title: Conflicting selective forces affect T cell receptor contacts in an immunodominant human immunodeficiency virus epitope.
abstract: Cytotoxic T lymphocytes (CTLs) are critical for the control of human immunodeficiency virus, but containment of virus replication can be undermined by mutations in CTL epitopes that lead to virus escape. We analyzed the evolution in vivo of an immunodominant, HLA-A2-restricted CTL epitope and found two principal, diametrically opposed evolutionary pathways that exclusively affect T cell-receptor contact residues. One pathway was characterized by acquisition of CTL escape mutations and the other by selection for wild-type amino acids. The pattern of CTL responses to epitope variants shaped which variant(s) prevailed in the virus population. The pathways notably influenced the amount of plasma virus, as patients with efficient CTL selection had lower plasma viral loads than did patients without efficient selection. Thus, viral escape from CTL responses does not necessarily correlate with disease progression.
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9AD, UK. aiversen@hammer.imm.ox.ac.uk
authors.forename: Astrid K N
authors.initials: AK
authors.lastname: Iversen
authors.forename: Guillaume
authors.initials: G
authors.lastname: Stewart-Jones
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Learn
authors.forename: Natasha
authors.initials: N
authors.lastname: Christie
authors.forename: Christina
authors.initials: C
authors.lastname: Sylvester-Hviid
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Armitage
authors.forename: Rupert
authors.initials: R
authors.lastname: Kaul
authors.forename: Tara
authors.initials: T
authors.lastname: Beattie
authors.forename: Jean K
authors.initials: JK
authors.lastname: Lee
authors.forename: Yanping
authors.initials: Y
authors.lastname: Li
authors.forename: Pojchong
authors.initials: P
authors.lastname: Chotiyarnwong
authors.forename: Tao
authors.initials: T
authors.lastname: Dong
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Xu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Luscher
authors.forename: Kelly
authors.initials: K
authors.lastname: MacDonald
authors.forename: Henrik
authors.initials: H
authors.lastname: Ullum
authors.forename: Bente
authors.initials: B
authors.lastname: Klarlund-Pedersen
authors.forename: Peter
authors.initials: P
authors.lastname: Skinhøj
authors.forename: Lars
authors.initials: L
authors.lastname: Fugger
authors.forename: Søren
authors.initials: S
authors.lastname: Buus
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.forename: P Anton
authors.initials: PA
authors.lastname: van der Merwe
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D005260:Female; D015683:Gene Products, gag / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D014644:Genetic Variation; D015488:HIV Antigens / Q000235:genetics* / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D010802:Phylogeny; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D012641:Selection, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014766:Viremia / Q000276:immunology / Q000821:virology; D054299:env Gene Products, Human Immunodeficiency Virus
chemical_list: D015683:Gene Products, gag; D015488:HIV Antigens; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D046912:Multiprotein Complexes; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D054299:env Gene Products, Human Immunodeficiency Virus; C473991:p17 gag peptide, human immunodeficiency virus