Cross-Reactivity to Mutated Viral Immune Targets Can Influence CD8⁺ T Cell Functionality: An Alternative Viral...

Area of Science:

• Immunology
• Virology
• Genomics

Background:

• Viruses adapt by altering epitopes to evade host immunity.
• Non-classical viral adaptation retains immune recognition, offering a survival benefit.
• Understanding HIV adaptation strategies is crucial for immune response modulation.

Purpose of the Study:

• To investigate HIV-specific CD8+ T cell responses to viral epitopes with non-classical adaptation.
• To analyze the transcriptomic and T cell receptor repertoires of T cells targeting adapted and non-adapted epitopes.
• To elucidate the impact of viral adaptation on T cell functionality and clonal selection.

Main Methods:

• Single-cell transcriptomic analysis of HIV-specific CD8+ T cells.
• T cell receptor repertoire sequencing.
• Identification of antigen-specific T cells using HLA class I tetramers and activation markers.
• Analysis of T cells from acute and chronic HIV-infected subjects.

Main Results:

• CD8+ T cells exhibited cross-reactivity between non-adapted epitopes (NAE) and adapted epitopes (AE).
• Single-reactive T cells were primarily observed in acute HIV infection, suggesting clonal selection over time.
• T cell transcriptomic profiles correlated with autologous virus adaptation, showing effective responses to NAE and altered responses to AE.
• Genes associated with polyfunctionality, cytotoxicity, and apoptosis (e.g., GZMB, IFNɣ) were differentially expressed.

Conclusions:

• Viral non-classical adaptation can modulate CD8+ T cell transcriptomes, potentially promoting viral survival.
• Single amino acid changes in epitopes can lead to less effective T cell responses in chronic infection.
• This adaptation strategy may involve selecting for less effective T cell clones during HIV progression.