Large Variations in HIV-1 Viral Load Explained by Shifting-Mosaic Metapopulation Dynamics

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.A novel metapopulation model of HIV suggests that within-host infections are characterized by a highly dynamic process of localized infection followed by clearance within T cell centers.Author Summary: When a person is infected with HIV, the initial peak level of virus in the blood is usually very high before a lower, relatively stable level is reached and maintained for the duration of the chronic infection. This stable level is known as the set-point viral load (SPVL) and is associated with severity of infection. SPVL is also highly variable among patients, ranging from 100 to a million copies of the virus per mL of blood. The replicative capacity of the infecting virus and the strength of the immune response both influence SPVL. However, standard mathematical models show that variation in these two factors cannot easily reproduce the observed distribution of SPVL among patients. Standard models typically treat infected individuals as well-mixed systems, but in reality viral replication is localised in T-cell centres, or patches, found in secondary lymphoid tissue. To account for this population structure, we developed a carefully parameterised metapopulation model. We find the system can reach a steady state at which the viral load in the blood is relatively stable, representing SPVL, but surprisingly, the patches are highly dynamic, characterised by bursts of infection followed by elimination of virus due to localised host immune responses. Significantly, this model can reproduce the wide distribution of SPVLs found among infected individuals for realistic distributions of viral replicative capacity and strength of immune response. Our model can also be used in the future to understand other aspects of chronic HIV infection.