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HLA-A2 and B35 restricted hantaan virus nucleoprotein CD8+ T-cell epitope-specific immune response correlates with milder disease in hemorrhagic fever with renal syndrome.

Ma Y, Wang J, Yuan B, Wang M, Zhang Y, Xu Z, Zhang C, Zhang Y, Liu B, Yi J, Yang K, Yang A, Zhuang R, Jin B - PLoS Negl Trop Dis (2013)

Bottom Line: Moreover, the frequency of epitope-specific CD8(+) T cells at acute stage was inversely associated with the peak level of serum creatinine and was positively associated with the nadir platelet counts during the hospitalization.The intracellular cytokine staining and the proliferation assay showed that the effective epitope-specific CD8(+) T cells were characterized with the production of interferon-γ, expression of CD69 and the strong capacity of proliferation.The novel HLA class I restricted HTNV nucleoprotein epitopes-specific CD8(+) T-cell responses would be closely related with the progression and the severity of the disease, which could provide the first step toward effective peptide vaccine development against HTNV infection in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, the Fourth Military Medical University, Xi'an, China.

ABSTRACT

Background: Hantaan virus (HTNV) infection in humans is a serious public health concern in Asia. A potent T cell activation peptide vaccine from HTNV structure protein represents a promising immunotherapy for disease control. However, the T cell epitopes of the HTNV restricted by the HLA alleles and the role of epitope-specific T cell response after HTNV infection remain largely unexplored.

Methodology/principal findings: Five well-conserved novel CD8(+) T-cell epitopes of the HTNV nucleoprotein restricted by the most popular HLA alleles in Chinese Han population were defined with interferon-γ enzyme-linked immunospot assay in 37 patients infected with HTNV during hospitalization. Two epitopes aa129-aa137 and aa131-aa139 restricted by HLA-A2 and B35, respectively, were selected to evaluate the epitope-specific CD8(+) T-cell response. HLA-peptide pentamer complex staining showed that the frequency of single epitope-specific CD8(+) T cell could be detected in patients (95% confidence interval for aa129-aa137: 0.080%-0.208%; for aa131-aa139: 0.030%-0.094%). The frequency of epitope-specific pentamer(+) CD8(+) T-cell response was much higher in mild/moderate patients than in severe/critical ones at the acute stage of the disease. Moreover, the frequency of epitope-specific CD8(+) T cells at acute stage was inversely associated with the peak level of serum creatinine and was positively associated with the nadir platelet counts during the hospitalization. The intracellular cytokine staining and the proliferation assay showed that the effective epitope-specific CD8(+) T cells were characterized with the production of interferon-γ, expression of CD69 and the strong capacity of proliferation.

Conclusion/significance: The novel HLA class I restricted HTNV nucleoprotein epitopes-specific CD8(+) T-cell responses would be closely related with the progression and the severity of the disease, which could provide the first step toward effective peptide vaccine development against HTNV infection in humans.

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Related in: MedlinePlus

The analysis of HTNV nucleoprotein epitope-specific CD8+ T-cell responses with the disease severity.The comparison of the epitope-specific CD8+ T-cell frequencies (A) between patients in mild/moderate group and patients in severe/critical group at the acute stage in the 18 donors with HLA-A2 or in the 8 donors with HLA-B35, (B) between the acute stage and the late stage in ten HLA-A2+ patients and in seven HLA-B35+ patients (Mann-Whitney U test). (C) The associations between the frequencies of the epitope-specific CD8+ T cells at the acute stage and the peak level of serum creatinine or nadir platelet counts during the hospitalization in 18 donors with HLA-A2 and in 8 donors with HLA-B35 (Spearman correlation test). P values of ≤0.05 were considered statistically significant. HLA, human leukocyte antigen; HFRS, hemorrhagic fever with renal syndrome.
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pntd-0002076-g004: The analysis of HTNV nucleoprotein epitope-specific CD8+ T-cell responses with the disease severity.The comparison of the epitope-specific CD8+ T-cell frequencies (A) between patients in mild/moderate group and patients in severe/critical group at the acute stage in the 18 donors with HLA-A2 or in the 8 donors with HLA-B35, (B) between the acute stage and the late stage in ten HLA-A2+ patients and in seven HLA-B35+ patients (Mann-Whitney U test). (C) The associations between the frequencies of the epitope-specific CD8+ T cells at the acute stage and the peak level of serum creatinine or nadir platelet counts during the hospitalization in 18 donors with HLA-A2 and in 8 donors with HLA-B35 (Spearman correlation test). P values of ≤0.05 were considered statistically significant. HLA, human leukocyte antigen; HFRS, hemorrhagic fever with renal syndrome.

