Dengue fever-dengue hemorrhagic fever (DF-DHF) is a complex of clinical syndromes caused by dengue (DEN) viruses of the genus Flavivirus (family Flaviviridae). DF-DHF has become a major global health problem over the past 25 years, producing more human illness than any other insect-transmitted viral disease (7). The geographic distribution of DEN viruses, their mosquito vectors (primarily Aedes aegypti), and the resulting disease burden continues to increase. The World Health Organization estimates that over 50 million new human infections occur annually. DF-DHF has become a leading cause of hospitalization and death among children in Southeast Asia (31), and the incidences of infection and disease are sharply rising in the Americas (8). There is currently no commercially available vaccine, chemoprophylactic, or effective therapeutic. Medical supportive care is the recommended primary treatment modality to improve the condition of severely infected patients (20).The DEN virus genome is an approximately 10.7-kb singlestranded RNA of positive polarity with a 5Ј cap and lacking a 3Ј poly(A) tail. DEN virus genomic RNA has a single long open reading frame (ORF) encoding three structural and seven nonstructural proteins. The mature DEN virus proteins are derived by co-or posttranslational cleavage of the polyprotein encoded by the ORF. The ORF is flanked by 5Ј and 3Ј untranslated regions (5Ј and 3Ј UTRs) that have various functions in the initiation and regulation of viral translation, replication, and assembly (21,24,34).Serologic and molecular analyses have defined four antigenically distinct serotypes of DEN virus (DEN virus serotype 1 [DEN-1 virus], DEN-2 virus, DEN-3 virus, and DEN-4 virus), which exhibit overall amino acid sequence identity of approximately 70% (12). Each serotype, in turn, contains several genotypic strains. The four DEN virus serotypes have pantropical distributions and cause similar spectra of clinical conditions (7). Persons who have experienced a single DEN virus infection generally develop a long-lasting immunity to DEN virus strains of the same serotype. However, subsequent infection with a different DEN virus serotype has a likelihood of leading to severe disease, at least in part through an immunologic process known as antibody-dependent enhancement (10,18,27). It is essential that a prospective vaccine and highly desirable that a prospective therapeutic be effective against all four DEN virus serotypes. Whether or not a safe and efficacious tetravalent DEN virus vaccine becomes available in the near future, there remains a critical need to develop effective therapeutics to treat patients suffering from severe DEN virus infection.Antisense compounds of various structural types have been successfully used to affect gene expression in several viral pathogens of humans (23). An antisense therapeutic for cytomegalovirus retinitis that targets the cytomegalovirus immediate-early gene 2 product has received approval from the Food and Drug Administration (25), and a number of oligonucleotide ...

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