Immunodominance Changes as a Function of the Infecting Dengue Virus Serotype and Primary versus Secondary Infection

Abstract

Dengue virus (DENV) is the causative agent of dengue fever (DF). This disease can be caused by any of four DENV serotypes (DENV1 to -4) which share 67 to 75% sequence homology with one another. The effect of subsequent infections with different serotypes on the T cell repertoire is not fully understood. We utilized mice transgenic for human leukocyte antigens (HLA) lacking the alpha/beta interferon (IFN-␣/␤) receptor to study responses to heterologous DENV infection. First, we defined the primary T cell response to DENV3 in the context of a wide range of HLA molecules. The primary DENV3 immune response recognized epitopes derived from all 10 DENV proteins, with a significant fraction of the response specific for structural proteins. This is in contrast to primary DENV2 infection, in which structural proteins are a minor component of the response, suggesting differential antigen immunodominance as a function of the infecting serotype. We next investigated the effect of secondary heterologous DENV infection on the T cell repertoire. In the case of both DENV2/3 and DENV3/2 heterologous infections, recognition of conserved/cross-reactive epitopes was either constant or expanded compared to that in homologous infection. Furthermore, in heterologous infection, previous infection with a different serotype impaired the development of responses directed to serotype-specific but not conserved epitopes. Thus, a detrimental effect of previous heterotypic responses might not be due to dysfunctional and weakly cross-reactive epitopes dominating the response. Rather, responses to the original serotype might limit the magnitude of responses directed against epitopes that are either cross-reactive to or specific for the most recently infecting serotype. IMPORTANCE DENV transmission occurs in more than

The Human CD8 + T Cell Responses Induced by a Live Attenuated Tetravalent Dengue Vaccine Are Directed against Highly Conserved Epitopes

“…Likewise, we did not see a difference in magnitude and breadth between these two groups. We have previously shown in a mouse model of DENV infection that secondary infection with the same serotype did not change the repertoire toward conserved epitopes, supporting this observation (20). We observed that after tetravalent vaccination the induction of responses predominantly targeting the nonstructural proteins NS3 and NS5, which are also preferentially targeted in natural DENV infection (9,21,22).…”

Analysis of cell-mediated immune responses in support of dengue vaccine development efforts

“…Although testing these postulates is highly relevant to understanding both protective and 300 detrimental immune responses in dengue, only a few studies have compared immune responses during 301 or after primary versus secondary DENV infections. Consistent with the predictions, differences have 302 been reported in the expression of some phenotypic markers [71], in the dominant epitopes targeted 303 [78], and in the profile of serotype cross-reactivity [52,82]. Surprisingly, no significant differences were 304 observed in the kinetics of the response or in the peak T cell frequencies during the acute infection [48, 305 52].…”

“…This is a particular problem in individuals who have been exposed to more than one 259 DENV serotype, either through sequential exposure or multivalent immunization. Although one study 260 concluded that serotype-specific epitopes could be defined based on sequence conservation alone [78], 261 other experimental data are directly contradictory [36, 37, 41]. Another study described a panel of CD4 262…”

Human CD4 + T Cell Responses to an Attenuated Tetravalent Dengue Vaccine Parallel Those Induced by Natural Infection in Magnitude, HLA Restriction, and Antigen Specificity

“…We previously found that 80% homology is required for cross-reactivity at the level of DENV CD8 ϩ responses; the data suggest that cross-reactivity of DENV epitopes is far more extensive for CD4 ϩ than for CD8 ϩ responses (28). Secondary T cell responses to conserved/cross-reactive regions may contribute to the heightened protection and lower disease severity observed for tertiary heterotypic DENV infections (6,29) and may thereby represent a desirable attribute of vaccine-induced cellular responses.…”