EVOLUTIONARY CONSEQUENCES OF DENGUE VIRUS EMERGENCE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Dengue virus (genus Flavivirus) the most significant threat to public health among the arthropod-borne viruses, circulates in two distinct life cycles. Epidemic dengue viruses, which cause human dengue fever, cycle between humans and peridomestic Aedes mosquitoes. Sylvatic dengue viruses cycle in the forest canopies of Africa and Asia between sylvatic Aedes species and non-human primates. Endemic and sylvatic viruses show high sequence homology, but sylvatic viruses do not cause outbreaks in humans. Our initial hypothesis to explain this apparent paradox was that an adaptive barrier prevents the emergence of sylvatic dengue virus, or more specifically that sylvatic dengue virus replicates poorly in either humans or in peridomestic Aedes species. However, in collaboration with INBRE mentor Scott Weaver (UTMB) and members of his lab, we have demonstrated that no such adaptive barrier exists, because sylvatic and endemic strains of DENV serotype 2 are equally infectious for models of virus replication in humans (Vasilakis et al. 2007, Vasilakis et al. in preparation) and for Ae. aegypti, the primary vector of endemic dengue (Hanley et al. in preparation). An alternative explanation for the restriction of sylvatic dengue to the forest cycle is that competition with endemic strains of DENV prevents emergence of sylvatic strains. At present, the paucity of data on competition in DENV makes it impossible to assess this hypothesis. Thus, our current research focuses on characterizing the strength and symmetry of competition among different serotypes of dengue virus. We chose to initiate this research using different serotypes rather than sylvatic and endemic strains within a serotype because tractable, antibody-based methods are available to distinguish and quantify replication of different serotypes. To date we have demonstrated in both cultured cells and live mosquitoes that intra-host competition between serotypes can cause decreased virus progeny production, that effects of co-infection are asymmetric among serotypes, and that a weaker competitor can gain an advantage if it infects host cells prior to a stronger competitor. We plan to build on this research to test the strength and symmetry of competition between endemic and sylvatic dengue virus strains, using a PCR-based assay to quantify relative replication of each strain.