In-host modeling of Tfh–Tfr–fCD8+ T cell dynamics on HIV reservoir persistence

Résumé

HIV persistence within germinal centers is driven by complex interactions among T follicular helper (Tfh), T follicular regulatory (Tfr), and follicular CD8+ (fCD8+) T cells. Yet, the mechanisms sustaining the viral reservoir remain poorly understood. We developed a mechanistic within-host mathematical model to quantify the coupled regulations of Tfh–Tfr–fCD8+ dynamics governing viral replication, immune control, and reservoir stability. Simulations revealed that Tfh cells provide structural support for sustained viral production and that disrupting their function reduces viral load and may collapse the reservoir. Tfr cells primarily modulated the amplitude and timing of infection, buffering Tfh-driven viral expansion, whereas cytotoxic CD8+ T cells reduced the infection burden but could not independently achieve eradication. The nonlinear nature of germinal center immune control was demonstrated by findings that increasing infected-cell lysis increased viral load and that deregulation of regulatory mechanisms altered infection dynamics in a different cell line. To destabilize the reservoir and guide sensible HIV cure therapies, effective therapeutic approaches must focus on network structure and helper-cell support rather than isolated immune components. We can better understand how the immune network architecture controls HIV replication, immunological containment, and long-term reservoir structure by applying mechanistic immunology and quantitative analysis. This theoretical framework can guide the strategic development of therapeutic approaches.

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