Background
HIV controllers are rare individuals who suppress viral replication without antiretroviral therapy (ART). We hypothesized that this might partly be driven by T-cell receptor (TCR) convergence, a phenomenon where different DNA sequences encode identical amino acids. TCR convergence may indicate antigen-driven selection, reflecting a more focused immune response. This study applies a novel method to calculate TCR convergence and its potential role in HIV control.
Methods
TCR RNA sequencing was performed on four subsets of CD8+ T-cells: naive, central memory (CM), effector memory (EM), and effector memory cells re-expressing CD45RA (TEMRA). Sample selection included 32 HIV-infected individuals (22 HIV controllers; 10 ART-treated) and 20 HIV-negative healthy donors (HDs). Sequencing reads from ~50,000 cells/subset were annotated using MiXCR. TCR diversity was expressed as Shannon diversity. TCR convergence scores were calculated by comparing TCR repertoires of HIV positive and HIV negative donors using an in-house method. Viral specificity was assessed using Immunewatch Detect (IMWD) and TCRs derived from a Gag activation assay in HIV controllers (n=14/22) and ART-treated individuals (n=7/10).
Results
HIV controllers, just as HDs, had a higher percentage of naive CD8+ T-cells compared to ART-treated individuals (p<0.01). TCR diversity was highest in naive subsets and declined through CM, EM, and TEMRA subsets across all groups. HDs showed greater TCR diversity in the TEMRA subset compared to ART-treated individuals (p<0.01), with no significant differences between HDs and controllers. Controllers displayed HIV-specific TCRs with high convergence scores, mainly in the EM subset. Clusters of Gag-associated TCRs were present in the convergent memory repertoires of controllers at a higher rate than in ART-treated individuals or HDs (p<0.001). About 75% of highly convergent HIV-specific TCRs in controllers were linked to the HIV Gag KRWIIMFLNK epitope, that has previously been associated with HIV control, validating the performance/accuracy of our method to identify control-associated TCRs.
Conclusions
HIV controllers exhibit distinct TCR specificity, primarily in the EM subset. Our TCR convergence-based method identified control-associated TCRs. The heightened convergent TCR specificity toward control-associated HIV epitopes suggests a more efficient, antigen-driven, and targeted immune response. This novel approach produced valuable insights into immune mechanisms underlying HIV control.
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