Herpes Simplex Virus-2 Genital Tract Shedding Is Not Predictable over Months or Years in Infected Persons

Herpes simplex virus-2 (HSV-2) is a chronic reactivating infection that leads to recurrent shedding episodes in the genital tract. A minority of episodes are prolonged, and associated with development of painful ulcers. However, currently, available tools poorly predict viral trajectories and timing of reactivations in infected individuals. We employed principal components analysis (PCA) and singular value decomposition (SVD) to interpret HSV-2 genital tract shedding time series data, as well as simulation output from a stochastic spatial mathematical model. Empirical and model-derived, time-series data gathered over >30 days consists of multiple complex episodes that could not be reduced to a manageable number of descriptive features with PCA and SVD. However, single HSV-2 shedding episodes, even those with prolonged duration and complex morphologies consisting of multiple erratic peaks, were consistently described using a maximum of four dominant features. Modeled and clinical episodes had equivalent distributions of dominant features, implying similar dynamics in real and simulated episodes. We applied linear discriminant analysis (LDA) to simulation output and identified that local immune cell density at the viral reactivation site had a predictive effect on episode duration, though longer term shedding suggested chaotic dynamics and could not be predicted based on spatial patterns of immune cell density. These findings suggest that HSV-2 shedding patterns within an individual are impossible to predict over weeks or months, and that even highly complex single HSV-2 episodes can only be partially predicted based on spatial distribution of immune cell density.Author Summary: Mathematical models are commonly used to better understand viral infections. Equations are simply rules to describe behavior of viruses, infected cells and the immune response, and are tested for their ability to reproduce serial viral levels in infected persons. Models provide insights regarding the pace of viral replication and timing of the immune response. Here we describe Herpes Simplex Virus-2 (HSV-2), an infection that defies standard modeling approaches. HSV-2 is sexually transmitted, and causes recurrent genital ulcers and frequent asymptomatic genital shedding episodes. Episodes initiate in a seemingly random fashion. Viral loads are erratic and complex during single episodes. We developed a mathematical model, which suggests that in general, shedding variability is due to heterogeneous density of immune cells in the genital tract. Yet, our model is unable to predict viral loads over time in individual patients. Here we employ several statistical tools to demonstrate that HSV-2 shedding is highly unpredictable, akin to weather patterns. Based on available spatial assessments of current viral and immunologic conditions, shedding can only be predicted over a few days, but not over ensuing weeks. These results have important clinical implications, and highlight limitations of attempting to predict outcomes in complex systems with simple mechanistic models.