Dengue: defining protective versus pathologic immunity

Abstract

Dengue is an expanding public health problem, and an effective vaccine remains elusive. This review discusses how the significant influence of sequential infection with different dengue virus serotypes on the severity of disease can be viewed in terms of beneficial and detrimental effects of heterologous immunity. A more complete understanding of these effects is likely to be critical for predicting optimal vaccine-induced immune responses.

Figure 1

Organization of the flavivirus genome and its resulting proteins and the location of the major targets of the immune response. The DENV genome is a single-stranded sense RNA with a single open reading frame (ORF; top). The ORF is translated as a single polyprotein (middle) that is cleaved by viral and host proteases to yield the ten viral proteins: the C protein; the M protein, which is synthesized as the larger precursor protein pre-M (pM); the major E glycoprotein; and seven NS proteins involved in viral replication among other functions (bottom). The strength of the antibody and T cell responses to individual viral proteins is indicated below.

Figure 2

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.