HBV-specific T-cell responses in healthy seronegative sexual partners of patients with chronic HBV infection.

The hepatitis B virus (HBV) is frequently transmitted by sexual intercourse. Thus, HBV-guidelines recommend vaccination. However, we have identified healthy hepatitis B surface antigen and anti-HBc-negative unvaccinated sexual partners of patients with chronic hepatitis B. We investigated whether HBV-specific cellular immune responses were present that could explain the apparent protection against HBV infection. In six anti-HBc-negative HBV-exposed sexual partners, HBV-specific T-cell responses were studied by proliferation assay and cytometric bead array after stimulation with 74 overlapping peptides spanning the HBV core, pre-S and S-encoding regions. Eleven HBV-unexposed individuals served as negative controls. HBV-DNA was undetectable in serum and peripheral blood mononuclear cells in all cases. HBV-specific cytokine secretion was observed in 4/6 seronegative partners, but only in 1/11 controls. Proliferative responses were detectable in 5/6 partners and 0/11 controls. HBV-specific cytokine secretion exists in healthy seronegative virus-exposed individuals. HBV core-directed immune responses indicate past, but controlled viral replication. T-cell immunity may prevent clinical manifestation of HBV infection in the absence of humoral immunity.

Clearance of chronic HCV infection during acute delta hepatitis.

The course of chronic hepatitis C in acute HDV/HBV superinfection is unknown. Here, we report a patient with chronic hepatitis C who cleared HCV during acute self-limited hepatitis B/D superinfection. Recovery from HCV was associated with the appearance of a strong and multispecific HDV-specific memory CD4+ and CD8+ T cell response - but only weak HCV-specific CD4+ T cell responses. These data suggest that HCV can be cleared by bystander mechanisms during acute infections with other pathogens which may be considered in the development of immunotherapies for hepatitis C.

Cross-genotype-reactivity of the immunodominant HCV CD8 T-cell epitope NS3-1073.

The HCV-specific HLA-A2-restricted NS3(1073) epitope is one of the most frequently recognized epitopes in hepatitis C. NS3(1073)-specific T-cell responses are associated with clearance of acute HCV-infection. Therefore this epitope is an interesting candidate for a HCV-peptide vaccine. However, heterogeneity between genotypes and mutations in the epitope has to be considered as an obstacle. We here identified 34 naturally occurring NS3(1073)-variants, as compared with the wild type genotype-1 variants (CVNGVCWTV/CINGVCWTV) by sequencing sera of 251 Greek and German patients and searching for published HCV-genomes. The frequency of variants among genotype-1 patients was 10%. Importantly, HLA-A2 binding was reduced only in 3 genotype 1 mutants while all non-genotype 1 variants showed strong HLA-A2-binding. By screening 28 variants in ELISPOT assays from T cell lines we could demonstrate that HCV-NS3(1073)-wild-type-specific T-cells displayed cross-genotype-reactivity, in particular against genotypes 4-6 variants. However, single aa changes within the TCR-binding domain completely abolished recognition even in case of conservative aa exchanges within genotype-1. NS3(1073)-specific T-cell lines from recovered, chronically infected, and HCV-negative individuals showed no major difference in the pattern of cross-recognition although the proliferation of NS3(1073)-specific T-cells differed significantly between the groups. Importantly, the recognition pattern against the 28 variants was also identical directly ex vivo in a patient with acute HCV infection and a healthy volunteer vaccinated with the peptide vaccine IC41 containing the NS3(1073)-wild-type peptide. Thus, partial cross-genotype recognition of HCV NS3(1073)-specific CD8 T cells is possible; however, even single aa exchanges can significantly limit the potential efficacy of vaccines containing the NS3(1073)-wild-type peptide.