title: Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA.
authors.forename: Angel
authors.initials: A
authors.lastname: Varela-Rohena
authors.forename: Peter E
authors.initials: PE
authors.lastname: Molloy
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dunn
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Megan M
authors.initials: MM
authors.lastname: Suhoski
authors.forename: Richard G
authors.initials: RG
authors.lastname: Carroll
authors.forename: Anita
authors.initials: A
authors.lastname: Milicic
authors.forename: Tara
authors.initials: T
authors.lastname: Mahon
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Sutton
authors.forename: Bruno
authors.initials: B
authors.lastname: Laugel
authors.forename: Ruth
authors.initials: R
authors.lastname: Moysey
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Cameron
authors.forename: Annelise
authors.initials: A
authors.lastname: Vuidepot
authors.forename: Marco A
authors.initials: MA
authors.lastname: Purbhoo
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Phillips
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: Bent K
authors.initials: BK
authors.lastname: Jakobsen
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
mesh_terms: 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
chemical_list: D015683:Gene Products, gag; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell