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

Abstract

BackgroundHantaan 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 FindingsFive 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/SignificanceThe 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.

Kinetics and Immunodominance of Virus-Specific T Cell Responses During Hantaan Virus Infection

“…Likewise, a recent HTNV study also showed that the frequency of the epitopespecific pentamer + CD8 + T cells was statistically higher in the early stage than that in the late stage (7). Further longitudinal analysis of the virus-specific T cell responses, however, was not available for measuring the discrepancy.…”

“…The protective immune responses elicited by the nucleocapsid protein are thought to be mainly cellular, since nucleocapsidspecific antibodies are neither neutralizing nor protective. In HFRS, most epitopes identified to date are on the nucleocapsid protein of HTNV and Puumala virus (PUUV) (5,7,13,14,17). Therefore, nucleocapsid protein seems an attractive target of hantavirus-specific immunotherapy.…”

“…Although HTNV has been studied for decades, few epitopes have been identified (5,7,13,17), and it is not known whether they are immunodominant or subdominant. Furthermore, longitudinal analysis of how host T cell immunity develops, provides protection or causes disease, and eventually generates long-lasting memory would be important to reveal the role of T cells in HFRS, but little is known about these in hantavirus infection (6,11).…”

CD8lowCD100−T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

“…To assess HTNV-specific responses, HTNV NP 9-mer peptide pools were used to stimulate the PBMCs of HFRS patients in vitro during the early phase. The peptide pools contained 14 peptides that were confirmed to be HTNV NP CTL epitopes in our previous study (14)(15)(16). Detailed information regarding the 14 epitopes can be found in Table 1.…”

Development of models for the study of the molecular mechanisms of host restriction and adaptation of hantaviruses.

“…From these studies it has been hypothesized that the strong CD8+ T-cell responses will eliminate virus, but that such intensive T-cell responses might also result in an excessive amount of cytokines, which promote capillary leakage and endothelial cell dysfunction [69,73]. In contrast to these findings, a recent study of HFRS patients shows that the prevalence of N-antigen-specific CD8+ T cells correlated with the early, acute stages of infection and declined thereafter [83]. Hence, the CD8+T cells would be expected to have a protective effect rather than promote immune pathology.…”