins of the mosquito vector. Virology 2011, 417, 179–187. [Google Scholar] [CrossRef]
- Lei, Y.; Huang, Y.; Zhang, H.; Yu, L.; Zhang, M.; Dayton, A. Functional interaction between cellular p100 and the Dengue virus 3' UTR. J. Gen. Virol. 2011, 92, 796–806. [Google Scholar] [CrossRef]
- Paranjape, S.M.; Harris, E. Y box-binding protein-1 binds to the Dengue virus 3'-untranslated region and mediates antiviral effects. J. Biol. Chem. 2007, 282, 30497–30508. [Google Scholar] [CrossRef]
- Reyes-del Valle, J.; del Angel, R.M. Isolation of putative Dengue virus receptor molecules by affinity chromatography using a recombinant E protein ligand. J. Virol. Methods 2004, 116, 95–102. [Google Scholar] [CrossRef]
- Upanan, S.; Kuadkitkan, A.; Smith, D.R. Identification of Dengue virus binding proteins using affinity chromatography. J. Virol. Methods 2008, 151, 325–328. [Google Scholar] [CrossRef]
- Ward, A.M.; Bidet, K.; Yinglin, A.; Ler, S.G.; Hogue, K.; Blackstock, W.; Gunaratne, J.; Garcia-Blanco, M.A. Quantitative mass spectrometry of DENV-2 RNA-interacting proteins reveals that the DEAD-box RNA helicase DDX6 binds the DB1 and DB2 3' UTR structures. RNA Biol. 2011, 8, 1173–1186. [Google Scholar] [CrossRef]
- Pijlman, G.P.; Funk, A.; Kondratieva, N.; Leung, J.; Torres, S.; van der Aa, L.; Liu, W.J.; Palmenberg, A.C.; Shi, P.Y.; Hall, R.A.; et al. A highly structured, nuclease-resistant, noncoding RNA produced by flaviviruses is required for pathogenicity. Cell Host Microbe 2008, 4, 579–591. [Google Scholar] [CrossRef]
- Brinton, M.A.; Dispoto, J.H. Sequence and secondary structure analysis of the 5'-terminal region of flavivirus genome RNA. Virology 1988, 162, 290–299. [Google Scholar] [CrossRef]
- Brinton, M.A.; FeRNAndez, A.V.; Dispoto, J.H. The 3'-nucleotides of flavivirus genomic RNA form a conserved secondary structure. Virology 1986, 153, 113–121. [Google Scholar] [CrossRef]
- Clyde, K.; Harris, E. Rna secondary structure in the coding region of Dengue virus type 2 directs translation start codon selection and is required for viral replication. J. Virol. 2006, 80, 2170–2182. [Google Scholar] [CrossRef]
- Hahn, C.S.; Hahn, Y.S.; Rice, C.M.; Lee, E.; Dalgarno, L.; Strauss, E.G.; Strauss, J.H. Conserved elements in the 3' untranslated region of flavivirus RNAs and potential cyclization sequences. J. Mol. Biol. 1987, 198, 33–41. [Google Scholar] [CrossRef]
- Krishnan, M.N.; Ng, A.; Sukumaran, B.; Gilfoy, F.D.; Uchil, P.D.; Sultana, H.; Brass, A.L.; Adametz, R.; Tsui, M.; Qian, F.; et al. RNA interference screen for human genes associated with West Nile virus infection. Nature 2008, 455, 242–245. [Google Scholar] [CrossRef]
- Sessions, O.M.; Barrows, N.J.; Souza-Neto, J.A.; Robinson, T.J.; Hershey, C.L.; Rodgers, M.A.; Ramirez, J.L.; Dimopoulos, G.; Yang, P.L.; Pearson, J.L.; et al. Discovery of insect and human Dengue virus host factors. Nature 2009, 458, 1047–1050. [Google Scholar] [CrossRef]
- Heaton, N.S.; Randall, G. Dengue virus-induced autophagy regulates lipid metabolism. Cell Host Microbe 2010, 8, 422–432. [Google Scholar] [CrossRef]
- Rothwell, C.; Lebreton, A.; Young Ng, C.; Lim, J.Y.; Liu, W.; Vasudevan, S.; Labow, M.; Gu, F.; Gaither, L.A. Cholesterol biosynthesis modulation regulates Dengue viral replication. Virology 2009, 389, 8–19. [Google Scholar] [CrossRef]
- Barrows, N.J.; Le Sommer, C.; Garcia-Blanco, M.A.; Pearson, J.L. Factors affecting reproducibility between genome-scale siRNA-based screens. J. Biomol. Screen. 2010, 15, 735–747. [Google Scholar] [CrossRef]
