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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.

Original publication

DOI

10.1038/mt.2016.114

Type

Journal article

Journal

Molecular therapy : the journal of the American Society of Gene Therapy

Publication Date

11/2016

Volume

24

Pages

1913 - 1925

Addresses

Nuffield Department of Medicine & Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.

Keywords

CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Line, Humans, HIV-1, HIV Infections, Receptors, Antigen, T-Cell, Antibodies, Monoclonal, HIV Antibodies, Antiretroviral Therapy, Highly Active, Virus Latency