title: Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells.
abstract: It has been suggested that mutations within immunodominant cytotoxic T-lymphocyte (CTL) epitopes may be exploited by viruses to evade protective immune responses critical for clearance. Viral escape could originate from passive mechanisms, such as mutations within crucial CTL epitopes, either affecting major histocompatibility complex binding or T-cell antigen receptor (TCR) recognition. Additionally, it has recently been shown that substitutions of TCR contact sites can yield analogue peptides that can still interact with the T-cell receptor but be unable to deliver a full stimulatory signal, thus inducing anergy or acting as an antagonist for the TCR. We report here that hepatitis B virus isolates derived from two chronically infected patients display variant epitopes that act as natural TCR antagonists with the capacity to inhibit the CTL response to the wild-type epitope. During natural infection, TCR antagonist mutations of CTL epitopes could contribute to the development of viral persistence, especially if the antiviral CTL response is monospecific or the epitope is strongly immunodominant.
authors.affiliation: Cattedra Malattie Infettive, Università di Parma, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bertoletti
authors.forename: A
authors.initials: A
authors.lastname: Sette
authors.forename: F V
authors.initials: FV
authors.lastname: Chisari
authors.forename: A
authors.initials: A
authors.lastname: Penna
authors.forename: M
authors.initials: M
authors.lastname: Levrero
authors.forename: M
authors.initials: M
authors.lastname: De Carli
authors.forename: F
authors.initials: F
authors.lastname: Fiaccadori
authors.forename: C
authors.initials: C
authors.lastname: Ferrari
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D002908:Chronic Disease; D015789:HLA-A2 Antigen / Q000276:immunology; D006509:Hepatitis B / Q000276:immunology / Q000382:microbiology; D006512:Hepatitis B Core Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009698:Nucleoproteins / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
chemical_list: D015789:HLA-A2 Antigen; D006512:Hepatitis B Core Antigens; D016056:Immunodominant Epitopes; D009698:Nucleoproteins; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma