title: Hepatitis E virus (HEV)-specific T-cell responses are associated with control of HEV infection.
abstract: Hepatitis E virus (HEV) infection is usually self-limited but may lead to acute hepatitis and rarely to fulminant hepatic failure. Persistent HEV infections have recently been described in organ transplant recipients receiving immunosuppressive medications, suggesting that HEV is controlled by adaptive immune responses. However, only few studies have investigated HEV-specific T-cell responses and immune correlates for the failure to clear HEV infection have not been established so far. We investigated T-cell responses against HEV in 38 subjects including anti-HEV-positive (exposed, n = 9) and anti-HEV-negative (n = 10) healthy controls, 12 anti-HEV-positive but HEV RNA-negative organ transplant recipients, and seven transplant recipients with chronic hepatitis E. Proliferation as well as cytokine production of CD4+ and CD8+ T cells was studied after stimulation with overlapping peptides spanning all proteins encoded by HEV-open reading frame (ORF)2 and HEV-ORF3. We show that (1) strong and multispecific HEV-specific T-cell responses are present in exposed healthy controls, and to a lesser extent also in recovered patients after transplantation; (2) that these responses are absent in patients with chronic hepatitis E but become detectable after viral clearance; and (3) that HEV-specific T-cell responses can be restored in vitro by blocking the PD-1 or CTLA-4 pathways. However, a combination of PD-1 and CTLA-4 blockade had no synergistic effects. We conclude that chronic hepatitis E is associated with impaired HEV-specific T-cell responses and suggest that enhancing adaptive cellular immunity against HEV might prevent persistent HEV infections.
authors: Department of Gastroenterology Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors: Pothakamuri Venkata
authors: PV
authors: Suneetha
authors: Sven
authors: S
authors: Pischke
authors: Verena
authors: V
authors: Schlaphoff
authors: Jan
authors: J
authors: Grabowski
authors: Paraskevi
authors: P
authors: Fytili
authors: Anna
authors: A
authors: Gronert
authors: Birgit
authors: B
authors: Bremer
authors: Antoaneta
authors: A
authors: Markova
authors: Jerzy
authors: J
authors: Jaroszewicz
authors: Christoph
authors: C
authors: Bara
authors: Michael P
authors: MP
authors: Manns
authors: Markus
authors: M
authors: Cornberg
authors: Heiner
authors: H
authors: Wedemeyer
mesh_terms: D000328:Adult; D000368:Aged; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D060908:CTLA-4 Antigen / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D016751:Hepatitis E / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016752:Hepatitis E virus / Q000502:physiology*; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D060908:CTLA-4 Antigen; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor