Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor.
HIV's considerable capacity to vary its HLA-I-restricted peptide antigens allows it to escape from host cytotoxic T lymphocytes (CTLs). Nevertheless, therapeutics able to target HLA-I-associated antigens, with specificity for the spectrum of preferred CTL escape mutants, could prove effective. Here we use phage display to isolate and enhance a T-cell antigen receptor (TCR) originating from a CTL line derived from an infected person and specific for the immunodominant HLA-A(*)02-restricted, HIVgag-specific peptide SLYNTVATL (SL9). High-affinity (K(D) < 400 pM) TCRs were produced that bound with a half-life in excess of 2.5 h, retained specificity, targeted HIV-infected cells and recognized all common escape variants of this epitope. CD8 T cells transduced with this supraphysiologic TCR produced a greater range of soluble factors and more interleukin-2 than those transduced with natural SL9-specific TCR, and they effectively controlled wild-type and mutant strains of HIV at effector-to-target ratios that could be achieved by T-cell therapy.
Varela-Rohena
Angel
A
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA.
Molloy
Peter E
PE
Dunn
Steven M
SM
Li
Yi
Y
Suhoski
Megan M
MM
Carroll
Richard G
RG
Milicic
Anita
A
Mahon
Tara
T
Sutton
Deborah H
DH
Laugel
Bruno
B
Moysey
Ruth
R
Cameron
Brian J
BJ
Vuidepot
Annelise
A
Purbhoo
Marco A
MA
Cole
David K
DK
Phillips
Rodney E
RE
June
Carl H
CH
Jakobsen
Bent K
BK
Sewell
Andrew K
AK
Riley
James L
JL
D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D015683:Gene Products, gag / Q000737:chemistry / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D012995:Solubility
D015683:Gene Products, gag; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell