HLA-A*0201-restricted CD8+ T-cell epitopes identified in dengue viruses.

BACKGROUND: All four dengue virus (DV) serotypes (D1V, D2V, D3V and D4V) can cause a series of disorders, ranging from mild dengue fever (DF) to severe dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). Previous studies have revealed that DV serotype-specific CD8(+) T cells are involved in controlling DV infection. Serotype cross-reactive CD8(+) T-cells may contribute to the immunopathogenesis of DHF/DSS. The aim of the study was to identify HLA-A*0201-binding peptides from four DV serotypes. We then examined their immunogenicity in vivo and cross-reactivity within heterologous peptides. METHODS: D1V-derived candidate CD8(+) T-cell epitopes were synthesized and evaluated for their affinity to the HLA-A*0201 molecule. Variant peptides representing heterologous D2V, D3V, D4V serotypes were synthesized. The immunogenicity of the high-affinity peptides were evaluated in HLA-A*0201 transgenic mice. RESULTS: Of the seven D1V-derived candidate epitopes [D1V-NS4a(56-64)(MLLALIAVL), D1V-C(46-54)(LVMAFMAFL), D1V-NS4b(562-570)(LLATSIFKL), D1V-NS2a(169-177)(AMVLSIVSL), D1V-NS4a(140-148)(GLLFMILTV), D1V-NS2a(144-152)(QLWAALLSL) and D1V-NS4b(183-191)(LLMRTTWAL)], three peptides [D1V-NS4a(140-148), D1V-NS2a(144-152) and D1V-NS4b(183-191)] had a high affinity for HLA-A*0201 molecules. Moreover, their variant peptides for D2V, D3V and D4V [D2V-NS4a(140-148)(AILTVVAAT), D3V-NS4a(140-148)(GILTLAAIV), D4V-NS4a(140-148)(TILTIIGLI), D2V-NS2a(144-152)(QLAVTIMAI), D3V-NS2a(144-152)(QLWTALVSL), D4V-NS2a(143-151)(QVGTLALSL), D2V-NS4b(182-190)(LMMRTTWAL), D3V-NS4b(182-190) (LLMRTSWAL) and D4V-NS4b(179-187)(LLMRTTWAF)] also had a high affinity for HLA-A*0201 molecules. Furthermore, CD8+ T cells directed to these twelve peptides were induced in HLA-A*0201 transgenic mice following immunization with these peptides. Additionally, cross-reactivity within four peptides (D1V-NS4b(183-191), D2V-NS4b(182-190), D3V-NS4b(182-190) and D4V-NS4b(179-187)) was observed. CONCLUSIONS: Two novel serotype-specific HLA-A*0201-restricted CD8(+) T-cell epitopes (NS4a(140-148) and NS2a(144-152)) and one cross-reactive HLA-A*0201-restricted CD8(+) T-cell epitopes which is similar to a previously identified epitope were identified in D1V-D4V. Combining prediction algorithms and HLA transgenic mice is an effective strategy to identify HLA-restricted epitopes. Serotype-specific epitopes would be used to determine the protective role of serotype-specific CD8(+) T cells, while cross-reactive epitopes may provide assistance in exploring the role of serotype cross-reactive CD8(+) T cells in the immunopathogenesis of DHF/DSS.

[Correlation of expression of nuclear factor kappaB, inhibitor protein kappaB, and Bcl-2 in cervical cancer to human papillomavirus infection].

BACKGROUND & OBJECTIVE: It was proved that nuclear factor kappaB (NF-kappaB) and its inhibitor protein kappaB (I-kappaB) played critical roles in regulating the expression of proapoptotic genes, and NF-kappaB is overexpressed in some tumors and related with tumorigenesis. However, the expression of NF-kappaB and I-kappaB in cervical cancer and its correlation to human papillomavirus (HPV) infection have not been reported yet. This study was to explore the correlation of the expression of NF-kappaB, I-kappaB, and Bcl-2 in cervical cancer to human papillomavirus (HPV) infection. METHODS: The expression of NF-kappaB, I-kappaB, and Bcl-2 were detected by immunohistochemistry in 46 specimens of cervical cancer and 26 specimens of normal cervical tissue. HPV DNA was detected by polymerase chain reaction (PCR). RESULTS: The positive rates of NF-kappaB and Bcl-2 were significantly higher in cervical cancer than in normal cervical tissue (60.9% vs. 23.1%, 52.2% vs. 0.0%, P < 0.01). The positive rate of I-kappaB was significantly lower in cervical cancer than in normal cervical tissue (30.4% vs. 57.7%, P < 0.05). The expression of NF-kappaB was closely related to Bcl-2 (P < 0.05). The positive rate of NF-kappaB was significantly higher in HPV DNA-positive cervical cancer than in HPV DNA-negative cervical cancer (81.3% vs. 35.7%, P < 0.05), but the positive rates of I-kappaB and Bcl-2 between these 2 groups had no significant difference (P >0.05). CONCLUSION: The high expression of NF-kappaB and Bcl-2 and the low expression of I-kappaB may be related to cervical carcinogenesis, and NF-kappaB expression may be related to HPV infection.