- Le Sommer, C.; Barrows, N.J.; Bradrick, S.S.; Pearson, J.L.; Garcia-Blanco, M.A. G protein-coupled receptor kinase 2 promotes flaviviridae entry and replication. PLoS Neglect. Trop. D. 2012, 6, e1820. [Google Scholar] [CrossRef]
- Mali, P.; Aach, J.; Stranges, P.B.; Esvelt, K.M.; Moosburner, M.; Kosuri, S.; Yang, L.; Church, G.M. CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nat. Biotechnol. 2013, 31, 833–838. [Google Scholar] [CrossRef]
- Khor, C.C.; Chau, T.N.; Pang, J.; Davila, S.; Long, H.T.; Ong, R.T.; Dunstan, S.J.; Wills, B.; Farrar, J.; Van Tram, T.; et al. Genome-wide association study identifies susceptibility loci for Dengue shock syndrome at MICB and PLCE1. Nat. Gen. 2011, 43, 1139–1141. [Google Scholar] [CrossRef]
- Whitehorn, J.; Chau, T.N.; Nguyet, N.M.; Kien, D.T.; Quyen, N.T.; Trung, D.T.; Pang, J.; Wills, B.; Van Vinh Chau, N.; Farrar, J.; et al. Genetic variants of MICB and PLCE1 and associations with non-severe Dengue. PLoS One 2013, 8, e59067. [Google Scholar] [CrossRef]
- Silva, L.K.; Blanton, R.E.; Parrado, A.R.; Melo, P.S.; Morato, V.G.; Reis, E.A.; Dias, J.P.; Castro, J.M.; Vasconcelos, P.F.; Goddard, K.A.; et al. Dengue hemorrhagic fever is associated with polymorphisms in JAK1. Euro. J. Hum. Gen. 2010, 18, 1221–1227. [Google Scholar] [CrossRef]
- Lim, J.K.; Lisco, A.; McDermott, D.H.; Huynh, L.; Ward, J.M.; Johnson, B.; Johnson, H.; Pape, J.; Foster, G.A.; Krysztof, D.; et al. Genetic variation in OAS1 is a risk factor for initial infection with West Nile virus in man. PLoS Pathog. 2009, 5, e1000321. [Google Scholar] [CrossRef]
- Bigham, A.W.; Buckingham, K.J.; Husain, S.; Emond, M.J.; Bofferding, K.M.; Gildersleeve, H.; Rutherford, A.; Astakhova, N.M.; Perelygin, A.A.; Busch, M.P.; et al. Host genetic risk factors for West Nile virus infection and disease progression. PLoS One 2011, 6, e24745. [Google Scholar] [CrossRef]
- Glass, W.G.; McDermott, D.H.; Lim, J.K.; Lekhong, S.; Yu, S.F.; Frank, W.A.; Pape, J.; Cheshier, R.C.; Murphy, P.M. CCR5 deficiency increases risk of symptomatic West Nile virus infection. J. Exp. Med. 2006, 203, 35–40. [Google Scholar] [CrossRef]
- Leyssen, P.; De Clercq, E.; Neyts, J. Perspectives for the treatment of infections with Flaviviridae. Clin. Microbiol. Rev. 2000, 13, 67–82, table of contents. [Google Scholar] [CrossRef]
- Leyssen, P.; Charlier, N.; Paeshuyse, J.; de Clercq, E.; Neyts, J. Prospects for antiviral therapy. Adv. Virus Res. 2003, 61, 511–553. [Google Scholar] [CrossRef]
- Cregar-HeRNAndez, L.; Jiao, G.S.; Johnson, A.T.; Lehrer, A.T.; Wong, T.A.; Margosiak, S.A. Small molecule pan-Dengue and West Nile virus NS3 protease inhibitors. Antivir. Chem. Chemother. 2011, 21, 209–217. [Google Scholar] [CrossRef]
- Stahla-Beek, H.J.; April, D.G.; Saeedi, B.J.; Hannah, A.M.; Keenan, S.M.; Geiss, B.J. Identification of a novel antiviral inhibitor of the flavivirus guanylyltransferase enzyme. J. Virol. 2012, 86, 8730–8739. [Google Scholar] [CrossRef]
- Stevens, A.J.; Gahan, M.E.; Mahalingam, S.; Keller, P.A. The medicinal chemistry of Dengue fever. J. Med. Chem. 2009, 52, 7911–7926. [Google Scholar] [CrossRef]
- Yin, Z.; Chen, Y.L.; Kondreddi, R.R.; Chan, W.L.; Wang, G.; Ng, R.H.; Lim, J.Y.; Lee, W.Y.; Jeyaraj, D.A.; Niyomrattanakit, P.; et al. N-sulfonylanthranilic acid derivatives as allosteric inhibitors of Dengue viral RNA-dependent RNA polymerase. J. Med. Chem. 2009, 52, 7934–7937. [Google Scholar] [CrossRef]
- Chen, Q.; Butler, D.; Querbes, W.; Pandey, R.K.; Ge, P.; Maier, M.A.; Zhang, L.; Rajeev, K.G.; Nechev, L.; Kotelianski, V.; et al. Lipophilic siRNAs mediate efficient gene silencing in oligodendrocytes with direct CNS delivery. J. Contr. Release 2010, 144, 227–232. [Google Scholar] [CrossRef]
