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.

To investigate the role of viral load in the pathogenesis of hemorrhagic fever with renal syndrome, the Hantaan virus RNA load in plasma from 101 patients was quantified, and the relationships between viral load and disease course, severity, and level of specific humoral immunity were analyzed. The viral load, detectable in 79 patients, ranged from 3.43 to 7.33 log10 copies/mL of plasma. In the early stage of disease, patients in severe/critical group were found to have higher viral loads than those in the mild/moderate group (5.90 vs 5.03 log10 copies/mL; P = .001), suggesting an association between Hantaan virus load and disease severity.

Taken together with published data on the similar associations with neutralizing antibody, these data suggest that IFN-gamma-producing T cells may help reduce the risk of progression to acute renal failure caused by HTNV infection.

The mechanism of hepatitis C virus (HCV) involvement in innate immune responses and immune modulation has not been well characterized. In the present work, we studied Toll-like receptor (TLR) 2 and TLR4, which were recently recognized as the important components of innate immunity, as well as CD4+ CD25+ CD127low/- regulatory T cells (Tregs), which actively suppress pathological and physiological immune response during HCV infection. The study involved 31 chronic hepatitis C patients and 20 healthy controls. TLR2 and TLR4 expression in peripheral blood monocytes and the number of Tregs were examined by flow cytometric analysis. Overexpression of TLR2 and TLR4 was found in chronic hepatitis C patients as compared with controls. Furthermore, increased cytokine production, including that of beta-interferon, tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, was observed in peripheral blood mononuclear cells from chronic hepatitis C patients after challenge with TLR2 and TLR4 agonists. The number of Tregs was significantly higher in chronic hepatitis C patients and the increased Tregs were associated with HCV genotype 1b. In vitro studies demonstrated that circulating Tregs suppress T-cell responses in chronic hepatitis C patients. Significant correlations were found between the viral load and Treg number and between TLR2 and TLR4 level in chronic hepatitis C patients. Taken together with other published data, these results suggest that TLR2, TLR4, and Tregs correlate closely with chronic HCV infection.

BackgroundHematological abnormalities often occur several days before kidney injury in patients with hemorrhagic fever with renal syndrome (HFRS). We aimed to investigate the prevalence and prognostic value of the early hematological markers in patients with HFRS caused by Hantaan virus (HTNV) infection.MethodsIn a retrospective cohort study, we analyzed the case records of 112 patients with acute HTNV infection and evaluated the hematological markers for early prediction and risk stratification of HFRS patients with acute kidney injury (AKI).ResultsOf 112 patients analyzed, 66 (59%) developed severe AKI, defined as either receipt of acute dialysis or increased serum creatinine ≥354 µmol/L. The prognostic accuracy of hematological markers, as quantified by the area under the receiver-operating-characteristic curve (AUC), was highest with the nadir platelet count (AUC, 0.89; 95% CI, 0.83–0.95), as compared with the admission platelet count (AUC, 0.84; 95% CI, 0.77–0.92), and the admission and peak leukocyte counts. The nadir platelet count correlated moderately with the levels of peak blood urea nitrogen (r = –0.616) and serum creatinine (r = –0.589), the length of hospital stay (r = –0.599), and the number of dialysis sessions that each patient received during hospital stay (r = –0.625). By multivariate analysis, decreased nadir platelet count remained independently associated with the development of severe AKI (odds ratio, 27.57; 95% CI, 6.96–109.16; P<0.0001).ConclusionsThrombocytopenia, rather than leukocytosis, is independently associated with subsequent severe AKI among patients with acute HTNV infection.