Functionally impaired HIV-specific CD8 T cells show high affinity TCR-ligand interactions

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Chronic HIV infection is characterized by impaired T cell responses.
• T cell receptor (TCR) affinity for viral epitopes is crucial for effective viral control.
• Understanding TCR-ligand interactions is key to deciphering HIV immune evasion.

Purpose of the Study:

• To investigate the functional consequences of different T cell receptor (TCR) affinities for HIV-derived epitopes.
• To explore the role of TCR-ligand interactions in HIV immune evasion mechanisms.

Main Methods:

• Isolation and characterization of clonotypic CD8 T cell subsets recognizing an HIV Pol-derived epitope.
• Kinetic analysis of TCR-HLA-peptide interactions using HLA tetramers.
• In vitro and ex vivo functional assays including cytolytic activity, cytokine production, and proliferation.
• Ectopic expression of TCR genes into primary human CD8 T cells.

Main Results:

• Two CD8 T cell subsets with differing affinities for an HIV Pol-derived epitope (IPLTEEAEL) and HLA-B35 were identified.
• A >3-fold difference in half-life was observed between the high- and moderate-affinity TCR-HLA-peptide complexes.
• The high-affinity TCR subset exhibited impaired functional avidity, cytolytic activity, cytokine production, and proliferation against HIV-infected cells compared to the moderate-affinity subset.
• Ectopic expression of the high-affinity TCR resulted in enhanced tetramer binding but reduced cytotoxic activity, confirming the parental cell findings.

Conclusions:

• Impaired T cell responsiveness during chronic HIV infection can arise from TCR-ligand interaction defects.
• High-affinity TCRs do not necessarily equate to superior antiviral function and can contribute to HIV immune evasion.
• These findings provide insights into the complex mechanisms by which HIV evades host immune surveillance.