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

• Published in: Molecular therapy Vol. 24; no. 11; pp. 1913 - 1925
• Main Authors: Yang, Hongbing, Buisson, Sandrine, Bossi, Giovanna, Wallace, Zoë, Hancock, Gemma, So, Chun, Ashfield, Rebecca, Vuidepot, Annelise, Mahon, Tara, Molloy, Peter, Oates, Joanne, Paston, Samantha J, Aleksic, Milos, Hassan, Namir J, Jakobsen, Bent K, Dorrell, Lucy
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2016; Elsevier Limited; Nature Publishing Group
• Subjects: Antibodies, Monoclonal - pharmacology; Antigens; Antiretroviral Therapy, Highly Active; Biomedical research; Cancer; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cell death; Cell Line; Drug therapy; Genetic engineering; HIV Antibodies - pharmacology; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - immunology; HIV-1 - physiology; Human immunodeficiency virus; Humans; Infections; Lentivirus; Leukocytes; Original; Peptides; Receptors, Antigen, T-Cell - immunology; Retroviridae; Transplants & implants; Vaccines; Viral infections; Virus Latency; Viruses; United Kingdom > UK
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2016.114

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.