HLA-E Restricted TCRs for Universal HIV-1 Targeting
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Solution Overview
Problem
Current treatments for HIV-1 infection, such as combination antiretroviral therapy, fail to completely eradicate the virus due to its stable integration into host cell chromosomes, leading to long-lived latently infected CD4+ T cells, and existing therapeutic T cell receptor (TCR) sequences are not widely applicable due to genetic diversity of HLA-A, -B, and -C molecules.
Innovation Solution
Development of HLA-E restricted T cell receptors (TCRs) specific to HIV-1, which are nonpolymorphic and can bind to specific peptides, allowing for universal application across all infected patients, reducing viral replication and treating or preventing HIV-1 infection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional TCR sequences targeting HLA-A, -B, or -C molecules are used, then HIV-1 infected cells can be recognized, but the therapeutic approach is limited by the genetic polymorphism of these HLA molecules, reducing widespread applicability
Solution Approach 1:
The patent applies universality by designing TCRs that target HLA-E, a non-polymorphic MHC class I molecule, allowing a single TCR sequence to be universally applicable across all patients regardless of their HLA genotype. This resolves the contradiction by making the therapeutic approach adaptable to diverse patients without being constrained by HLA genetic diversity.
Solution Approach 2:
The patent changes the target parameter from polymorphic HLA-A/B/C molecules to non-polymorphic HLA-E molecule. This parameter change eliminates the variability issue while maintaining the ability to recognize HIV-1 infected cells, thereby resolving the contradiction between versatility and complexity.
2Reliability
If combination antiretroviral therapy is used, then viral replication is controlled, but the virus cannot be completely eradicated due to stable integration into host cell chromosomes
Solution Approach 1:
The patent extracts and eliminates the latent infected cell reservoir by using TCR-engineered T cells that specifically recognize and destroy HIV-1 infected cells. This complementary approach removes the harmful reservoir that ART cannot eliminate, while maintaining the viral suppression achieved by ART.
Solution Approach 2:
The patent introduces TCR-engineered T cells as an intermediary mechanism to bridge the gap between ART's ability to suppress viral replication and the need to eliminate latent reservoirs. These engineered T cells act as mediators that specifically target and eliminate infected cells without interfering with ART's antiviral activity.
3Adaptability or versatility
If TCR therapy is developed to target specific peptide epitopes, then universal application is possible, but the ability to recognize diverse viral variants may be limited
Solution Approach 1:
The patent achieves universality by targeting HLA-E presented peptide epitopes that are conserved across HIV-1 variants. The TCRs recognize a specific peptide sequence (e.g., RMYSPTSIL from HIV-1 Gag) presented by HLA-E, providing broad coverage while maintaining universal applicability across all patients.
Data Source
AI summary
The invention relates to a T cell receptor (TCR) which is HIV-1 specific and HLA-E restricted. Particularly, the TCR is capable of binding to a peptide of RMYSPTSIL or a peptide of RMYSPTSIL in complex with HLA-E, or a peptide of ILVESPAVL or a peptide of ILVESPAVL in complex with HLA-E. The invention also relates to a nucleic acids and vector encoding the TCR.