Conflicting selective forces affect T cell receptor contacts in an immunodominant human immunodeficiency virus epitope.
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.
Iversen
Astrid K N
AK
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9AD, UK. aiversen@hammer.imm.ox.ac.uk
Stewart-Jones
Guillaume
G
Learn
Gerald H
GH
Christie
Natasha
N
Sylvester-Hviid
Christina
C
Armitage
Andrew E
AE
Kaul
Rupert
R
Beattie
Tara
T
Lee
Jean K
JK
Li
Yanping
Y
Chotiyarnwong
Pojchong
P
Dong
Tao
T
Xu
Xiaoning
X
Luscher
Mark A
MA
MacDonald
Kelly
K
Ullum
Henrik
H
Klarlund-Pedersen
Bente
B
Skinhøj
Peter
P
Fugger
Lars
L
Buus
Søren
S
Mullins
James I
JI
Jones
E Yvonne
EY
van der Merwe
P Anton
PA
McMichael
Andrew J
AJ
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
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