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Original Antigenic Sin in Dengue Revisited

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Original Antigenic Sin in Dengue Revisited COMMENTARY COMMENTARY Original antigenic sin in dengue revisited Simona Zompi and Eva Harris1 DENV infections has been the low number Division of Infectious Diseases and Vaccinology, School of Public Health, University of of characterized DENV T-cell epitopes. California, Berkeley, CA 94720-3370 + Weiskopf et al. (4) focused on the CD8 T-cell response, thus on MHC class I mole- The four dengue virus serotypes (DENV-1 hospitalizations attributable to dengue each cules, in Sri Lankan blood donors. They to -4) cause the most important arthro- year, with case fatality rates as high as 10– started by synthesizing a very large number pod-borne viral disease of humans, with 20% without appropriate treatment (9). of peptides (8,088) that bound the 27 most ∼100 million cases each year and over 3 Dengue constitutes a substantial economic prominent MHC class I alleles (HLA-A and billion people at risk for infection (1). The burden in endemic countries (10), which HLA-B) identified in the Sri Lankan pop- immune response to DENV infection is are mostly low- and middle-income coun- ulation. By choosing this set of 27 alleles, the complex, because it can be either protective tries. No specific treatment exists, and an authors were able to match three of four or pathogenic. The “original antigenic sin” in incomplete understanding of the immune MHC class I alleles in 90% of the donors secondary (2°) DENV infections is defined as response has hindered vaccine development. (figure 1 in ref. 4). Among these, they iden- the dominance of cross-reactive antibodies or Primary (1°) infection with any of the four tified 408 unique DENV epitopes, increasing T-cell responses to a first infecting DENV DENV serotypes is believed to confer life- by fivefold the number of DENV epitopes serotype (the “original antigen”) over the cur- long protection to the homologous serotype; currently available in the Immune Epitope rent infecting serotype. In acute DENV infec- however, 2° infection with a different DENV Database. These epitopes are publicly acces- tions, cross-reactive T-cell responses have serotype is the major risk factor for severe sible to the research community and will be been associated with more severe disease, disease (11). This may be attributable to useful for future T-cell studies. Among these consigning cross-reactive T-cell responses cross-reactive T cells (3) or to “antibody- 408 epitopes, the authors were able to char- to a pathogenic role (2, 3). In this issue of dependent enhancement” (12), where cross- acterize only 25 immunodominant epitopes PNAS, Weiskopf et al. (4) challenge the idea reactive anti-DENV antibodies facilitate entry that account for 50% of the T-cell responses that cross-reactive T-cell responses are only of DENV into constant fragment receptor- in the population studied, thus enabling fu- + associated with pathogenesis by demonstrat- bearing cells. However, the majority of 2° ture measurement of CD8 T-cell responses + ing that although CD8 T-cell responses DENV infections are asymptomatic or result usingsmallvolumesofblood.Thisispar- were indeed skewed toward the first DENV in only mild disease. The immune mech- ticularly relevant for DENV infections, be- infection, this did not result in impaired anisms underlying protection against a cause many symptomatic and severe cases responses, either qualitatively or quantita- heterologous DENV infection are not well are reported in children, and pediatric sam- tively. Furthermore, they found that higher understood. The unexpected results of the ples are always available in limited amounts. magnitude T-cell responses were associated first proof-of-concept dengue tetravalent In addition, the previous definition of im- with HLA alleles that have been linked to live attenuated vaccine efficacy trial, in which munodominant peptides could be skewed. reduced susceptibility to severe dengue. the CYD23 vaccine failed to protect against Although several groups have reported im- Thus, these results suggest that human DENV-2 (13), highlight the critical need to munodominant epitopes in NS5, NS4B, and cross-reactive T-cell responses can be asso- better understand the immune response to E (14, 15), most of the DENV T-cell epitopes ciated with a robust and multifunctional re- natural DENV infections and vaccine can- studied thus far are localized in the NS3 sponse that can induce protection, as has didates and to identify robust correlates of protein (3). The work of Weiskopf et al. now – provides a broader picture of the immu- been shown in dengue mouse models (5 7). protection, especially because in vitro neu- + tralization titers did not correlate with vac- nodominant CD8 T-cell epitope repertoire Dengue epidemiology and immune cine efficacy. CYD23 is a chimeric vaccine acrosstheentireDENVgenome(4). response containing the nonstructural proteins from Dengue is endemic throughout the world’s A protective role for original antigenic sin