The polypyrimidine tract-binding protein (PTB) functions primarily as an IRES trans-acting factor in the propagation of hepatitis C virus and picornaviruses. PTB interacts with secondary structures within the 3-and 5-untranslated regions of these viral genomes to mediate efficient IRES-mediated viral translation. PTB has also been reported to bind to the untranslated region of the single-stranded RNA dengue virus (DENV), suggesting a similar function for PTB in flaviviruses. Indeed small interfering RNA-mediated PTB knockdown inhibited the production of infectious DENV, and this inhibition was specific to PTB knockdown and not due to a nonspecific anti-viral state. In fact, PTB depletion did not inhibit the production infectious yellow fever virus, another flavivirus. Nevertheless, whereas PTB knockdown led to a significant decrease in the accumulation of DENV viral RNAs, it did not impair translation. Moreover, PTB was shown to interact with the DENV nonstructural 4A protein, a known component of the viral replication complex, and with the DENV genome during infection. These data suggest that PTB interacts with the replication complex of DENV and is acting at the level of viral RNA replication. Dengue virus (DENV)3 is the etiologic agent of dengue fever, currently the most prevalent arthropod-borne viral disease of humans (1). Dengue fever can be caused by any of four closely related but antigenically distinct DENV serotypes (DENV-1, DENV-2, DENV-3, and DENV-4). DENV belongs to the Flaviviridae family, which comprises other medically important pathogens including the Japanese encephalitis, yellow fever (YFV), and hepatitis C (HCV) viruses (2).The Flaviviridae family of viruses has single-stranded positive polarity RNA genomes, which are mRNAs coding viral proteins required for replication. The viral RNA-dependent RNA polymerase, NS5, in conjunction with other viral nonstructural (NS) proteins and host cellular proteins, copies complementary negative strand RNAs from the genomic RNA template, which in turn serve as templates for the synthesis of new positive strand RNAs (2). Replication, transcription, and assembly of virions require cis-acting elements within the 5Ј-and 3Ј-UTRs of the viral genomic RNA (3-6). These elements interact with host cellular RNA-binding proteins including the polypyrimidine tract-binding protein (PTB). PTB, a heterogeneous nuclear ribonucleoprotein (7), is involved in multiple aspects of cellular mRNA metabolism, including the regulation of alternative splicing, RNA stability, and internal ribosomal entry (IRES)-mediated translation of viral and cellular mRNAs (8 -10).The role of PTB in the propagation of the positive singlestranded RNA viruses has largely been studied with HCV and picornaviruses, for which PTB primarily functions as an IRES trans-acting factor (ITAF), activating viral translation initiation (11,12). Its role in RNA replication of these viruses is however still debated (13-16). PTB has also been reported to bind to the UTR of the DENV-4 (17) and Japanese encephalitis ...
Dengue virus (DENV) is the etiologic agent for dengue fever, for which there is no approved vaccine or specific anti-viral drug. As a remedy for this, we explored the use of compounds that interfere with the action of required host factors and describe here the characterization of a kinase inhibitor (SFV785), which has selective effects on NTRK1 and MAPKAPK5 kinase activity, and anti-viral activity on Hepatitis C, DENV and yellow fever viruses. SFV785 inhibited DENV propagation without inhibiting DENV RNA synthesis or translation. The compound did not cause any changes in the cellular distribution of non-structural 3, a protein critical for DENV RNA synthesis, but altered the distribution of the structural envelope protein from a reticulate network to enlarged discrete vesicles, which altered the co-localization with the DENV replication complex. Ultrastructural electron microscopy analyses of DENV-infected SFV785-treated cells showed the presence of viral particles that were distinctly different from viable enveloped virions within enlarged ER cisternae. These viral particles were devoid of the dense nucleocapsid. The secretion of the viral particles was not inhibited by SFV785, however a reduction in the amount of secreted infectious virions, DENV RNA and capsid were observed. Collectively, these observations suggest that SFV785 inhibited the recruitment and assembly of the nucleocapsid in specific ER compartments during the DENV assembly process and hence the production of infectious DENV. SFV785 and derivative compounds could be useful biochemical probes to explore the DENV lifecycle and could also represent a new class of anti-virals.
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