Treatment induced clearance of hepatitis E viruses by interferon‐lambda in liver‐humanized mice

Abstract

Background: Hepatitis E viruses (HEV) are an underestimated global cause of enterically transmitted viral hepatitis, which may persist in immunocompromised hosts, posing a risk for progressive liver fibrosis with limited treatment options. We previously established liver-humanized mice as a model for chronic HEV infections, which can be cleared by a 2-week pegylated (peg)-Interferon(IFN)α treatment course.However, severe side effects may hamper the use of IFNα in immunocompromised transplant recipient patients. IFNλ may be a valuable alternative, as its receptor is less ubiquitously expressed. Aims:In this study, we assess the in vitro and in vivo potency of pegIFNλ to induce innate immune signalling in liver cells and to clear a persistent HEV infection in liverhumanized mice. Methods & Results:We found that human liver cells expressed the IFNλ receptor (IFNLR1) and are responsive to pegIFNλ. Treatment with pegIFNλ of liver-humanized mice persistently infected with HEV genotype 3 showed that pegIFNλ was well tolerated. Dose escalation studies showed that although HEV was not cleared at pegIFNλ doses up to 0.12 mg/kg for a maximum of 8 weeks, a dose of 0.3 mg/kg pegIFNλ treatment resulted in complete clearance of HEV antigen and HEV RNA from the liver in 8 out of 9 liver-humanized mice.

Hepatitis E Virus-induced antiviral response by plasmacytoid dendritic cells is modulated by the ORF2 protein

“…1b-c ). The level of IFN- λ 1 mRNA, which has known anti-viral role against HEV in mice (Sari et al, 2021) , increased upon viral replication in both cell types ( Fig. 2a-b ; left panels).…”

Chronic hepatitis E: Advancing research and patient care

“…Various strategies [147][148][149][150][151][152][153][154] including screening of drug libraries, 155 exploration of preclinical 104 or natural 156,157 compounds as well as in silico docking 158 have been dedicated to the quest to find novel HEV inhibitors (Table 2). When transferred into T cells obtained from patients with chronic HEV, engineered T-cell receptors have been shown to recognise virus-specific epitopes and mediate killing of the target cells in cell culture, 159 indicating that T cell-based immunotherapy could be used to treat chronic HEV infection.…”

“…Only used for a few cases of chronic HEV; risk of causing transplant rejection Sofosbuvir 98,138,139,142 Viral RdRp inhibitor Cell lines; Stem cell-derived HLCs Rabbits Chronic HEV patients A phase II trial demonstrated failure to clear HEV in patients with chronic infection Interferon-lambda 151 Activating innate antiviral response…”