Proposed model of heterologous immunity in secondary dengue virus infections and its implications for the pathogenesis of dengue hemorrhagic fever. Primary DENV-2 infection and sequential DENV-1 and DENV-2 infections are compared for illustration purposes. The naive T cell repertoire (pale colors) likely contains some cells with higher avidity for DENV-1 than DENV-2 (red; DENV-1 > DENV-2) and other cells with higher avidity for DENV-2 than DENV-1 (blue; DENV-2 > DENV-1). During primary infection, T cell populations with higher avidity for the infecting serotype are preferentially expanded and enter the memory pool (shown as darker colors). When DENV-2 infection follows DENV-1 infection, the memory T cell populations with higher avidity for the earlier infection expand more rapidly than do naive T cell populations. Because these DENV-1–specific memory T cells have lower avidity for DENV-2, viral clearance mechanisms are suboptimal, whereas proinflammatory responses contribute to disease.