- Niyomrattanakit, P.; Chen, Y.L.; Dong, H.; Yin, Z.; Qing, M.; Glickman, J.F.; Lin, K.; Mueller, D.; Voshol, H.; Lim, J.Y.; et al. Inhibition of Dengue virus polymerase by blocking of the RNA tunnel. J. Virol. 2010, 84, 5678–5686. [Google Scholar] [CrossRef]
- Lescar, J.; Luo, D.; Xu, T.; Sampath, A.; Lim, S.P.; Canard, B.; Vasudevan, S.G. Towards the design of antiviral inhibitors against flaviviruses: The case for the multifunctional NS3 protein from Dengue virus as a target. Antivir. Res. 2008, 80, 94–101. [Google Scholar] [CrossRef]
- Tomlinson, S.M.; Malmstrom, R.D.; Russo, A.; Mueller, N.; Pang, Y.P.; Watowich, S.J. Structure-based discovery of Dengue virus protease inhibitors. Antivir. Res. 2009, 82, 110–114. [Google Scholar] [CrossRef]
- Yusof, R.; Clum, S.; Wetzel, M.; Murthy, H.M.; Padmanabhan, R. Purified NS2B/NS3 serine protease of Dengue virus type 2 exhibits cofactor NS2B dependence for cleavage of substrates with dibasic amino acids in vitro. J. Biol. Chem. 2000, 275, 9963–9969. [Google Scholar]
- Kiat, T.S.; Pippen, R.; Yusof, R.; Ibrahim, H.; Khalid, N.; Rahman, N.A. Inhibitory activity of cyclohexenyl chalcone derivatives and flavonoids of fingerroot, boesenbergia rotunda (L.), towards Dengue-2 virus NS3 protease. Bioorg. Med. Chem. Lett. 2006, 16, 3337–3340. [Google Scholar] [CrossRef]
- Prusis, P.; Junaid, M.; Petrovska, R.; Yahorava, S.; Yahorau, A.; Katzenmeier, G.; Lapins, M.; Wikberg, J.E. Design and evaluation of substrate-based octapeptide and non substrate-based tetrapeptide inhibitors of Dengue virus NS2B-NS3 proteases. Biochem. Biophys. Res. Comm. 2013, 434, 767–772. [Google Scholar] [CrossRef]
- Goulet, M.L.; Olagnier, D.; Xu, Z.; Paz, S.; Belgnaoui, S.M.; Lafferty, E.I.; Janelle, V.; Arguello, M.; Paquet, M.; Ghneim, K.; et al. Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity. PLoS Pathog. 2013, 9, e1003298. [Google Scholar]
- Ahmed, A.; Daneshtalab, M. Nonclassical biological activities of quinolone derivatives. J. Pharm. Pharm. Sci. 2012, 15, 52–72. [Google Scholar]
- Deng, J.; Li, N.; Liu, H.; Zuo, Z.; Liew, O.W.; Xu, W.; Chen, G.; Tong, X.; Tang, W.; Zhu, J.; et al. Discovery of novel small molecule inhibitors of Dengue viral NS2B-NS3 protease using virtual screening and scaffold hopping. J. Med. Chem. 2012, 55, 6278–6293. [Google Scholar] [CrossRef]
- Mastrangelo, E.; Pezzullo, M.; de Burghgraeve, T.; Kaptein, S.; Pastorino, B.; Dallmeier, K.; de Lamballerie, X.; Neyts, J.; Hanson, A.M.; Frick, D.N.; et al. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: New prospects for an old drug. J. Antimicrob. Chemother. 2012, 67, 1884–1894. [Google Scholar] [CrossRef]
- Holden, K.L.; Stein, D.A.; Pierson, T.C.; Ahmed, A.A.; Clyde, K.; Iversen, P.L.; Harris, E. Inhibition of Dengue virus translation and RNA synthesis by a morpholino oligomer targeted to the top of the terminal 3' stem-loop structure. Virology 2006, 344, 439–452. [Google Scholar] [CrossRef]
- Kumar, P.; Lee, S.K.; Shankar, P.; Manjunath, N. A single siRNA suppresses fatal encephalitis induced by two different flaviviruses. PLoS Med. 2006, 3, e96. [Google Scholar] [CrossRef]
- Mehlhop, E.; Diamond, M.S. The molecular basis of antibody protection against West Nile virus. Curr. Top. Microbiol. Immunol. 2008, 317, 125–153. [Google Scholar]
- Kuritzkes, D.R. HIV-1 entry inhibitors: An overview. Curr. Opin. HIV AIDS 2009, 4, 82–87. [Google Scholar] [CrossRef]
- Heaton, N.S.; Perera, R.; Berger, K.L.; Khadka, S.; Lacount, D.J.; Kuhn, R.J.; Randall, G. Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. Proc. Natl. Acad. Sci. USA 2010, 107, 17345–17350. [Google Scholar] [CrossRef]
