Christiane Mummert1, Christian Hofmann, Angela G Hückelhoven, Silke Bergmann, Sandra M Mueller-Schmucker, Ellen G Harrer, Jan Dörrie, Niels Schaft, Thomas Harrer. 1. aInfectious Diseases Section, Department of Internal Medicine III bDepartment of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany cGerman Competence Network on HIV/AIDS. *Current address: Division of Infectious Diseases, University of California, Los Angeles, California, USA. †Current address: Department of Internal Medicine 5, University Hospital Heidelberg, Heidelberg, Germany.
Abstract
OBJECTIVES: Strategies to cure HIV-1 infection require the eradication of viral reservoirs. An innovative approach for boosting the cytotoxic T-lymphocyte response is the transfer of T-cell receptors (TCRs). Previously, we have shown that electroporation of TCR-encoding mRNA is able to reprogram CD8 T cells derived from healthy donors. So far, it is unknown whether the transfer of HIV-1-specific TCRs is capable to reprogram CD8 T cells of HIV-1-infected patients. To assess the efficiency of TCR-transfer by mRNA electroporation and the functionality of reprogramed T cells in HIV-1-infected patients, we performed an in-vitro analysis of TCR-transfer into T cells from HIV-1-infected patients in various stages of disease and from healthy controls. METHODS: Peripheral blood mononuclear cells from 16 HIV-1-infected patients (nine HLA-A02-positive, seven HLA-A02-negative) and from five healthy controls were electroporated with mRNA-constructs encoding TCRs specific for the HLA-A02/HIV-1-gag p17 epitope SLYNTVATL (SL9). Functionality of the TCRs was measured by γIFN-ELISpot assays. RESULTS: SL9/TCR transfection into peripheral blood mononuclear cells from both HLA-A02-positive and HLA-A02-negative HIV-1-infected patients and from healthy blood donors reprogramed T cells for recognition of SL9-presenting HLA-A02-positive cells in γIFN-ELISpot assays. SL9/TCR-transfer into T cells from an immunodeficient AIDS patient could induce recognition of SL9-expressing target cells only after reversion of T-cell dysfunction by antiretroviral therapy. CONCLUSION: The transfer of HIV-1-p17-specific TCRs into T cells is functional both in HIV-1-infected patients as well as in healthy blood donors. TCR-transfer is a promising method to boost the immune system against HIV-1.
OBJECTIVES: Strategies to cure HIV-1 infection require the eradication of viral reservoirs. An innovative approach for boosting the cytotoxic T-lymphocyte response is the transfer of T-cell receptors (TCRs). Previously, we have shown that electroporation of TCR-encoding mRNA is able to reprogram CD8 T cells derived from healthy donors. So far, it is unknown whether the transfer of HIV-1-specific TCRs is capable to reprogram CD8 T cells of HIV-1-infectedpatients. To assess the efficiency of TCR-transfer by mRNA electroporation and the functionality of reprogramed T cells in HIV-1-infectedpatients, we performed an in-vitro analysis of TCR-transfer into T cells from HIV-1-infectedpatients in various stages of disease and from healthy controls. METHODS: Peripheral blood mononuclear cells from 16 HIV-1-infectedpatients (nine HLA-A02-positive, seven HLA-A02-negative) and from five healthy controls were electroporated with mRNA-constructs encoding TCRs specific for the HLA-A02/HIV-1-gag p17 epitope SLYNTVATL (SL9). Functionality of the TCRs was measured by γIFN-ELISpot assays. RESULTS: SL9/TCR transfection into peripheral blood mononuclear cells from both HLA-A02-positive and HLA-A02-negative HIV-1-infectedpatients and from healthy blood donors reprogramed T cells for recognition of SL9-presenting HLA-A02-positive cells in γIFN-ELISpot assays. SL9/TCR-transfer into T cells from an immunodeficient AIDSpatient could induce recognition of SL9-expressing target cells only after reversion of T-cell dysfunction by antiretroviral therapy. CONCLUSION: The transfer of HIV-1-p17-specific TCRs into T cells is functional both in HIV-1-infectedpatients as well as in healthy blood donors. TCR-transfer is a promising method to boost the immune system against HIV-1.
Authors: Katja G Schmidt; Krystelle Nganou-Makamdop; Matthias Tenbusch; Boutaina El Kenz; Clara Maier; Dennis Lapuente; Klaus Überla; Bernd Spriewald; Silke Bergmann; Ellen G Harrer; Thomas Harrer Journal: Front Immunol Date: 2021-04-28 Impact factor: 7.561