yellow fever virus and the structural proteins Several lines of evidence suggest that both subtropical and tropical regions, especially in + + (prM/M and E) from DENV. Because most CD4 and CD8 T cells help resolve DENV Asia and Latin America, and it is considered + T-cell epitopes are found in the nonstruc- infection; for instance, serotype-specificCD4 an emerging infectious disease threat in the + tural proteins, this vaccine does not induce and CD8 T-cell responses are observed in United States and a category A pathogen. fi + a DENV-speci cCD8 T-cell response. humans with 1° DENV infection (16), and Increased urbanization, globalization, and + Thus, it will be important to explore T-cell DENV-specifichumanCD4 T cells specific travel, as well as climate change, all contrib- responses as possible correlates of protection. γ ute to its uncontrolled expansion (8). The for NS3 proliferate, produce IFN- ,andcan acute febrile illness dengue fever (DF) can Expansion of the DENV T cell epitope lyse target cells (17). However, altered T-cell progress to a potentially life-threatening database vascular leakage syndrome, known as dengue T-cell epitopes are ∼10–20 aa in length, Author contributions: S.Z. and E.H. wrote the paper. hemorrhagic fever/dengue shock syndrome presented on the surface of antigen-present- The authors declare no conflict of interest. (DHF/DSS), the latter characterized by hy- ing cells, that bind major histocompatibility See companion article on page E2046. potension and circulatory failure, most often complex (MHC) on the surface of T cells. 1To whom correspondence should be addressed. E-mail: eharris@ affecting children (9). There are ∼500,000 One limitation of T-cell studies in human berkeley.edu. www.pnas.org/cgi/doi/10.1073/pnas.1306333110 PNAS | May 28, 2013 | vol. 110 | no. 22 | 8761–8762 Downloaded by guest on September 29, 2021 responses during 2° infections with a different hypothesis of original antigenic sin (i.e., population, and sampling likely occurred DENV serotype may contribute to the “cy- conserved, or cross-reactive, epitopes dom- several years after the last DENV infection. + tokine storm” and immunopathogenesis of inate the CD8 T-cell response in 2° DENV As such, these data are not necessarily in DHF/DSS. Several studies have shown that infections). contradiction with previously published data serotype cross-reactive T cells are prefer- Weiskopf et al. (4) describe a thorough showing a pathogenic role for T cells during + entially activated during 2° infection and and comprehensive analysis of CD8 T-cell acute DENV infections (2). A robust cross- exhibit suboptimal degranulation and en- functions. Of note, these experiments were reactive T-cell response could be protective hanced TNF-α and IFN-γ production (2). conducted directly ex vivo, in contrast to in general but in specific cases, seen in the Another study found the ratio of TNF-α– to responses measured after in vitro stimulation acute phase of certain 2° DENV infections IFN-γ–producing cells was higher when for several days. Importantly, no difference in with severe disease, cross-reactive T-cell + + DENV-specificCD4 T cells were stimulated CD8 T-cell responses were noted in terms responses might contribute to pathogenesis. ex vivo with antigens from the heterologous of magnitude, phenotype, CD107a expression Pathogenesis of acute 2° DENV infections vs. homologous serotype (18). Increased (a marker of cytotoxicity), cytokine profile/ is complex, and numerous factors influence TNF-α production by T cells could facilitate polyfunctionality, and avidity in serotype- how cross-reactive T cells behave during the vascular leakage, as TNF-α has been detected specific vs. conserved responses. Thus, in acute phase of the infection, including pre- more frequently and at higher levels in the addition to its role in pathogenesis, “original existing immunity, the time interval between serum of patients with DHF/DSS than with antigenic sin” in human DENV infections DENV infections, host genetic factors, the DF (19). Overall, studies in human DENV has now been associated with T-cell functions sequence of serotypes, and viral load. infections thus far have mostly focused on characteristic of T-cell–mediated protection. the potential role of T cells in pathogenesis Another important feature of this paper is Conclusions and the association between HLA alleles that the authors HLA-typed the same donors These results provide a refreshing view of the and disease severity. and associated HLA genotyping with T-cell role of T cells in human DENV infection. The sequence of infecting DENV serotypes function (4). Previous data have shown an Both T and B cells can play a protective or can modulate disease severity (20). Defining association between HLA types and dengue pathogenic role in dengue but more data are the sequence of infecting DENV serotypes disease susceptibility (22). Rather than the needed in human populations, and Weiskopf fi fi et al. (4) provide important evidence of the is dif cult, except in the context of cohort serotype-speci c vs.
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