Are Partial Lytic States Stable Attractors? A Nonlinear Model of Epstein–Barr Virus Persistence

Epstein–Barr virus (EBV) establishes lifelong persistence in most humans and is traditionally described as alternating between latency and productive lytic replication. However, accumulating molecular and single-cell evidence indicates that EBV frequently occupies incomplete, abortive forms of lytic reactivation characterized by immediate-early/early (IE/E) gene expression without full viral DNA replication or virion production. The regulatory principles governing the stability of these states remain poorly understood.

Here, we propose a multi-scale nonlinear regulatory model in which EBV persistence emerges from threshold-dependent switching and feedback-controlled transitions between latent and lytic programs. We conceptualize latency and partial lytic reactivation as distinct attractor states separated by an activation threshold (T₁), while progression to productive replication requires crossing a higher replication threshold (T₂). In most physiological contexts, infected cells remain below T₂, forming a stabilized partial lytic attractor (IE/E expression, X<T₂). Positive feedback between IE/E expression, inflammatory signaling, and local immune modulation reinforces this state, whereas antiviral immunity (IFN signaling, NK/CD8⁺ responses) imposes negative constraints, generating hysteresis and dynamic equilibrium.

Rare transitions above T₂ initiate full lytic replication, leading to virion production and immune-mediated clearance. These transient events may nevertheless sustain infection at the population level by seeding newly infected B cells. The model further integrates therapeutic interventions, including replication inhibitors and “kick-and-kill” strategies, as modulators of threshold positioning and immune clearance efficiency.

This systems-oriented framework provides a mechanistic explanation for chronic immune activation, the frequent discordance between molecular markers of viral activity and detectable viremia, and the proposed associations between EBV and inflammatory or autoimmune conditions. By formalizing EBV reactivation as a nonlinear, feedback-regulated process, the model highlights replication thresholds as central determinants of viral persistence and potential therapeutic targets.