- Martin-Acebes, M.A.; Blazquez, A.B.; Jimenez de Oya, N.; Escribano-Romero, E.; Saiz, J.C. West nile virus replication requires fatty acid synthesis but is independent on phosphatidylinositol-4-phosphate lipids. PLoS One 2011, 6, e24970. [Google Scholar]
- Mackenzie, J.M.; Khromykh, A.A.; Parton, R.G. Cholesterol manipulation by West Nile virus perturbs the cellular immune response. Cell Host Microbe 2007, 2, 229–239. [Google Scholar] [CrossRef]
- Martinez-Gutierrez, M.; Castellanos, J.E.; Gallego-Gomez, J.C. Statins reduce Dengue virus production via decreased virion assembly. Intervirology 2011, 54, 202–216. [Google Scholar] [CrossRef]
- Poh, M.K.; Shui, G.; Xie, X.; Shi, P.Y.; Wenk, M.R.; Gu, F. U18666A, an intra-cellular cholesterol transport inhibitor, inhibits Dengue virus entry and replication. Antivir. Res. 2012, 93, 191–198. [Google Scholar] [CrossRef]
- Leyssen, P.; Balzarini, J.; de Clercq, E.; Neyts, J. The predominant mechanism by which ribavirin exerts its antiviral activity in vitro against flaviviruses and paramyxoviruses is mediated by inhibition of IMP dehydrogenase. J. Virol. 2005, 79, 1943–1947. [Google Scholar] [CrossRef]
- Morrey, J.D.; Smee, D.F.; Sidwell, R.W.; Tseng, C. Identification of active antiviral compounds against a New York isolate of West Nile virus. Antivir. Res. 2002, 55, 107–116. [Google Scholar] [CrossRef]
- Takhampunya, R.; Ubol, S.; Houng, H.S.; Cameron, C.E.; Padmanabhan, R. Inhibition of Dengue virus replication by mycophenolic acid and ribavirin. J. Gen. Virol. 2006, 87, 1947–1952. [Google Scholar] [CrossRef]
- Qing, M.; Zou, G.; Wang, Q.Y.; Xu, H.Y.; Dong, H.; Yuan, Z.; Shi, P.Y. Characterization of Dengue virus resistance to brequinar in cell culture. Antimicrob. Agents Chemother. 2010, 54, 3686–3695. [Google Scholar] [CrossRef]
- Mohan, S.; McAtamney, S.; Jayakanthan, K.; Eskandari, R.; von Itzstein, M.; Pinto, B.M. Antiviral activities of sulfonium-ion glucosidase inhibitors and 5-thiomannosylamine disaccharide derivatives against Dengue virus. Int. J. Antimicrob. Agents 2012, 40, 273–276. [Google Scholar] [CrossRef]
- Rathore, A.P.; Paradkar, P.N.; Watanabe, S.; Tan, K.H.; Sung, C.; Connolly, J.E.; Low, J.; Ooi, E.E.; Vasudevan, S.G. Celgosivir treatment misfolds Dengue virus ns1 protein, induces cellular pro-survival genes and protects against lethal challenge mouse model. Antivir. Res. 2011, 92, 453–460. [Google Scholar] [CrossRef]
- Whitby, K.; Pierson, T.C.; Geiss, B.; Lane, K.; Engle, M.; Zhou, Y.; Doms, R.W.; Diamond, M.S. Castanospermine, a potent inhibitor of Dengue virus infection in vitro and in vivo. J. Virol. 2005, 79, 8698–8706. [Google Scholar]
- Chang, J.; Schul, W.; Butters, T.D.; Yip, A.; Liu, B.; Goh, A.; Lakshminarayana, S.B.; Alonzi, D.; Reinkensmeier, G.; Pan, X.; et al. Combination of alpha-glucosidase inhibitor and ribavirin for the treatment of Dengue virus infection in vitro and in vivo. Antivir. Res. 2011, 89, 26–34. [Google Scholar] [CrossRef]
- Chang, J.; Schul, W.; Yip, A.; Xu, X.; Guo, J.T.; Block, T.M. Competitive inhibitor of cellular alpha-glucosidases protects mice from lethal Dengue virus infection. Antivir. Res. 2011, 92, 369–371. [Google Scholar] [CrossRef]
- Qing, M.; Yang, F.; Zhang, B.; Zou, G.; Robida, J.M.; Yuan, Z.; Tang, H.; Shi, P.Y. Cyclosporine inhibits flavivirus replication through blocking the interaction between host cyclophilins and viral ns5 protein. Antimicrob. Agents Chemother. 2009, 53, 3226–3235. [Google Scholar] [CrossRef]
- Nag, D.K.; Finley, D. A small-molecule inhibitor of deubiquitinating enzyme usp14 inhibits Dengue virus replication. Virus Res. 2012, 165, 103–106. [Google Scholar] [CrossRef]
