Abstract
The viral population of HIV-1, like many pathogens that cause systemic infection, is structured and differentiated within the body. The dynamics of cellular immune trafficking through the blood and within compartments of the body has also received wide attention. Despite these advances, mathematical models, which are widely used to interpret and predict viral and immune dynamics in infection, typically treat the infected host as a well-mixed homogeneous environment. Here, we present mathematical, analytical, and computational results that demonstrate that consideration of the spatial structure of the viral population within the host radically alters predictions of previous models. We study the dynamics of virus replication and cytotoxic T lymphocytes (CTLs) within a metapopulation of spatially segregated patches, representing T cell areas connected by circulating blood and lymph. The dynamics of the system depend critically on the interaction between CTLs and infected cells at the within-patch level. We show that for a wide range of parameters, the system admits an unexpected outcome called the shifting-mosaic steady state. In this state, the whole body’s viral population is stable over time, but the equilibrium results from an underlying, highly dynamic process of local infection and clearance within T-cell centers. Notably, and in contrast to previous models, this new model can explain the large differences in set-point viral load (SPVL) observed between patients and their distribution, as well as the relatively low proportion of cells infected at any one time, and alters the predicted determinants of viral load variation.
Highlights
In 1979, Bormann and Likens introduced the concept of the shifting-mosaic steady state (SMSS) to describe biomass in forested ecosystems
We study the dynamics of virus replication and cytotoxic T lymphocytes (CTLs) within a metapopulation of spatially segregated patches, representing T cell areas connected by circulating blood and lymph
We find the system can reach a steady state at which the viral load in the blood is relatively stable, representing Set-point viral load (SPVL), but surprisingly, the patches are highly dynamic, characterised by bursts of infection followed by elimination of virus due to localised host immune responses
Summary
In 1979, Bormann and Likens introduced the concept of the shifting-mosaic steady state (SMSS) to describe biomass in forested ecosystems. Introducing more complicated functions to describe the rate at which CTLs accumulate in response to the number of infected cells can help to explain more of the variation in SPVL [18,19,20,21,22], as can small differences in a large number of parameters [20]. Even with these models, though, it is still hard to explain orders of magnitude differences in SPVLs without fine-tuning parameters, and especially to reproduce the left tail of the distribution composed of patients with low viral loads. As a further refinement to these models, incorporating activation of cells from a viral reservoir can explain very low viral loads (below the level of detection by conventional assays) for parameters in which otherwise the virus is expected to go extinct, e.g., [22,23], not the large number of patients with low viral loads but above the level of detection
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