Virus and CTL dynamics in the extrafollicular and follicular tissue compartments in SIV-infected macaques

Data from SIV-infected macaques indicate that virus-specific cytotoxic T lymphocytes (CTL) are mostly present in the extrafollicular (EF) compartment of the lymphoid tissue, with reduced homing to the follicular (F) site. This contributes to the majority of the virus being present in the follicle and represents a barrier to virus control. Using mathematical models, we investigate these dynamics. Two models are analyzed. The first assumes that CTL can only become stimulated and expand in the extrafollicular compartment, with migration accounting for the presence of CTL in the follicle. In the second model, follicular CTL can also undergo antigen-induced expansion. Consistent with experimental data, both models predict increased virus compartmentalization in the presence of stronger CTL responses and lower virus loads, and a more pronounced rise of extrafollicular compared to follicular virus during CD8 cell depletion experiments. The models, however, differ in other aspects. The follicular expansion model results in dynamics that promote the clearance of productive infection in the extrafollicular site, with any productively infected cells found being the result of immigration from the follicle. This is not observed in the model without follicular CTL expansion. The models further predict different consequences of introducing engineered, follicular-homing CTL, which has been proposed as a therapeutic means to improve virus control. Without follicular CTL expansion, this is predicted to result in a reduction of virus load in both compartments. The follicular CTL expansion model, however, makes the counter-intuitive prediction that addition of F-homing CTL not only results in a reduction of follicular virus load, but also in an increase in extrafollicular virus replication. These predictions remain to be experimentally tested, which will be relevant for distinguishing between models and for understanding how therapeutic introduction of F-homing CTL might impact the overall dynamics of the infection.Author summary: A better understanding of immune response dynamics and virus control in HIV infection is an important goal of current research. While measurements are often recorded in the blood, intricate dynamics occur in the lymphoid tissue. Recent data indicate that killer T cell responses, or CTL, show reduced homing to the follicular compartment of the lymphoid tissue, while the majority of the CTL remain in the extrafollicular site, which appears to contribute to the observed unequal distribution of virus load in the two locations. Here, these dynamics are studied with 2-compartment mathematical models. They reproduce previously published as well as newly presented experimental data from CTL depletion studies. Beyond this, the models indicate that so far unknown details of the CTL dynamics, in particular the potential of CTL to undergo antigen-induced expansion in the follicular compartment, can be important determinants of outcome. We find that antigen-induced expansion of CTL in the follicular site can result in more pronounced virus compartmentalization, and essentially in clearance of virus-producing cells from the extrafollicular site. We use the models to predict how experimental addition of engineered, follicular-homing CTL to macaques, influence the overall infection dynamics and level of virus control. Understanding these dynamics is an important step in attempts to improve the level of immune-mediated virus control.