Mentions: We compared the epitope-specific CD8+ T-cell frequencies between patients with mild/moderate HFRS and those with severe/critical HFRS at the earliest available acute stage time point in the 18 patients with HLA-A2 and in the 8 patients with HLA-B35 from whom PBMCs had been collected. The statistical analyses showed that the frequencies of the epitope-specific CD8+ T cells were much higher in the mild/moderate HFRS patients than that in the severe/critical patients (Mann–Whitney U test, for HLA-A2 restricted epitope: P = 0.007, for HLA-B35 restricted epitope: P = 0.021) (Figure 4A). There was no difference in the frequency between the two groups at the late stage of the disease (data not shown). Then we compared the frequencies of the epitope-specific CD8+ T-cell response between the acute stage and the late stage (diuretic and convalescence stage) during the illness in ten HLA-A2+ patients and in seven HLA-B35+ patients, and the results showed that the frequency of the epitope-specific CD8+ T cells in the acute stage was higher than that in the late stage in patients (Mann–Whitney U test, for HLA-A2 restricted epitope: P = 0.041, for HLA-B35 restricted epitope: P = 0.009) (Figure 4B). The analysis of the associations between the HTNV-NP epitope-specific CD8+ T-cell responses and the clinical parameters showed that the frequency of epitope-specific CD8+ T cells at the acute stage was inversely associated with the peak level of serum creatinine (Spearman correlation test, for HLA-A2 restricted epitope: P = 0.030, r = −0.511; for HLA-B35 restricted epitope: P = 0.021, r = −0.786) and positively associated with the nadir of platelet counts (for HLA-A2 restricted epitope: P = 0.018, r = 0.549; for HLA-B35 restricted epitope: P = 0.010, r = 0.833) during the clinical course of the HFRS (Figure 4C).


HLA-A2 and B35 restricted hantaan virus nucleoprotein CD8+ T-cell epitope-specific immune response correlates with milder disease in hemorrhagic fever with renal syndrome.

Ma Y, Wang J, Yuan B, Wang M, Zhang Y, Xu Z, Zhang C, Zhang Y, Liu B, Yi J, Yang K, Yang A, Zhuang R, Jin B - PLoS Negl Trop Dis (2013)

The analysis of HTNV nucleoprotein epitope-specific CD8+ T-cell responses with the disease severity.The comparison of the epitope-specific CD8+ T-cell frequencies (A) between patients in mild/moderate group and patients in severe/critical group at the acute stage in the 18 donors with HLA-A2 or in the 8 donors with HLA-B35, (B) between the acute stage and the late stage in ten HLA-A2+ patients and in seven HLA-B35+ patients (Mann-Whitney U test). (C) The associations between the frequencies of the epitope-specific CD8+ T cells at the acute stage and the peak level of serum creatinine or nadir platelet counts during the hospitalization in 18 donors with HLA-A2 and in 8 donors with HLA-B35 (Spearman correlation test). P values of ≤0.05 were considered statistically significant. HLA, human leukocyte antigen; HFRS, hemorrhagic fever with renal syndrome.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585118&req=5

