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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 identification of HTNV nucleoprotein CD8+ T-cell epitopes from HFRS patients.(A) The determination of effective epitope-specific T-cell responses. PBMCs from the four donors were depleted of CD4+ or CD8+ T cells, and stimulated with the indicated four 15-mer peptides, respectively. (B) Five novel nonamer peptides recognized by CD8+ T cells in the four donors were defined as HTNV nucleoprotein epitopes within the sequences of the 15-mer peptides nested inside. The ex vivo IFN-γ ELISPOT assay was performed. PBMC, peripheral blood mononuclear cell.
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pntd-0002076-g001: The identification of HTNV nucleoprotein CD8+ T-cell epitopes from HFRS patients.(A) The determination of effective epitope-specific T-cell responses. PBMCs from the four donors were depleted of CD4+ or CD8+ T cells, and stimulated with the indicated four 15-mer peptides, respectively. (B) Five novel nonamer peptides recognized by CD8+ T cells in the four donors were defined as HTNV nucleoprotein epitopes within the sequences of the 15-mer peptides nested inside. The ex vivo IFN-γ ELISPOT assay was performed. PBMC, peripheral blood mononuclear cell.

Mentions: We identified five novel CD8+ T-cell epitopes on HTNV-NP from four HFRS patients through a similar investigation protocol as before [27]. The single-positive 15-mer peptides which could primarily stimulate the CD8+ T-cell response were screened out in Figure 1A, indicating that these peptides contained the CTL epitopes. The definition of the epitopes recognized by the CD8+ T cells showed that the aa129–aa137 (FVVPILLKA), aa131–aa139 (VPILLKALY), aa247–aa255 (LPDTAAVSL), aa167–aa175 (DVNGIRKPK), and aa277–aa285 (ETKESKAIR) were the HTNV-NP CTL epitopes that can simulate strong IFN-γ responses (Figure 1B).


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 identification of HTNV nucleoprotein CD8+ T-cell epitopes from HFRS patients.(A) The determination of effective epitope-specific T-cell responses. PBMCs from the four donors were depleted of CD4+ or CD8+ T cells, and stimulated with the indicated four 15-mer peptides, respectively. (B) Five novel nonamer peptides recognized by CD8+ T cells in the four donors were defined as HTNV nucleoprotein epitopes within the sequences of the 15-mer peptides nested inside. The ex vivo IFN-γ ELISPOT assay was performed. PBMC, peripheral blood mononuclear cell.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585118&req=5

pntd-0002076-g001: The identification of HTNV nucleoprotein CD8+ T-cell epitopes from HFRS patients.(A) The determination of effective epitope-specific T-cell responses. PBMCs from the four donors were depleted of CD4+ or CD8+ T cells, and stimulated with the indicated four 15-mer peptides, respectively. (B) Five novel nonamer peptides recognized by CD8+ T cells in the four donors were defined as HTNV nucleoprotein epitopes within the sequences of the 15-mer peptides nested inside. The ex vivo IFN-γ ELISPOT assay was performed. PBMC, peripheral blood mononuclear cell.
Mentions: We identified five novel CD8+ T-cell epitopes on HTNV-NP from four HFRS patients through a similar investigation protocol as before [27]. The single-positive 15-mer peptides which could primarily stimulate the CD8+ T-cell response were screened out in Figure 1A, indicating that these peptides contained the CTL epitopes. The definition of the epitopes recognized by the CD8+ T cells showed that the aa129–aa137 (FVVPILLKA), aa131–aa139 (VPILLKALY), aa247–aa255 (LPDTAAVSL), aa167–aa175 (DVNGIRKPK), and aa277–aa285 (ETKESKAIR) were the HTNV-NP CTL epitopes that can simulate strong IFN-γ responses (Figure 1B).

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