We have shown here that the exact ADE value has important implications for setting the prevalence and incidence of serotypes and competition between serotypes. ADE, because greater levels of enhancement induce large amplitude oscillations in incidence of all dengue virus infections, threatening the persistence of both the enhanced and nonenhanced serotypes. Although the models presented here are specifically designed for dengue, our results are applicable to any epidemiological system in which partial immunity increases pathogen replication rates. Our results suggest that enhancement is most advantageous in settings where multiple serotypes circulate and where a large host population is usually available to support pathogen persistence during the deep troughs of ADE-induced large amplitude oscillations of virus replication. (9) and in nonhuman primates (10). Additionally, the presence of transplacentally acquired maternal dengue antibodies has been associated with DHF in infants (4). Higher viremia has been observed in individuals experiencing their second dengue contamination than those undergoing primary contamination, although one other study was inconclusive (11, 12). There is also evidence that viral strains vary in virulence (13). It is most likely that both viral factors and immune status are important in determining the severity of disease. Epidemics in the Americas demonstrate that both viral factors and host immune states play clear roles in disease severity. Secondary infections of dengue serotype 2 have been associated with severe disease Afuresertib HCl in several settings in the Americas, but only for viruses of Southeast Asian origin, not those of American origin (14-16). Because ADE appears to be a characteristic of some dengue viruses and not others, the present work seeks to explore the particular dynamic mechanisms and settings that make ADE an advantageous strategy. Although the model we present is usually specific to dengue, the results are applicable to any microbial agent affected Afuresertib HCl Afuresertib HCl by immune enhancement. ADE has been observed for other families of pathogens, including retroviruses and coronaviruses (17-19). Accordingly, ADE is a concern in the development of vaccines against HIV and severe acute respiratory syndrome as well as dengue (17, 20). ADE of dengue viruses was first observed in Southeast Asia (21), and all four serotypes of dengue have circulated in Southeast Asia for at least 50 years (22). The association of DHF with secondary contamination and ADE has been observed in Southeast Asia for many years as well (21). We hypothesize that this large urban centers of Southeast Asia where multiple serotypes of dengue circulate at high Rabbit Polyclonal to NDUFB10 levels of transmission provide the most advantageous environment for the emergence of ADE. In a previous study, we observed spatial-temporal traveling waves in the incidence of DHF that emanated from Bangkok Afuresertib HCl and spread radially throughout the country (23). In that work, we hypothesized that Bangkok acts as a pacemaker for the surrounding region because all four serotypes are maintained there, providing a source of periodic reintroductions of particular serotypes to the surrounding region. In this study, we take steps toward addressing these hypotheses by studying the dynamics of dengue circulation in a single population. We develop a model of the dynamics of dengue transmission in the presence of ADE. We model the cocirculation of four serotypes as occurs in nature and, more generally, serotypes to study the effect of ADE in systems of varying numbers of cocirculating serotypes. We use this model to determine the impact of ADE on competition between serotypes and on the persistence of multiple serotypes in a single population. We speculate that ADE confers a fitness advantage on enhanced viruses, and that there is ongoing natural selection for such strains. We hold that it will be important to disease control efforts to understand the processes, such as ADE, that affect the evolution and pathogenicity of dengue viruses. Although new serotypes have been reported prematurely in the literature (24), no new serotypes beyond the four known have emerged. We explore the consequences of emergence of new dengue serotypes by comparing the dynamics of model systems with two to.