Format

Send to

Choose Destination
Mol Ther. 2016 Nov;24(11):1913-1925. doi: 10.1038/mt.2016.114. Epub 2016 Jun 6.

Elimination of Latently HIV-infected Cells from Antiretroviral Therapy-suppressed Subjects by Engineered Immune-mobilizing T-cell Receptors.

Author information

1
Nuffield Department of Medicine & Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
2
Immunocore Ltd, Abingdon, Oxfordshire, UK.
3
Nuffield Department of Medicine & Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK. Electronic address: lucy.dorrell@ndm.ox.ac.uk.

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.

PMID:
27401039
PMCID:
PMC5154472
DOI:
10.1038/mt.2016.114
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center