Defining the Influence of HLA Polymorphisms and T Cell Phenotype and Function in Dengue Disease Pathogenesis

Nguyen Thi Phuong Dung (2011). Defining the Influence of HLA Polymorphisms and T Cell Phenotype and Function in Dengue Disease Pathogenesis. PhD thesis The Open University.



Dengue virus presents a growing threat to public health in a number of tropical and subtropical countries. Over half of the world’s population lives in areas at risk of infection. In its most serious forms, dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS), it is also a major cause of morbidity and mortality, particularly in Southeast Asia where it is the principle reason for paediatric admission to hospital during the rainy season. There is no vaccine available and the pathogenesis and viral factors that underlie clinical disease and protective immunity remain poorly understood. Epidemiological and clinical observations have shown that both host and viral factors determine the severity of the disease.

A study of genetic susceptibility to DHF/DSS was carried out to investigate the association of HLA alleles and DHF/DSS in Vietnamese children with secondary DENV-2 infection. This study has found that HLA Class I and II polymorphism significantly influences genetic susceptibility to DSS, in particular, secondary DENV-2 infected children with HLA-B*44 were likely to have DSS, whereas secondary DENV-2 infected children with HLA-Cw*12 and HLA-DQB1*03 were at increase risk of DHF when compared with the controls. HLA-A and HLA-DRB1 polymorphisms were not associated to DSS. This implies that HLA Class I-and II-restricted immune responses may play an important role in DHF disease.

T-cell responses to dengue viruses may be important in both protective immunity and pathogenesis. The study of 51 Vietnamese adults with secondary dengue virus infections defined the breadth and magnitude of peripheral T-cell responses to 260 overlapping peptide antigens derived from a dengue virus serotype 2 (DV2) isolate. There are forty-seven different peptides evoked significant IFN-y ELISPOT responses in 39 patients, and of these, 34 peptides contained potentially novel T cell epitopes. NS3, and particularly NS200-324, were important T cell targets. The breadth and magnitude of ELISPOT responses to DENV-2 peptides was independent of the infecting dengue serotype. Acute ELISPOT responses were weakly correlated with the extent of haemoconcentration in individual patients, but not with the nadir of thrombocytopaenia or the overall clinical disease grade. NS3556-564 and Env414-422 were identified as novel HLA-A*24 and B*07-restricted CD8+ T cell epitopes, respectively. Acute T cell responses to natural variants of Env414-422 and NS3556-564 were largely crossreactive and peaked during disease convalescence.

By phenotyping CD8+ T cells (CD38+/HLA-DR+, CD38+/Ki-67+ or HLA-DR+/Ki-67+) in serial blood samples from children with dengue, we found, no evidence of increased CD8+ T cell activation prior to the commencement of resolution of viraemia or haemoconcentration. Investigations with MHC class I tetramers to detect NS3133-142- specific CD8+ T cells in two independent cohorts of children suggested the commencement of haemoconceritration and thrombocytopaenia in DHF patients generally begins before the appearance of measurable frequencies of NS3133-142- specific CD8+T cells.

The results highlight the importance of NS3 and cross-reactive T cells during acute secondary infection but suggest the overall breadth and magnitude of the T cell response is not significantly related to clinical parameters. The temporal mismatch between the appearance of surface activated and DENV-specific CD8+ T cells suggests other mechanisms are responsible for triggering capillary leakage in children with DHF.

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