- Chu, J.J.; Yang, P.L. C-src protein kinase inhibitors block assembly and maturation of Dengue virus. Proc. Natl. Acad. Sci.USA 2007, 104, 3520–3525. [Google Scholar] [CrossRef]
- De Wispelaere, M.; LaCroix, A.J.; Yang, P.L. The small molecules azd0530 and dasatinib inhibit Dengue virus RNA replication via fyn kinase. J. Virol. 2013, 87, 7367–7381. [Google Scholar] [CrossRef]
- Anwar, A.; Hosoya, T.; Leong, K.M.; Onogi, H.; Okuno, Y.; Hiramatsu, T.; Koyama, H.; Suzuki, M.; Hagiwara, M.; Garcia-Blanco, M.A. The kinase inhibitor sfv785 dislocates Dengue virus envelope protein from the replication complex and blocks virus assembly. PLoS One 2011, 6, e23246. [Google Scholar] [CrossRef]
- Van Cleef, K.W.; Overheul, G.J.; Thomassen, M.C.; Kaptein, S.J.; Davidson, A.D.; Jacobs, M.; Neyts, J.; van Kuppeveld, F.J.; van Rij, R.P. Identification of a new Dengue virus inhibitor that targets the viral ns4b protein and restricts genomic RNA replication. Antivir. Res. 2013, 99, 165–171. [Google Scholar] [CrossRef]
- Low, J.S.; Wu, K.X.; Chen, K.C.; Ng, M.M.; Chu, J.J. Narasin, a novel antiviral compound that blocks Dengue virus protein expression. Antivir. Ther. 2011, 16, 1203–1218. [Google Scholar] [CrossRef]
- Aoki, C.; Hidari, K.I.; Itonori, S.; Yamada, A.; Takahashi, N.; Kasama, T.; Hasebe, F.; Islam, M.A.; Hatano, K.; Matsuoka, K.; et al. Identification and characterization of carbohydrate molecules in mammalian cells recognized by Dengue virus type 2. J. Biochem. 2006, 139, 607–614. [Google Scholar] [CrossRef]
- Chen, C.J.; Kuo, M.D.; Chien, L.J.; Hsu, S.L.; Wang, Y.M.; Lin, J.H. Rna-protein interactions: Involvement of NS3, NS5, and 3' noncoding regions of japanese encephalitis virus genomic RNA. J. Virol. 1997, 71, 3466–3473. [Google Scholar]
- Kato, D.; Era, S.; Watanabe, I.; Arihara, M.; Sugiura, N.; Kimata, K.; Suzuki, Y.; Morita, K.; Hidari, K.I.; Suzuki, T. Antiviral activity of chondroitin sulphate E targeting Dengue virus envelope protein. Antivir. Res. 2010, 88, 236–243. [Google Scholar] [CrossRef]
- Hidari, K.I.; Takahashi, N.; Arihara, M.; Nagaoka, M.; Morita, K.; Suzuki, T. Structure and anti-Dengue virus activity of sulfated polysaccharide from a marine alga. Biochem. Biophys. Res. Comm. 2008, 376, 91–95. [Google Scholar] [CrossRef]
- Talarico, L.B.; Pujol, C.A.; Zibetti, R.G.; Faria, P.C.; Noseda, M.D.; Duarte, M.E.; Damonte, E.B. The antiviral activity of sulfated polysaccharides against Dengue virus is dependent on virus serotype and host cell. Antivir. Res. 2005, 66, 103–110. [Google Scholar] [CrossRef]
- Lee, E.; Pavy, M.; Young, N.; Freeman, C.; Lobigs, M. Antiviral effect of the heparan sulfate mimetic, PI-88, against Dengue and encephalitic flaviviruses. Antivir. Res. 2006, 69, 31–38. [Google Scholar] [CrossRef]
- Arroyo, J.I.; Apperson, S.A.; Cropp, C.B.; Marafino, B.J., Jr.; Monath, T.P.; Tesh, R.B.; Shope, R.E.; Garcia-Blanco, M.A. Effect of human gamma interferon on yellow fever virus infection. Am. J. Trop. Med. Hyg. 1988, 38, 647–650. [Google Scholar]
- Daffis, S.; Suthar, M.S.; Gale, M., Jr.; Diamond, M.S. Measure and countermeasure: Type I IFN (IFN-alpha/beta) antiviral response against West Nile Virus. J. Innate Immun. 2009, 1, 435–445. [Google Scholar] [CrossRef]
- Diamond, M.S.; Harris, E. Interferon inhibits Dengue virus infection by preventing translation of viral RNA through a PKR-independent mechanism. Virology 2001, 289, 297–311. [Google Scholar] [CrossRef]
- Johnson, A.J.; Roehrig, J.T. New mouse model for Dengue virus vaccine testing. J. Virol. 1999, 73, 783–786. [Google Scholar]
