HEV-specific T-cell responses were weak or undetectable selleck inhibitor in the peripheral blood during persistent HEV infection. Thus, the next question we addressed was if these weak T-cell responses could be restored by in vitro blockade of the coinhibitory receptors PD-1 and CTLA-4. Expression levels of these molecules was studied ex vivo in patients with chronic HEV infection, and their expression was detectable on both CD4+ and CD8+ T cells in all the patients included in the study (Supporting Information Fig. 2). Restoration of HEV-specific CD4+ T-cell

responses was observed in 4/5 patients by PD-1 blocking, whereas adding anti-CTLA-4 increased HEV-specific CD4+ proliferative responses in only one subject (Fig. 5). Of note, the combination of PDL-1 and CTLA-4 antibodies did not further enhance CD4+ T-cell proliferation in most subjects. In contrast, blocking both PD-1 and CTLA-4 pathways together seemed to be even counterproductive in subjects LTxC2, HTxC6, and KTxC7, as the increased proliferation induced by PD-1 blockade alone was diminished by the combination. Also, for HEV-specific CD8+ T-cell responses

the effects of blocking coinhibitory receptors in vitro was diverse and varied between patients (Fig. 5). Two subjects responded to adding PDL-1 antibodies to the culture, whereas patient KTxC7 showed an increased proliferation medchemexpress Apoptosis inhibitor of CD8+ T-cells by blocking CTLA-4 only. Again, the combination of blocking PD-1 and CTLA-4 pathways showed synergistic effects in only one individual (LTxC2) (Fig. 5). Thus, HEV-specific T-cell responses could

be restored in vitro by blocking coinhibitory receptors to some extent in all patients. However, there was a considerable interindividual variability of the distinct effects of anti-PDL-1 and anti-CTLA-4 antibodies, including intraindividual differences between CD4+ and CD8+ T-cells. Chronic hepatitis E has been recognized as an increasing clinical problem in immunocompromised patients since several groups across Europe and North America reported cases of progressive severe liver disease associated with HEV infection. 7, 10, 15 Defining immune correlates for the failure to clear HEV infection could therefore be of importance, in particular as therapeutic options for chronic hepatitis E are still limited. 8, 15 Even though ribavirin has recently proven some efficacy against HEV, 31, 32 the potential side effects of ribavirin treatment may limit its use in some groups of organ transplant recipients. The present study is the first investigating HEV-specific T-cell responses in patients with persistent HEV infection.