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

Gulce Sari; Claudia E. Mulders; Jingting Zhu; Gertine W. van Oord; Zongdi Feng; Jolanda J.C. Kreeft-Voermans; Andre Boonstra; Thomas Vanwolleghem

doi:10.1111/liv.15033

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

Gulce Sari
, Claudia E. Mulders
, Jingting Zhu
, Gertine W. van Oord
, Zongdi Feng
, Jolanda J.C. Kreeft-Voermans
, Andre Boonstra
, Thomas Vanwolleghem^*

^*Corresponding author for this work

Nationwide Children’s Hospital
Ohio State University
University of Antwerp

Research output: Contribution to journal › Article › Academic › peer-review

11 Citations (Scopus)

87 Downloads (Pure)

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 liver-humanized 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. Conclusions: PegIFNλ is well tolerated in mice and leads to clearance of a persistent HEV infection in liver-humanized mice.

Original language	English
Pages (from-to)	2866-2873
Number of pages	8
Journal	Liver International
Volume	41
Issue number	12
Early online date	15 Aug 2021
DOIs	https://doi.org/10.1111/liv.15033
Publication status	Published - Dec 2021

Bibliographical note

Funding Information:
AB has received research grants from GlaxoSmithKline, Janssen Pharmaceuticals, Gilead Sciences, Inc and Fujirebio. TV has participated in Advisory Committees or Review Panels for: Gilead Sciences, Abbvie, BMS. He has also received grant/research support from: Gilead Sciences, BMS and speaking and teaching support from: Gilead Sciences, BMS.

Funding Information:
This work was supported by The Foundation for Liver and Gastrointestinal Research (SLO), Rotterdam (to AB). AB is a recipient of GlaxoSmithKline, Janssen Pharmaceuticals, Gilead Sciences, Inc and Fujirebio grants. TV is a recipient of a mandate of the Belgian Foundation against Cancer (number 2014‐087) and a senior clinical investigator grant of the Research Foundation Flanders (number 18B2821N).

Publisher Copyright:
© 2021 The Authors. Liver International published by John Wiley & Sons Ltd.

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Treatment induced clearance of hepatitis E viruses by interferon-lambda in liver-humanized miceFinal published version, 907 KBLicence: CC BY-NC

Cite this

@article{4d11b8caab2c4113b0a3a77d98c1edb2,

title = "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 liver-humanized 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. Conclusions: PegIFNλ is well tolerated in mice and leads to clearance of a persistent HEV infection in liver-humanized mice.",

author = "Gulce Sari and Mulders, \{Claudia E.\} and Jingting Zhu and \{van Oord\}, \{Gertine W.\} and Zongdi Feng and Kreeft-Voermans, \{Jolanda J.C.\} and Andre Boonstra and Thomas Vanwolleghem",

note = "Funding Information: AB has received research grants from GlaxoSmithKline, Janssen Pharmaceuticals, Gilead Sciences, Inc and Fujirebio. TV has participated in Advisory Committees or Review Panels for: Gilead Sciences, Abbvie, BMS. He has also received grant/research support from: Gilead Sciences, BMS and speaking and teaching support from: Gilead Sciences, BMS. Funding Information: This work was supported by The Foundation for Liver and Gastrointestinal Research (SLO), Rotterdam (to AB). AB is a recipient of GlaxoSmithKline, Janssen Pharmaceuticals, Gilead Sciences, Inc and Fujirebio grants. TV is a recipient of a mandate of the Belgian Foundation against Cancer (number 2014‐087) and a senior clinical investigator grant of the Research Foundation Flanders (number 18B2821N). Publisher Copyright: {\textcopyright} 2021 The Authors. Liver International published by John Wiley \& Sons Ltd.",

year = "2021",

month = dec,

doi = "10.1111/liv.15033",

language = "English",

volume = "41",

pages = "2866--2873",

number = "12",

}

TY - JOUR

T1 - Treatment induced clearance of hepatitis E viruses by interferon-lambda in liver-humanized mice

AU - Sari, Gulce

AU - Mulders, Claudia E.

AU - Zhu, Jingting

AU - van Oord, Gertine W.

AU - Feng, Zongdi

AU - Kreeft-Voermans, Jolanda J.C.

AU - Boonstra, Andre

AU - Vanwolleghem, Thomas

N1 - Funding Information: AB has received research grants from GlaxoSmithKline, Janssen Pharmaceuticals, Gilead Sciences, Inc and Fujirebio. TV has participated in Advisory Committees or Review Panels for: Gilead Sciences, Abbvie, BMS. He has also received grant/research support from: Gilead Sciences, BMS and speaking and teaching support from: Gilead Sciences, BMS. Funding Information: This work was supported by The Foundation for Liver and Gastrointestinal Research (SLO), Rotterdam (to AB). AB is a recipient of GlaxoSmithKline, Janssen Pharmaceuticals, Gilead Sciences, Inc and Fujirebio grants. TV is a recipient of a mandate of the Belgian Foundation against Cancer (number 2014‐087) and a senior clinical investigator grant of the Research Foundation Flanders (number 18B2821N). Publisher Copyright: © 2021 The Authors. Liver International published by John Wiley & Sons Ltd.

PY - 2021/12

Y1 - 2021/12

N2 - 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 liver-humanized 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. Conclusions: PegIFNλ is well tolerated in mice and leads to clearance of a persistent HEV infection in liver-humanized mice.

AB - 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 liver-humanized 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. Conclusions: PegIFNλ is well tolerated in mice and leads to clearance of a persistent HEV infection in liver-humanized mice.

UR - https://www.scopus.com/pages/publications/85113600527

U2 - 10.1111/liv.15033

DO - 10.1111/liv.15033

M3 - Article

C2 - 34392598

AN - SCOPUS:85113600527

SN - 1478-3223

VL - 41

SP - 2866

EP - 2873

JO - Liver International

JF - Liver International

IS - 12

ER -

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

Abstract

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