A role for interferon (IFN) in modulating infection

Although prior studies have investigated cellular infection by dengue virus (DV), many have used highly passaged strains. We have reassessed cellular infection by DV type 2 (DV2) using prototype and low-passage isolates representing genotypes from different geographic areas. We observed marked variation in the susceptibility to infection among cell types by different DV2 strains. HepG2 hepatoma cells were susceptible to infection by all DV2 strains assayed. Although the prototype strain generated higher titers of secreted virus than the low-passage isolates, this difference did not correspond to positive-or negative-strand viral RNA levels and thus may reflect variation in efficiency among DV2 isolates to translate viral proteins or package and/or secrete virus. In contrast, human foreskin fibroblasts were susceptible to the prototype and low-passage Thai isolates but not to five Nicaraguan strains tested, as reflected by the absence of accumulation of negative-strand viral RNA, viral antigen, and infectious virus. A similar pattern was observed with the antibody-dependent pathway of infection. U937 and THP-1 myeloid cells and peripheral blood monocytes were infected in the presence of enhancing antibodies by the prototype strain but not by low-passage Nicaraguan isolates. Again, the barrier appeared to be prior to negative-strand accumulation. Thus, depending on the cell type and viral isolate, blocks that limit the production of infectious virus in vitro may occur at distinct steps in the pathway of cellular infection.Dengue virus (DV) is a single-stranded positive-polarity enveloped RNA flavivirus that causes dengue fever (DF), the most prevalent arthropod-borne viral illness in humans. Four DV serotypes are transmitted by mosquitoes, and infection results in a clinical spectrum ranging from an acute, self-limited febrile illness (DF) to a life-threatening syndrome (dengue hemorrhagic fever/dengue shock syndrome [DHF/DSS]). Globally, DV causes an estimated 100 million new cases of DF and 250,000 cases of DHF/DSS per year, with 2.5 billion people at risk (40). Despite the worldwide morbidity associated with DV infection, neither the molecular virology nor the pathogenesis of DV is well characterized.In primary DV infection, DV enters target cells after the envelope protein E attaches to an uncharacterized receptor that may display highly sulfated glycosaminoglycans (7). Secondary infection occurs after inoculation with a different DV serotype. In this case, the virus enters cells through a primary receptor but also may form immune complexes with preexisting nonneutralizing antibodies and interact with alternate receptors (9) such as Fc␥ receptors I and II (32), resulting in antibody-dependent enhancement of infection (ADE) (14, 16). ADE is hypothesized to contribute to the pathogenesis of severe dengue illness (16, 23), as epidemiological studies have identified secondary infection as a risk factor for DHF and have shown that the presence of preexisting anti-DV antibodies correlates with DHF (6, 54). Nonethele...

Viruses have developed numerous mechanisms to usurp the host cell translation apparatus. Dengue virus (DEN) and other flaviviruses, such as West Nile and yellow fever viruses, contain a 5 m 7 GpppN-capped positive-sense RNA genome with a nonpolyadenylated 3 untranslated region (UTR) that has been presumed to undergo translation in a cap-dependent manner. However, the means by which the DEN genome is translated effectively in the presence of capped, polyadenylated cellular mRNAs is unknown. This report demonstrates that DEN replication and translation are not affected under conditions that inhibit cap-dependent translation by targeting the cap-binding protein eukaryotic initiation factor 4E, a key regulator of cellular translation. We further show that under cellular conditions in which translation factors are limiting, DEN can alternate between canonical cap-dependent translation initiation and a noncanonical mechanism that appears not to require a functional m 7 G cap. This DEN noncanonical translation is not mediated by an internal ribosome entry site but requires the interaction of the DEN 5 and 3 UTRs for activity, suggesting a novel strategy for translation of animal viruses.

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