- Kurane, I.; Ennis, F.A. Production of interferon alpha by Dengue virus-infected human monocytes. J. Gen. Virol. 1988, 69, 445–449. [Google Scholar] [CrossRef]
- Suthar, M.S.; Diamond, M.S.; Gale, M., Jr. West nile virus infection and immunity. Nat. Rev. Microbiol. 2013, 11, 115–128. [Google Scholar] [CrossRef]
- Rodriguez-Pulido, M.; Martin-Acebes, M.A.; Escribano-Romero, E.; Blazquez, A.B.; Sobrino, F.; Borrego, B.; Saiz, M.; Saiz, J.C. Protection against West Nile virus infection in mice after inoculation with type I interferon-inducing RNA transcripts. PLoS One 2012, 7, e49494. [Google Scholar]
- Shoji-Kawata, S.; Sumpter, R.; Leveno, M.; Campbell, G.R.; Zou, Z.; Kinch, L.; Wilkins, A.D.; Sun, Q.; Pallauf, K.; MacDuff, D.; et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 2013, 494, 201–206. [Google Scholar] [CrossRef]
- Lee, Y.R.; Lei, H.Y.; Liu, M.T.; Wang, J.R.; Chen, S.H.; Jiang-Shieh, Y.F.; Lin, Y.S.; Yeh, T.M.; Liu, C.C.; Liu, H.S. Autophagic machinery activated by Dengue virus enhances virus replication. Virology 2008, 374, 240–248. [Google Scholar] [CrossRef]
- McLean, J.E.; Wudzinska, A.; Datan, E.; Quaglino, D.; Zakeri, Z. Flavivirus NS4A-induced autophagy protects cells against death and enhances virus replication. J. Biol. Chem. 2011, 286, 22147–22159. [Google Scholar] [CrossRef]
- Souza, D.G.; Fagundes, C.T.; Sousa, L.P.; Amaral, F.A.; Souza, R.S.; Souza, A.L.; Kroon, E.G.; Sachs, D.; Cunha, F.Q.; Bukin, E.; et al. Essential role of platelet-activating factor receptor in the pathogenesis of Dengue virus infection. Proc. Natl. Acad. Sci. USA 2009, 106, 14138–14143. [Google Scholar] [CrossRef]
- Bai, F.; Town, T.; Qian, F.; Wang, P.; Kamanaka, M.; Connolly, T.M.; Gate, D.; Montgomery, R.R.; Flavell, R.A.; Fikrig, E. IL-10 signaling blockade controls murine West Nile virus infection. PLoS Pathog. 2009, 5, e1000610. [Google Scholar] [CrossRef]
- Verma, S.; Kumar, M.; Nerurkar, V.R. Cyclooxygenase-2 inhibitor blocks the production of West Nile virus-induced neuroinflammatory markers in astrocytes. J. Gen. Virol. 2011, 92, 507–515. [Google Scholar] [CrossRef]
- Verma, S.; Kumar, M.; Gurjav, U.; Lum, S.; Nerurkar, V.R. Reversal of West Nile virus-induced blood-brain barrier disruption and tight junction proteins degradation by matrix metalloproteinases inhibitor. Virology 2010, 397, 130–138. [Google Scholar] [CrossRef]
- St John, A.L.; Rathore, A.P.; Raghavan, B.; Ng, M.L.; Abraham, S.N. Contributions of mast cells and vasoactive products, leukotrienes and chymase, to Dengue virus-induced vascular leakage. eLife 2013, 2, e00481. [Google Scholar] [CrossRef]
- Medigeshi, G.R.; Hirsch, A.J.; Streblow, D.N.; Nikolich-Zugich, J.; Nelson, J.A. West nile virus entry requires cholesterol-rich membrane microdomains and is independent of alphavbeta3 integrin. J. Virol. 2008, 82, 5212–5219. [Google Scholar] [CrossRef]
- Lee, C.J.; Lin, H.R.; Liao, C.L.; Lin, Y.L. Cholesterol effectively blocks entry of flavivirus. J. Virol. 2008, 82, 6470–6480. [Google Scholar] [CrossRef]
- Diamond, M.S.; Zachariah, M.; Harris, E. Mycophenolic acid inhibits Dengue virus infection by preventing replication of viral RNA. Virology 2002, 304, 211–221. [Google Scholar] [CrossRef]
- McDowell, M.; Gonzales, S.R.; Kumarapperuma, S.C.; Jeselnik, M.; Arterburn, J.B.; Hanley, K.A. A novel nucleoside analog, 1-beta-d-ribofuranosyl-3-ethynyl-[1,2,4]triazole (ETAR), exhibits efficacy against a broad range of flaviviruses in vitro. Antivir. Res. 2010, 87, 78–80. [Google Scholar] [CrossRef]
- Vasudevan, S.; Duke-NUS Graduate Medical School, Singapore. Personal communication, 2014.
