Hepatitis C virus-specific T-cell immune responses in seronegative injection drug users

T-cell responses to hepatitis C virus (HCV) antigens have been reported in high-risk HCV seronegative persons, suggesting that an effective cellular immune response might be able to clear infection without the development of antibodies. Such findings, however, could be explained by waning antibody or cross-reactivity to other antigens. To address these issues, we evaluated HCV-specific T-cell responses in 26 young (age 18-33 years) aviremic, seronegative injection drug users (IDUs) (median duration of injection, 6 years) by interferon-gamma enzyme-linked immunospot (ELISpot) assay using 429 overlapping HCV peptides pooled in 21 mixes. Seventeen aviremic, seropositive IDUs (spontaneous resolvers) and 15 healthy people were used as positive and negative controls, respectively. The percentage of patients with HCV-specific cellular immune responses was similar in seronegative and seropositive aviremic IDUs (46%vs 59%, P = 0.4), while these responses were not detected in any of the negative controls. Among the seronegative IDUs, six (23%) had intermediate to very strong responses to 10-20 peptide mixes and another six (23%) had moderately strong responses for two to six mixes. The 12 seronegative IDUs with HCV-specific T-cell responses had higher demographical and behavioural risk profiles than the 14 IDUs without T-cell responses (estimated risk of HCV infection, 0.47 vs 0.26, P < 0.01). In conclusion, HCV-specific T-cell responses are common among high-risk, seronegative IDUs. The responses are broad and are associated with risk factors for HCV exposure, suggesting that they reflect true exposure to HCV in seronegative persons.