A study of innate immune and genetic factors that play a role in protecting seronegative blood recipients exposed to hepatitis C

Abstract

Hepatitis C virus (HCV) infects the liver and typically causes chronic infection. Some individuals exposed to HCV have been observed to remain aviraemic and seronegative, thus are presumed to be uninfected. These exposed seronegative (ESN) individuals have an enhanced innate immune response to HCV when compared with seropositive subjects, although the exact mechanisms involved are unknown. Until now, ESN cases have only been described in individuals exposed to low doses of HCV. This study examined a population of 1340 blood recipients who received HCV-contaminated blood to determine: i) whether a subset of them remained seronegative following transfusion of HCV-contaminated blood; if so, ii) what innate immune and genetic factors played a role in protecting them from HCV. A total of 8 blood recipients were identified with a confirmed exposure to HCV, but without any serological or virologic evidence of infection. The following were analysed: receptor expression and effector function of natural killer (NK) cells, T cell responses to HCV, and genetic polymorphism profiling. Findings in the ESN group were compared with 10 healthy controls, 10 spontaneous resolvers (SRs), and 10 subjects with chronic infection. The NK cells of ESN recipients exhibited significantly higher expression of the activating receptor, NKp30, than that observed in the other groups. NK cell cytotoxicity, in turn, was directly correlated with NKp30 expression and found to be enhanced in ESN recipients but not in SRs. On a genetic level, several rare polymorphisms involving innate immune genes were found in ESN recipients, but not in the general population or individuals with spontaneously resolved/chronic infection. HCV-specific T cell responses were observed in some ESN recipients but were low in amplitude. In conclusion, this study describes for the first time a subset of blood recipients who were seemingly uninfected following high-dose exposure to HCV. NK cells of these ESN recipients had a more activated phenotype and greater killing potential than seropositive recipients, which supports the importance of innate immunity in protecting ESN recipients from HCV. HCV-specific cellular immunity, however, was weak, likely to represent exposure rather than a mechanism of anti-HCV defence. Importantly, specific polymorphisms affecting innate immune genes were present in ESN recipients but not in recipients with spontaneously resolved or chronic infection. This indicates that ESN recipients are a population distinct from SRs, and different immune mechanisms are likely to be involved in their response to HCV.