- Gilfoy, F.; Fayzulin, R.; Mason, P.W. West nile virus genome amplification requires the functional activities of the proteasome. Virology 2009, 385, 74–84. [Google Scholar] [CrossRef]
- Wagstaff, K.M.; Sivakumaran, H.; Heaton, S.M.; Harrich, D.; Jans, D.A. Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and Dengue virus. Biochem. J. 2012, 443, 851–856. [Google Scholar] [CrossRef]
- Shum, D.; Smith, J.L.; Hirsch, A.J.; Bhinder, B.; Radu, C.; Stein, D.A.; Nelson, J.A.; Fruh, K.; Djaballah, H. High-content assay to identify inhibitors of Dengue virus infection. Assay Drug Dev. Technol. 2010, 8, 553–570. [Google Scholar] [CrossRef]
- Hidari, K.I.; Suzuki, T. Dengue virus receptor. Trop. Med. Health 2011, 39, 37–43. [Google Scholar] [CrossRef]
- Miller, J.L.; de Wet, B.J.; Martinez-Pomares, L.; Radcliffe, C.M.; Dwek, R.A.; Rudd, P.M.; Gordon, S. The mannose receptor mediates Dengue virus infection of macrophages. PLoS Pathog. 2008, 4, e17. [Google Scholar] [CrossRef]
- Reyes-Del Valle, J.; Chavez-Salinas, S.; Medina, F.; Del Angel, R.M. Heat shock protein 90 and heat shock protein 70 are components of Dengue virus receptor complex in human cells. J. Virol. 2005, 79, 4557–4567. [Google Scholar] [CrossRef]
- Jindadamrongwech, S.; Thepparit, C.; Smith, D.R. Identification of GRP 78 (BIP) as a liver cell expressed receptor element for Dengue virus serotype 2. Arch. Virol. 2004, 149, 915–927. [Google Scholar] [CrossRef]
- Thepparit, C.; Smith, D.R. Serotype-specific entry of Dengue virus into liver cells: Identification of the 37-kilodalton/67-kilodalton high-affinity laminin receptor as a Dengue virus serotype 1 receptor. J. Virol. 2004, 78, 12647–12656. [Google Scholar] [CrossRef]
- Meertens, L.; Carnec, X.; Lecoin, M.P.; Ramdasi, R.; Guivel-Benhassine, F.; Lew, E.; Lemke, G.; Schwartz, O.; Amara, A. The tim and tam families of phosphatidylserine receptors mediate Dengue virus entry. Cell Host Microbe 2012, 12, 544–557. [Google Scholar] [CrossRef]
- Hidari, K.I.; Abe, T.; Suzuki, T. Crabohydrate-related inhibitors of Dengue virus entry. Viruses 2013, 5, 605–618. [Google Scholar] [CrossRef]
- Chen, Y.; Maguire, T.; Hileman, R.E.; Fromm, J.R.; Esko, J.D.; Linhardt, R.J.; Marks, R.M. Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate. Nat. Med. 1997, 3, 866–871. [Google Scholar] [CrossRef]
- Navarro-Sanchez, E.; Altmeyer, R.; Amara, A.; Schwartz, O.; Fieschi, F.; Virelizier, J.L.; Arenzana-Seisdedos, F.; Despres, P. Dendritic-cell-specific ICAM3-grabbing non-integrin is essential for the productive infection of human dendritic cells by mosquito-cell-derived Dengue viruses. EMBO Rep. 2003, 4, 723–728. [Google Scholar] [CrossRef]
- Tassaneetrithep, B.; Burgess, T.H.; Granelli-Piperno, A.; Trumpfheller, C.; Finke, J.; Sun, W.; Eller, M.A.; Pattanapanyasat, K.; Sarasombath, S.; Birx, D.L.; et al. DC-sign (CD209) mediates Dengue virus infection of human dendritic cells. J. Exp. Med. 2003, 197, 823–829. [Google Scholar] [CrossRef]
- Brandler, S.; Tangy, F. Vaccines in development against West Nile virus. Viruses 2013, 5, 2384–2409. [Google Scholar] [CrossRef]
- Coller, B.A.; Clements, D.E.; Bett, A.J.; Sagar, S.L.; Ter Meulen, J.H. The development of recombinant subunit envelope-based vaccines to protect against Dengue virus induced disease. Vaccine 2011, 29, 7267–7275. [Google Scholar] [CrossRef]
- Danko, J.R.; Beckett, C.G.; Porter, K.R. Development of Dengue DNA vaccines. Vaccine 2011, 29, 7261–7266. [Google Scholar] [CrossRef]
