Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in human immunodeficiency virus type 1 infection.
Numerous studies now support that human immunodeficiency virus type 1 (HIV-1) evolution is influenced by immune selection pressure, with population studies showing an association between specific HLA alleles and mutations within defined cytotoxic T-lymphocyte epitopes. Here we combine sequence data and functional studies of CD8 T-cell responses to demonstrate that allele-specific immune pressures also select for mutations flanking CD8 epitopes that impair antigen processing. In persons expressing HLA-A3, we demonstrate consistent selection for a mutation in a C-terminal flanking residue of the normally immunodominant Gag KK9 epitope that prevents its processing and presentation, resulting in a rapid decline in the CD8 T-cell response. This single amino acid substitution also lies within a second HLA-A3-restricted epitope, with the mutation directly impairing recognition by CD8 T cells. Transmission of the mutation to subjects expressing HLA-A3 was shown to prevent the induction of normally immunodominant acute-phase responses to both epitopes. However, subsequent in vivo reversion of the mutation was coincident with delayed induction of new CD8 T-cell responses to both epitopes. These data demonstrate that mutations within the flanking region of an HIV-1 epitope can impair recognition by an established CD8 T-cell response and that transmission of these mutations alters the acute-phase CD8(+) T-cell response. Moreover, reversion of these mutations in the absence of the original immune pressure reveals the potential plasticity of immunologically selected evolutionary changes.
Allen
Todd M
TM
Howard Hughes Medical Institute, Partners AIDS Research Center, Infectious Disease Division, Massachusetts General Hospital, and Division of AIDS, Harvard Medical School, Boston, MA, USA.
Altfeld
Marcus
M
Yu
Xu G
XG
O'Sullivan
Kristin M
KM
Lichterfeld
Mathias
M
Le Gall
Sylvie
S
John
Mina
M
Mothe
Bianca R
BR
Lee
Paul K
PK
Kalife
Elizabeth T
ET
Cohen
Daniel E
DE
Freedberg
Kenneth A
KA
Strick
Daryld A
DA
Johnston
Mary N
MN
Sette
Alessandro
A
Rosenberg
Eric S
ES
Mallal
Simon A
SA
Goulder
Philip J R
PJ
Brander
Christian
C
Walker
Bruce D
BD
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D017951:Antigen Presentation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D019143:Evolution, Molecular; D015683:Gene Products, gag / Q000235:genetics*; D015488:HIV Antigens / Q000235:genetics*; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015791:HLA-A3 Antigen / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D008969:Molecular Sequence Data; D012641:Selection, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics*; D054301:gag Gene Products, Human Immunodeficiency Virus
D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D015488:HIV Antigens; D015791:HLA-A3 Antigen; D016056:Immunodominant Epitopes; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1