NDLI: Fine-tuning of T-cell receptor avidity to increase HIV epitope variant recognition by cytotoxic T lymphocytes.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Bennett, Michael S. Joseph, Aviva Ng, Hwee L. Goldstein, Harris Yang, Otto O.
Description	Country affiliation: United States Author Affiliation: Bennett MS ( Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, USA.)
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. DESIGN: 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. CONCLUSION: 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.
File Format	HTM / HTML
ISSN	02699370
e-ISSN	14735571
DOI	10.1097/QAD.0b013e32833f7b22
Journal	AIDS
Issue Number	17
Volume Number	24
Language	English
Publisher	Lippincott Williams & Wilkins
Publisher Date	2010-11-13
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Discipline Immunology Epitopes, T-lymphocyte Immunology Hiv Antigens Hiv-1 Receptors, Antigen, T-cell T-lymphocytes, Cytotoxic Gag Gene Products, Human Immunodeficiency Virus Cell Differentiation Cytotoxicity Tests, Immunologic Genetics Mutation Virology Viral Proteins Research Support, N.i.h., Extramural
Content Type	Text
Resource Type	Article
Subject	Infectious Diseases Immunology and Allergy Immunology

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Fine Tuning of T Cell Receptor Avidity to Increase HIV Epitope Variant Recognition by Cytotoxic T Lymphocytes

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The link between CD8⁺ T-cell antigen-sensitivity and HIV-suppressive capacity depends on HLA restriction, target epitope and viral isolate

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Copresentation of natural HIV-1 agonist and antagonist ligands fails to induce the T cell receptor signaling cascade.

Heteroantibody duplexes target cells for lysis by cytotoxic T lymphocytes.

Interdisciplinary analysis of HIV-specific CD8+ T cell responses against variant epitopes reveals restricted TCR promiscuity.

HIV-1 evolution in gag and env is highly correlated but exhibits different relationships with viral load and the immune response.

Specific human cytotoxic T cells recognize B-cell lines persistently infected with respiratory syncytial virus.

Fine-tuning of T-cell receptor avidity to increase HIV epitope variant recognition by cytotoxic T lymphocytes.

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Fine Tuning of T Cell Receptor Avidity to Increase HIV Epitope Variant Recognition by Cytotoxic T Lymphocytes

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The link between CD8⁺ T-cell antigen-sensitivity and HIV-suppressive capacity depends on HLA restriction, target epitope and viral isolate

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Copresentation of natural HIV-1 agonist and antagonist ligands fails to induce the T cell receptor signaling cascade.

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Fine-tuning of T-cell receptor avidity to increase HIV epitope variant recognition by cytotoxic T lymphocytes.