Partially-functional exhausted CD8+ T cells can contribute to short-term viral suppression: a computational prediction for children with perinatal HIV

Abstract

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. Author SummaryCytotoxic CD8+ T cells are vital for our ability to kill infected cells. However, chronic stimulation of CD8+ T cells can result in T cell exhaustion, leading to cellular dysfunction and reduced ability to fight infections. Here we ask: What impact does CD8+ T cell exhaustion have on the ability to control HIV replication over the short term? We answer this using a computational model, anchored in experimental data from children with perinatal HIV. We use participant-specific data on dozens of immune markers that characterize the state of their immune system. We carefully map these markers to known immune cell functions and use our model to predict how immune cells with these participant-specific markers would respond to HIV infection. Our results suggest that earlier viral suppression can lead to better immune function in children with perinatal HIV. Our findings also suggest that exhausted CD8+ T cells could still contribute to fighting HIV infection, but only if there are enough of them to compensate for their reduced functionality. Our work uses computational models to put valuable participant-specific data into context, allowing us to predict short-term infection outcomes and better understand immune function in children with perinatal HIV.