title: Kaposi's sarcoma-associated herpesvirus cytotoxic T lymphocytes recognize and target Darwinian positively selected autologous K1 epitopes.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of Kaposi's sarcoma (KS) and certain lymphoproliferations particularly in the context of human immunodeficiency virus (HIV) type 1-induced immunosuppression. The introduction of effective therapies to treat HIV has led to a decline in the incidence of KS, suggesting that immune responses may play a role in controlling KSHV infection and pathogenesis. Cytotoxic-T-lymphocyte (CTL) activity against KSHV proteins has been demonstrated; however, the identification of KSHV CTL epitopes remains elusive and problematic. Although the herpesvirus genomic layout is generally conserved, KSHV encodes a unique hypervariable protein, K1, with intense biological selection pressure at specific amino acid sites. To investigate whether this variability is partly driven by cellular immunity, we designed K1 peptides that match only the unique viral sequence for every individual studied here (autologous peptides). We identified functional CTL epitopes within K1's most variable areas, and we show that a given individual responds only to autologous peptides and not to peptides from other individuals. Furthermore, these epitopes are highly conserved sequences within KSHV isolates from a specific strain but are not conserved between different strains. We conclude that CTL recognition contributes to K1, and therefore to KSHV, evolution.
authors.affiliation: Cancer Research U.K. Viral Oncology Group, The Wolfson Institute for Biomedical Research, University College London, United Kingdom.
authors.forename: Justin
authors.initials: J
authors.lastname: Stebbing
authors.forename: Dimitra
authors.initials: D
authors.lastname: Bourboulia
authors.forename: Margaret
authors.initials: M
authors.lastname: Johnson
authors.forename: Stephen
authors.initials: S
authors.lastname: Henderson
authors.forename: Ian
authors.initials: I
authors.lastname: Williams
authors.forename: Natalie
authors.initials: N
authors.lastname: Wilder
authors.forename: Mervyn
authors.initials: M
authors.lastname: Tyrer
authors.forename: Mike
authors.initials: M
authors.lastname: Youle
authors.forename: Nesrina
authors.initials: N
authors.lastname: Imami
authors.forename: Toru
authors.initials: T
authors.lastname: Kobu
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kuon
authors.forename: Joachim
authors.initials: J
authors.lastname: Sieper
authors.forename: Frances
authors.initials: F
authors.lastname: Gotch
authors.forename: Chris
authors.initials: C
authors.lastname: Boshoff
mesh_terms: D000595:Amino Acid Sequence; D000940:Antigenic Variation; D000956:Antigens, Viral / Q000235:genetics*; D001483:Base Sequence; D003602:Cytotoxicity, Immunologic; D004279:DNA, Viral / Q000235:genetics; D000939:Epitopes / Q000235:genetics; D015658:HIV Infections / Q000150:complications; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D012514:Sarcoma, Kaposi / Q000150:complications / Q000276:immunology / Q000821:virology; D012641:Selection, Genetic; D017386:Sequence Homology, Amino Acid; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D004279:DNA, Viral; D000939:Epitopes; C111600:K1 protein, Human herpesvirus 8; D014764:Viral Proteins