Partially-functional exhausted CD8+ T cells can contribute to short-term viral suppression: a computational...

We and others have reported evidence of T cell exhaustion in children with perinatal HIV with increased expression of inhibitory receptors PD-1, CD160, and TIM-3, but there is limited data on the virologic functional consequences of this immune exhaustion. We address this by using an immune database from Kenyan children with perinatal HIV and unexposed controls. We computationally integrate T cell profiles of differentiation, activation and exhaustion in an agent-based model (ABM) to predict how T cell exhaustion impacts viral control following HIV exposure in vitro. Our ABM includes macrophages, CD4 and CD8 T cells, cytokines, and HIV. Model mechanisms include viral dynamics, macrophage activation, T cell activation and proliferation, cytotoxic T cell killing, and cytokine/HIV diffusion and degradation. Participants are grouped by HIV plasma viremia and by age, less than 5 years or 5-18 years. Our findings indicate that cells from virally active participants, who have the highest levels of exhaustion, have lower predicted viral concentrations and infected cells compared to other participant groups during new infection. However, this coincides with higher cell death, suggesting that short-term viral control is associated with excessive inflammation, which could be detrimental long-term. Cells from virally suppressed participants older than 5 years can maintain lower viral concentrations while limiting cell death, reflecting a more sustainable short-term immune response. In virally suppressed children younger than 5 years, immune response patterns strongly resemble the age-matched healthy control group, suggesting early viral suppression may preserve antiviral immune responses. Our model predicts unique patterns of cell death for each participant group, with CD8 T cell death being dominant in virally active groups and CD4 T cell and macrophage death being dominant in healthy and virally suppressed groups. Finally, exhausted CD8 T cells are predicted to contribute significantly to CD8 T cell killing, proliferation, and activation in the virally active group, indicating partially functional CD8 T cells can still contribute to short-term viral control. Our analysis functionally integrates participant-specific immunophenotypic data to allow quantification of the extent, mechanisms, and impact of immune dysfunction in perinatal HIV and could inform pediatric HIV remission and cure strategies.