Background
Virus-specific CD8+ T cells are important for controlling chronic viral infections such as HIV. However, it remains unclear how the cumulative duration of antigen exposure following acute infection before complete viral suppression via ART impacts the quality of the memory T cell repertoire. In this study, we investigated this relationship to better understand how antigen exposure duration influences the evolution of HIV-specific T cell receptors (TCRs).
Methods
This study included twelve female participants from the FRESH (Females Rising Through Education, Support, and Health) cohort, all of whom were identified in Fiebig stage I/II and had the protective HLA-B58:01 genotype and well-defined periods of detectable viremia before ART-mediated suppression. We defined the autologous HLA-B*58:01-epitope sequences and then used barcoded tetramer labeling to FACS-sort HIV-reactive T cells. Targeted V(D)J and CITE-Seq enrichment was performed using 10X Genomics, with data processed through Cell Ranger and Seurat. Statistical analyses, including dot plots, non-parametric correlations (Spearman), and Mann-Whitney U tests, were conducted using GraphPad Prism 8.0. All subjects were evaluated following complete viral suppression to define the T cell repertoire.
Results
We observed variability in T cell responses to HIV epitopes restricted by the HLA-B*58:01 allele during the acute phase of HIV-1 infection, with minimal detectable ex-vivo responses in individuals treated earliest during the acute phase. In each case, the immunodominant autologous epitope generated in participants was capable of stabilizing HLA-B*58:01 surface expression. Following complete suppression of viremia with ART, analysis of peripheral blood mononuclear cells revealed a significant enrichment of high-avidity HIV-specific TCRs in individuals with limited antigen exposure compared to those with prolonged exposure (p<0.0001). This enrichment was consistent across three immunodominant epitopes restricted by the HLA-B*58:01 allele. Importantly, these high-avidity TCRs were not enriched for specific V gene usage and demonstrated enhanced antigen sensitivity.
Conclusions
Our findings highlight the critical role of antigen exposure duration prior to ART-mediated viral suppression in shaping the avidity of virus-specific T cells. These insights are important for developing strategies to enhance immune responses against HIV-1 through vaccination and other therapeutic interventions, advancing efforts toward a functional cure for HIV.
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