pntd-0002076-g004: The analysis of HTNV nucleoprotein epitope-specific CD8+ T-cell responses with the disease severity.The comparison of the epitope-specific CD8+ T-cell frequencies (A) between patients in mild/moderate group and patients in severe/critical group at the acute stage in the 18 donors with HLA-A2 or in the 8 donors with HLA-B35, (B) between the acute stage and the late stage in ten HLA-A2+ patients and in seven HLA-B35+ patients (Mann-Whitney U test). (C) The associations between the frequencies of the epitope-specific CD8+ T cells at the acute stage and the peak level of serum creatinine or nadir platelet counts during the hospitalization in 18 donors with HLA-A2 and in 8 donors with HLA-B35 (Spearman correlation test). P values of ≤0.05 were considered statistically significant. HLA, human leukocyte antigen; HFRS, hemorrhagic fever with renal syndrome.
Mentions: We compared the epitope-specific CD8+ T-cell frequencies between patients with mild/moderate HFRS and those with severe/critical HFRS at the earliest available acute stage time point in the 18 patients with HLA-A2 and in the 8 patients with HLA-B35 from whom PBMCs had been collected. The statistical analyses showed that the frequencies of the epitope-specific CD8+ T cells were much higher in the mild/moderate HFRS patients than that in the severe/critical patients (Mann–Whitney U test, for HLA-A2 restricted epitope: P = 0.007, for HLA-B35 restricted epitope: P = 0.021) (Figure 4A). There was no difference in the frequency between the two groups at the late stage of the disease (data not shown). Then we compared the frequencies of the epitope-specific CD8+ T-cell response between the acute stage and the late stage (diuretic and convalescence stage) during the illness in ten HLA-A2+ patients and in seven HLA-B35+ patients, and the results showed that the frequency of the epitope-specific CD8+ T cells in the acute stage was higher than that in the late stage in patients (Mann–Whitney U test, for HLA-A2 restricted epitope: P = 0.041, for HLA-B35 restricted epitope: P = 0.009) (Figure 4B). The analysis of the associations between the HTNV-NP epitope-specific CD8+ T-cell responses and the clinical parameters showed that the frequency of epitope-specific CD8+ T cells at the acute stage was inversely associated with the peak level of serum creatinine (Spearman correlation test, for HLA-A2 restricted epitope: P = 0.030, r = −0.511; for HLA-B35 restricted epitope: P = 0.021, r = −0.786) and positively associated with the nadir of platelet counts (for HLA-A2 restricted epitope: P = 0.018, r = 0.549; for HLA-B35 restricted epitope: P = 0.010, r = 0.833) during the clinical course of the HFRS (Figure 4C).

Bottom Line: Moreover, the frequency of epitope-specific CD8(+) T cells at acute stage was inversely associated with the peak level of serum creatinine and was positively associated with the nadir platelet counts during the hospitalization.The intracellular cytokine staining and the proliferation assay showed that the effective epitope-specific CD8(+) T cells were characterized with the production of interferon-γ, expression of CD69 and the strong capacity of proliferation.The novel HLA class I restricted HTNV nucleoprotein epitopes-specific CD8(+) T-cell responses would be closely related with the progression and the severity of the disease, which could provide the first step toward effective peptide vaccine development against HTNV infection in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, the Fourth Military Medical University, Xi'an, China.

ABSTRACT

Background: Hantaan virus (HTNV) infection in humans is a serious public health concern in Asia. A potent T cell activation peptide vaccine from HTNV structure protein represents a promising immunotherapy for disease control. However, the T cell epitopes of the HTNV restricted by the HLA alleles and the role of epitope-specific T cell response after HTNV infection remain largely unexplored.

Methodology/principal findings: Five well-conserved novel CD8(+) T-cell epitopes of the HTNV nucleoprotein restricted by the most popular HLA alleles in Chinese Han population were defined with interferon-γ enzyme-linked immunospot assay in 37 patients infected with HTNV during hospitalization. Two epitopes aa129-aa137 and aa131-aa139 restricted by HLA-A2 and B35, respectively, were selected to evaluate the epitope-specific CD8(+) T-cell response. HLA-peptide pentamer complex staining showed that the frequency of single epitope-specific CD8(+) T cell could be detected in patients (95% confidence interval for aa129-aa137: 0.080%-0.208%; for aa131-aa139: 0.030%-0.094%). The frequency of epitope-specific pentamer(+) CD8(+) T-cell response was much higher in mild/moderate patients than in severe/critical ones at the acute stage of the disease. Moreover, the frequency of epitope-specific CD8(+) T cells at acute stage was inversely associated with the peak level of serum creatinine and was positively associated with the nadir platelet counts during the hospitalization. The intracellular cytokine staining and the proliferation assay showed that the effective epitope-specific CD8(+) T cells were characterized with the production of interferon-γ, expression of CD69 and the strong capacity of proliferation.

Conclusion/significance: The novel HLA class I restricted HTNV nucleoprotein epitopes-specific CD8(+) T-cell responses would be closely related with the progression and the severity of the disease, which could provide the first step toward effective peptide vaccine development against HTNV infection in humans.

Show MeSH
Related in: MedlinePlus