title: Elimination of Latently HIV-infected Cells from Antiretroviral Therapy-suppressed Subjects by Engineered Immune-mobilizing T-cell Receptors.
abstract: Persistence of human immunodeficiency virus (HIV) in a latent state in long-lived CD4+ T-cells is a major barrier to eradication. Latency-reversing agents that induce direct or immune-mediated cell death upon reactivation of HIV are a possible solution. However, clearance of reactivated cells may require immunotherapeutic agents that are fine-tuned to detect viral antigens when expressed at low levels. We tested the antiviral efficacy of immune-mobilizing monoclonal T-cell receptors against viruses (ImmTAVs), bispecific molecules that redirect CD8+ T-cells to kill HIV-infected CD4+ T-cells. T-cell receptors specific for an immunodominant Gag epitope, SL9, and its escape variants were engineered to achieve supraphysiological affinity and fused to a humanised CD3-specific single chain antibody fragment. Ex vivo polyclonal CD8+ T-cells were efficiently redirected by immune-mobilising monoclonal T-cell receptors against viruses to eliminate CD4+ T-cells from human histocompatibility leukocyte antigen (HLA)-A*0201-positive antiretroviral therapy-treated patients after reactivation of inducible HIV in vitro. The efficiency of infected cell elimination correlated with HIV Gag expression. Immune-mobilising monoclonal T-cell receptors against viruses have potential as a therapy to facilitate clearance of reactivated HIV reservoir cells.
authors.affiliation: Nuffield Department of Medicine & Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Yang
authors.affiliation: Immunocore Ltd, Abingdon, Oxfordshire, UK.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Buisson
authors.affiliation: Immunocore Ltd, Abingdon, Oxfordshire, UK.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bossi
authors.affiliation: Nuffield Department of Medicine & Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: Zoë
authors.initials: Z
authors.lastname: Wallace
authors.affiliation: Nuffield Department of Medicine & Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: Gemma
authors.initials: G
authors.lastname: Hancock
authors.affiliation: Nuffield Department of Medicine & Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: Chun
authors.initials: C
authors.lastname: So
authors.affiliation: Immunocore Ltd, Abingdon, Oxfordshire, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ashfield
authors.affiliation: Immunocore Ltd, Abingdon, Oxfordshire, UK.
authors.forename: Annelise
authors.initials: A
authors.lastname: Vuidepot
authors.affiliation: Immunocore Ltd, Abingdon, Oxfordshire, UK.
authors.forename: Tara
authors.initials: T
authors.lastname: Mahon
authors.affiliation: Immunocore Ltd, Abingdon, Oxfordshire, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Molloy
authors.affiliation: Immunocore Ltd, Abingdon, Oxfordshire, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Oates
authors.affiliation: Immunocore Ltd, Abingdon, Oxfordshire, UK.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Paston
authors.affiliation: Immunocore Ltd, Abingdon, Oxfordshire, UK.
authors.forename: Milos
authors.initials: M
authors.lastname: Aleksic
authors.affiliation: Immunocore Ltd, Abingdon, Oxfordshire, UK.
authors.forename: Namir J
authors.initials: NJ
authors.lastname: Hassan
authors.affiliation: Immunocore Ltd, Abingdon, Oxfordshire, UK.
authors.forename: Bent K
authors.initials: BK
authors.lastname: Jakobsen
authors.affiliation: Nuffield Department of Medicine & Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK. Electronic address: lucy.dorrell@ndm.ox.ac.uk.
authors.forename: Lucy
authors.initials: L
authors.lastname: Dorrell
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D015483:HIV Antibodies / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D017735:Virus Latency
chemical_list: D000911:Antibodies, Monoclonal; D015483:HIV Antibodies; D011948:Receptors, Antigen, T-Cell