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.

Molecular mechanisms of T cell sensitivity to antigen

“…The copy number of any single pMHC is unlikely to be large. This is consistent with a study that found that a recombinant TCR was only able to recognize 8‐46 pMHCs after in vitro infection with HIV . In addition, viruses such as HIV and CMV, are known to downregulate pMHC as an escape mechanism (eg, CMV can downregulate expression from 10 000 to less than 100 copies per cell ).…”

Control of the HIV-1 DNA Reservoir Is AssociatedIn VivoandIn Vitrowith NKp46/NKp30 (CD335 CD337) Inducibility and Interferon Gamma Production by Transcriptionally Unique NK Cells

“…Finally, current programs and protocols for HIV eradication, including histone deacetylase inhibitor (HDACi) administration and immunotherapy, reportedly need improved immunotherapeutic strategies to clear virus in reactivated cells and to limit new virus integration (43,55,59,72,73). Selection and expansion of NK cells with high NCR and IFN-␥ inducibility may represent a useful tool to efficiently clear HIV-1 when combined within the frame of virus eradication strategies exploiting latency exit induction and immuno-/antiretroviral therapy (72)(73)(74).…”

“…Selection and expansion of NK cells with high NCR and IFN-␥ inducibility may represent a useful tool to efficiently clear HIV-1 when combined within the frame of virus eradication strategies exploiting latency exit induction and immuno-/antiretroviral therapy (72)(73)(74).…”

A New Agent in the Strategy to Cure AIDS

“…3 ImmTACs have already entered clinical trials in melanoma patients (ClinicalTrials.gov identifier NCT02570308). The first in vitro use of an anti-HIV-1 ImmTAV is described in the report by Yang et al as a TCR specific for HIV-1 p17 cloned and genetically linked to an scFv that binds to CD3 + CD8 + T cells (CD8).…”

“…2 The only HIV-1 vaccine trial showing any efficacy in humans, the ALVAC-prime AIDSVAX-boost RV144 trial, only reduced the infection rate by 31.2%. 3 The protection afforded in this …”