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Author Notes:

Christopher Walker., Abigail Wexner Research Institute, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus OH, USA 43205. Email: christopher.walker@nationwidechildrens.org

C.M. Walker was responsible for the study concepts and design, analysis and interpretation of data, drafting and revision of the manuscript for intellectual content, and obtaining funding. Z. Feng assisted with study concept design, acquisition and analysis of data, and obtaining funding. W. Bremer, H. Blasczyk and X. Yin acquired and analyzed data. A. Grakoui and E. Salinas Duron assisted with study concepts and design.

The authors gratefully acknowledge Dr. S. Emerson for providing the HEV gt3 Kernow inoculum and key reagents used in these studies. We also thank the NIH Tetramer Core Facility for production of class I and II tetramers and the Non-Human Primate Reagent Resource for provision of M-T807R1. We are grateful to Dr. Laurie Goodchild, DVM, and staff of the Nationwide Children’s Animal Resource Core for expert veterinary care and technical assistance.

Disclosure: None


Research Funding:

Research reported in this manuscript was funded in part by the National Institutes of Allergy and Infectious Diseases of the National Institutes of Health under award numbers R01AI139511 and R21AI137912.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Gastroenterology & Hepatology
  • Hepatitis E Virus
  • CD4+and CD8+T lymphocyte
  • depletion
  • rhesus macaque
  • HEV

Resolution of hepatitis E virus infection in CD8+T cell-depleted rhesus macaques


Journal Title:



Volume 75, Number 3


, Pages 557-564

Type of Work:

Article | Post-print: After Peer Review


Background & Aims: HEV is a significant cause of acute hepatitis globally. Some genotypes establish persistent infection when immunity is impaired. Adaptive immune mechanisms that mediate resolution of infection have not been identified. Herein, the requirement for CD8+ T cells to control HEV infection was assessed in rhesus macaques, a model of acute and persistent HEV infection in humans. Methods: Rhesus macaques were untreated or treated with depleting anti-CD8α monoclonal antibodies before challenge with an HEV genotype (gt)3 isolate derived from a chronically infected human patient. HEV replication, alanine aminotransferase, anti-capsid antibody and HEV-specific CD4+ and CD8+ T cell responses were assessed after infection. Results: HEV control in untreated macaques coincided with the onset of a neutralizing IgG response against the ORF2 capsid and liver infiltration of functional HEV-specific CD4+ and CD8+ T cells. Virus control was delayed by 1 week in CD8+ T cell-depleted macaques. Infection resolved with onset of a neutralizing IgG antibody response and a much more robust expansion of CD4+ T cells with antiviral effector function. Conclusions: Liver infiltration of functional CD8+ T cells coincident with HEV clearance in untreated rhesus macaques, and a 1-week delay in HEV clearance in CD8+ T cell-depleted rhesus macaques, support a role for this subset in timely control of virus replication. Resolution of infection in the absence of CD8+ T cells nonetheless indicates that neutralizing antibodies and/or CD4+ T cells may act autonomously to inhibit HEV replication. HEV susceptibility to multiple adaptive effector mechanisms may explain why persistence occurs only with generalized immune suppression. The findings also suggest that neutralizing antibodies and/or CD4+ T cells should be considered as a component of immunotherapy for chronic infection. Lay summary: The hepatitis E virus (HEV) is a major cause of liver disease globally. Some genetic types (genotypes) of HEV persist in the body if immunity is impaired. Our objective was to identify immune responses that promote clearance of HEV. Findings indicate that HEV may be susceptible to multiple arms of the immune response that can act independently to terminate infection. They also provide a pathway to assess immune therapies for chronic HEV infection.

Copyright information:

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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