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ObjectiveMucosal-associated invariant T (MAIT) cells comprise a subpopulation of T cells that can be activated by bacterial products and cytokines to produce IFN-γ. Since little is known on MAIT cells during HCV infection, we compared their phenotype and function in comparison to HIV and HCV/HIV co-infected patients, and determined the effect of IFN-α-based and direct-acting antiviral therapy on MAIT cells of HCV patients.MethodsBlood samples from patients with chronic HCV (CHCV), virologically suppressed HIV, acute HCV/HIV co-infection (AHCV/HIV) and healthy individuals were examined by flowcytometry for phenotype and function of MAIT and NK cells.Results and ConclusionsCompared to healthy individuals, the frequency of CD161+Vα7.2+ MAIT cells was significantly decreased in patients with CHCV, HIV and AHCV/HIV co-infection. CD38 expression on MAIT cells was increased in AHCV/HIV patients. MAIT cells were responsive to IFN-α in vitro as evidenced by enhanced frequencies of IFN-γ producing cells. IFN-α-based therapy for CHCV decreased the frequency of IFN-γ+ MAIT cells, which was still observed 24 weeks after successful therapy. Importantly, even after successful IFN-α-based as well as IFN-α-free therapy for CHCV, decreased frequencies of MAIT cells persisted. We show that the frequencies of MAIT cells are reduced in blood of patients with CHCV, HIV and in AHCV/HIV co-infection compared to healthy individuals. Successful therapy for CHCV did not normalize MAIT cell frequencies at 24 weeks follow up. The impact of HIV and HCV infection on the numbers and function of MAIT cells warrant further studies on the impact of viral infections and the antimicrobial function of MAIT cells.

We demonstrate that, in sharp contrast to hepatitis C virus and human immunodeficiency virus patients, MAIT cells isolated from HBV patients are not deleted but are more activated, which can be normalized by nucleoside analog therapy. These observations may aid in deciphering the role of MAIT cells in immune responses to HBV.

Background & AimsMucosal‐associated invariant T (MAIT) cells are important innate T cells with antimicrobial and immunoregulatory activity, recently found to be depleted in blood of patients with HIV and HCV mono‐infections. In this study, we assessed the impact of HIV, HCV and HCV/HIV co‐infection on circulating and intrahepatic MAIT‐cells and correlations with liver fibrosis.MethodsIn this cross‐sectional study, nine healthy subjects, nine HIV, 20 HCV and 22 HCV/HIV co‐infected patients were included. Blood and liver fine needle aspirate biopsies were studied using flowcytometry for CD3+ CD161+Vα7.2+ MAIT‐cell frequency, phenotype and function in HCV mono‐infected and HCV/HIV co‐infected patients without or with mild fibrosis (Metavir‐score F0‐F1) or severe fibrosis to cirrhosis (Metavir‐score F3‐F4).ResultsCirculating MAIT‐cells were decreased in blood of HCV, HIV and HCV/HIV patients with F0‐F1. In HCV/HIV co‐infected individuals with severe fibrosis to cirrhosis, the frequency of circulating MAIT‐cells was even further depleted, whereas their function was comparable to HCV/HIV co‐infected patients with low or absent fibrosis. In contrast, in HCV mono‐infected patients, MAIT‐cell frequencies were not related to fibrosis severity; however, MAIT‐cell function was impaired in mono‐infected patients with more fibrosis. More advanced liver fibrosis in HCV or HCV/HIV‐infected patients was not reflected by increased accumulation of MAIT‐cells in the affected liver.ConclusionsSevere liver fibrosis is associated with dysfunctional MAIT‐cells in blood of HCV mono‐infected patients, and lower MAIT frequencies in blood of HCV/HIV co‐infected patients, without evidence for accumulation in the liver.

Antiviral treatment options for chronic Hepatitis E Virus (HEV) infections are limited and immunological determinants of viral persistence remain largely unexplored. We studied the antiviral potency of pegylated interferon-α (pegIFNα) against HEV infections in humanized mice and modelled intrahepatic interferon stimulated gene (ISG) responses. Human gene expression levels in humanized mouse livers were analyzed by qPCR and Nanostring. Human CXCL10 was measured in mouse serum. HEV genotype 3 (gt3) infections were cleared from liver and feces within 8 pegIFNα doses in all mice and relapsed after a single pegIFNα injection in only half of treated animals. Rapid viral clearance by pegIFNα was confirmed in HEV gt1, but not in Hepatitis B Virus infected animals. No ISG induction was observed in untreated HEV gt3 and gt1 infected humanized livers compared to control chimeric mice, irrespective of the human hepatocyte donor, viral isolate or HEV infection duration. Human specific ISG transcript levels in mouse liver increased significantly after pegIFNα treatment and induced high circulating human CXCL10 in mouse serum. In conclusion, HEV gt1 and gt3 infections do not elicit innate intrahepatic immune responses and remain highly sensitive to pegIFNα in immunocompromised humanized mice.