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

Abstract. Background and Aim 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. Here, 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 gt3 isolate derived from a chronically infected human subject. HEV replication, ALT, 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 RM, and a 1 week delay in HEV clearance in CD8+ T cell depleted RM, 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 Abstract The hepatitis E virus 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.