- Heinz, F.X.; Stiasny, K. Flaviviruses and flavivirus vaccines. Vaccine 2012, 30, 4301–4306. [Google Scholar] [CrossRef]
- Iyer, A.V.; Kousoulas, K.G. A review of vaccine approaches for West Nile virus. IJERPH 2013, 10, 4200–4223. [Google Scholar] [CrossRef]
- Saito, T.; Gale, M., Jr. Principles of intracellular viral recognition. Curr. Opin. Immunol. 2007, 19, 17–23. [Google Scholar] [CrossRef]
- Kalil, A.C.; Devetten, M.P.; Singh, S.; Lesiak, B.; Poage, D.P.; Bargenquast, K.; Fayad, P.; Freifeld, A.G. Use of interferon-alpha in patients with West Nile encephalitis: Report of 2 cases. Clin. Infect. Dis. 2005, 40, 764–766. [Google Scholar] [CrossRef]
- Chan-Tack, K.M.; Forrest, G. Failure of interferon alpha-2B in a patient with West Nile virus meningoencephalitis and acute flaccid paralysis. Scan. J. Infect. Dis. 2005, 37, 944–946. [Google Scholar] [CrossRef]
- Ajariyakhajorn, C.; Mammen, M.P., Jr.; Endy, T.P.; Gettayacamin, M.; Nisalak, A.; Nimmannitya, S.; Libraty, D.H. Randomized, placebo-controlled trial of nonpegylated and pegylated forms of recombinant human alpha interferon 2A for suppression of Dengue virus viremia in rhesus monkeys. Antimicrob. Agents Chemother. 2005, 49, 4508–4514. [Google Scholar] [CrossRef]
- Borden, E.C.; Williams, B.R. Interferon-stimulated genes and their protein products: What and how? J. Interferon Cytokine Res. 2011, 31, 1–4. [Google Scholar] [CrossRef]
- Lin, R.J.; Yu, H.P.; Chang, B.L.; Tang, W.C.; Liao, C.L.; Lin, Y.L. Distinct antiviral roles for human 2',5'-oligoadenylate synthetase family members against Dengue virus infection. J. Immunol. 2009, 183, 8035–8043. [Google Scholar] [CrossRef]
- Scherbik, S.V.; Paranjape, J.M.; Stockman, B.M.; Silverman, R.H.; Brinton, M.A. RNase L plays a role in the antiviral response to West Nile virus. J. Virol. 2006, 80, 2987–2999. [Google Scholar]
- Thillier, Y.; Stevens, S.K.; Moy, C.; Taylor, J.; Vasseur, J.J.; Beigelman, L.; Debart, F. Solid-phase synthesis of 5'-triphosphate 2'-5'-oligoadenylates analogs with 3'-o-biolabile groups and their evaluation as RNase L activators and antiviral drugs. Bioorg. Med. Chem. 2013, 21, 5461–5469. [Google Scholar] [CrossRef]
- Liu, S.Y.; Aliyari, R.; Chikere, K.; Li, G.; Marsden, M.D.; Smith, J.K.; Pernet, O.; Guo, H.; Nusbaum, R.; Zack, J.A.; et al. Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity 2013, 38, 92–105. [Google Scholar]
- Beatman, E.; Oyer, R.; Shives, K.D.; Hedman, K.; Brault, A.C.; Tyler, K.L.; Beckham, J.D. West nile virus growth is independent of autophagy activation. Virology 2012, 433, 262–272. [Google Scholar]
- Mateo, R.; Nagamine, C.M.; Spagnolo, J.; Mendez, E.; Rahe, M.; Gale, M., Jr.; Yuan, J.; Kirkegaard, K. Inhibition of cellular autophagy deranges Dengue virion maturation. J. Virol. 2013, 87, 1312–1321. [Google Scholar] [CrossRef]
- Arjona, A.; Foellmer, H.G.; Town, T.; Leng, L.; McDonald, C.; Wang, T.; Wong, S.J.; Montgomery, R.R.; Fikrig, E.; Bucala, R. Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion. J. Clin. Invest. 2007, 117, 3059–3066. [Google Scholar] [CrossRef]
- Wang, P.; Dai, J.; Bai, F.; Kong, K.F.; Wong, S.J.; Montgomery, R.R.; Madri, J.A.; Fikrig, E. Matrix metalloproteinase 9 facilitates West Nile virus entry into the brain. J. Virol. 2008, 82, 8978–8985. [Google Scholar] [CrossRef]
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