Escape from highly effective public CD8+ T-cell clonotypes by HIV

Area of Science:

• Immunology
• Virology
• Vaccine Development

Background:

• CD8(+) T-cell responses are crucial for controlling viral infections, including HIV.
• Specific T-cell clonotypes targeting the HIV p24 Gag KK10 epitope, restricted by HLA-B*2705, are associated with better viral control.
• Understanding the characteristics of these effective T-cell responses is key for designing effective vaccines.

Purpose of the Study:

• To comprehensively analyze the CD8(+) T-cell clonotypes responsible for recognizing the HIV p24 Gag KK10 epitope.
• To investigate the features of T-cell receptor (TCR) gene rearrangements in effective clonotypes.
• To understand how viral mutations impact the recognition by these T-cell responses.

Main Methods:

• Analysis of T-cell clonotypes specific for the HIV p24 Gag KK10 epitope in HLA-B*2705 individuals.
• Identification of T-cell receptor (TCR) gene rearrangements (TRBV, TRBJ) in selected clonotypes.
• Assessment of TCR avidity, antigen sensitivity, and viral escape mechanisms.

Main Results:

• Identified specific TRBV4-3/TRBJ1-3 gene rearrangements in preferential, shared "public" CD8(+) T-cell clonotypes.
• These public clonotypes demonstrated high TCR avidity and antigen sensitivity, contributing to effective HIV suppression.
• An early L(268)M mutation in the KK10 epitope allows HIV to evade recognition by these dominant T-cell clonotypes.

Conclusions:

• Mechanistic insights into effective CD8(+) T-cell responses against HIV are provided.
• The findings highlight the importance of specific T-cell clonotypes and TCR characteristics in viral control.
• Viral escape mutations underscore the need for diverse T-cell responses in vaccine strategies.