Enhanced TLR3 Responsiveness in Hepatitis C Virus Resistant Women From the Irish Anti-D Cohort

Background: Natural resistance to viral infection is an overlooked outcome following hepatitis C virus (HCV) exposure. Between 1977-79, 1,200 Rhesus negative Irish women were exposed to highly infectious batches of HCV contaminated anti-D immunoglobulin. Data from this period indicate that just over 50% of recipients who received vials of anti-D from highly infectious batches became infected and developed HCV specific antibodies. No previous study has explored mechanisms of viral resistance in the women who did not become infected.

Methods A national campaign was launched to recruit Rhesus negative women who had received HCV contaminated anti-D in 1977-179. We screened HCV resistant and susceptible donors for an anti-HCV adaptive immune reponse using ELISpots for IFNg producting T cells and VirScan, a bacteriophage display system for global antibody profiling. We performed standardized ex vivo whole blood stimulation (TruCulture) assays with antiviral ligands and used NanoString transcriptomics along with Luminex and Simoa proteomics to assess anti-viral responses. We used cytokine gene signature scores after stimulation to examine cytokine specific responses in our cohort.

Results Thirty-four exposed seronegative (ESN) women who tested PCR and antibody negative following high viral exposure were successfully recruited to the study, along with 98 women who were anti-HCV antibody seropositive (SP) when tested in the early 1990s. ESNs had a higher polyIC (TLR3) induced type I interferon (IFN-I) gene signature when compared with SP women. Production of several inflammatory cytokines, including CCL8, CCL2 and IL-6 in response to polyIC stimulation was increased in ESNs compared to SPs. In contrast, transcriptomic and cytokine responses to other ligands (R848, IFNa2) were similar in both groups.

Conclusions This study identifies a specific enhanced IFN-I gene signature in response to polyIC in exposed seronegative women compared to seropositive donors. This enhanced anti-viral responsiveness may have contributed to innate immune protection against HCV infection.

Keywords: viral resistance, exposed seronegative, abortive infection, hepatitis C virus, inter-individual variation, VirScan, TruCulture

Suggested Citation: Suggested Citation

Sugrue, Jamie A. and Posseme, Celine and Tan, Ziyang and Pou, Christian and Charbit, Bruno and Bondet, Vincent and Bourke, Nollaig M. and Brodin, Petter and Duffy, Darragh and O'Farrelly, Cliona, Enhanced TLR3 Responsiveness in Hepatitis C Virus Resistant Women From the Irish Anti-D Cohort. Available at SSRN: https://ssrn.com/abstract=4064101 or http://dx.doi.org/10.2139/ssrn.4064101

This version of the paper has not been formally peer reviewed.