title: Fine-tuning of T-cell receptor avidity to increase HIV epitope variant recognition by cytotoxic T lymphocytes.
abstract: OBJECTIVE
  T-cell receptor (TCR) gene therapy is an approach being considered for HIV-1, but epitope mutation is a significant barrier. We assessed whether HIV-specific TCR can be modified to have broader coverage of epitope variants by recombining polymorphisms between public clonotype TCR sequences.
  
  
  METHODS
  Public clonotype TCRs recognizing the same epitope often differ by polymorphisms in their third complementarity determining regions (CDR3). We assessed whether novel combinations of such polymorphisms could improve TCR recognition of epitope variation.
  
  
  METHODS
  A TCR recognizing the HLA A*0201-restricted epitope SLYNTVATL (Gag 77-85, SL9) was engineered to have combinations of four polymorphisms in the CDR3 regions compared to another SL9-specific TCR. These novel TCRs were screened for functional avidities against SL9 epitope variants and abilities to mediate cytotoxic T-lymphocyte suppression of HIV-1 containing the same epitope variants.
  
  
  RESULTS
  The TCRs varied modestly in functional avidities for SL9 variants, due to alterations in affinity. This translated to differences in antiviral activities against HIV-1 when functional avidity changes crossed the previously defined threshold required for efficient recognition of HIV-1-infected cells. Higher avidity TCR mutants had generally broader recognition of SL9 variants.
  
  
  CONCLUSIONS
  These results indicate that rationally targeted increases in functional avidities can be utilized to maximize the antiviral breadth of transgenic TCRs. In contrast to previously reported random mutagenesis to markedly increase functional avidities, tuning through recombining naturally occurring polymorphisms may offer a more physiologic approach that minimizes the risk of deleterious TCR reactivities.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Bennett
authors.forename: Aviva
authors.initials: A
authors.lastname: Joseph
authors.forename: Hwee L
authors.initials: HL
authors.lastname: Ng
authors.forename: Harris
authors.initials: H
authors.lastname: Goldstein
authors.forename: Otto O
authors.initials: OO
authors.lastname: Yang
mesh_terms: D002454:Cell Differentiation; D003601:Cytotoxicity Tests, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D015488:HIV Antigens / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D009154:Mutation / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D014764:Viral Proteins / Q000276:immunology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015488:HIV Antigens; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus