Conflicting selective forces affect T cell receptor contacts in an immunodominant human immunodeficiency virus epitope

TY - JOUR

T1 - Conflicting selective forces affect T cell receptor contacts in an immunodominant human immunodeficiency virus epitope

AU - Iversen, Astrid K N

AU - Stewart-Jones, Guillaume

AU - Learn, Gerald H

AU - Christie, Natasha

AU - Sylvester-Hviid, Christina

AU - Armitage, Andrew E

AU - Kaul, Rupert

AU - Beattie, Tara

AU - Lee, Jean K

AU - Li, Yanping

AU - Chotiyarnwong, Pojchong

AU - Dong, Tao

AU - Xu, Xiaoning

AU - Luscher, Mark A

AU - MacDonald, Kelly

AU - Ullum, Henrik

AU - Klarlund-Pedersen, Bente

AU - Skinhøj, Peter

AU - Fugger, Lars

AU - Buus, Søren

AU - Mullins, James I

AU - Jones, E Yvonne

AU - van der Merwe, P Anton

AU - McMichael, Andrew J

N1 - Keywords: Adult; Amino Acid Sequence; Crystallography, X-Ray; Evolution, Molecular; Female; Gene Products, gag; Genetic Variation; HIV Antigens; HIV Infections; HIV-1; HLA-A2 Antigen; Humans; Immunodominant Epitopes; Models, Molecular; Molecular Sequence Data; Multiprotein Complexes; Mutation; Peptide Fragments; Phylogeny; Receptors, Antigen, T-Cell; Selection (Genetics); T-Lymphocytes, Cytotoxic; Viremia; env Gene Products, Human Immunodeficiency Virus

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

U2 - 10.1038/ni1298

DO - 10.1038/ni1298

M3 - Journal article

C2 - 16388312

SN - 1529-2908

VL - 7

SP - 179

EP - 189

JO - Nature Immunology

JF - Nature Immunology

IS - 2

ER -