Compartmental structure in the secondary lymphoid tissue can slow downin vivoHIV-1 evolution in the presence of strong CTL responses

Human immunodeficiency virus (HIV-1) replicates in the secondary lymphoid tissues, which are characterized by complex compartmental structures. While Cytotoxic T lymphocytes (CTL) readily access infected cells in the extrafollicular compartments, they do not home to follicular compartments, which thus represent an immune-privileged site. Using mathematical models, we have previously shown that this compartmental tissue structure can delay the emergence of CTL escape mutants. Here, we show computationally that the compartmental structure can have an impact on the evolution of advantageous mutants that are not related to CTL recognition: (i) Compartmental structure can influence the fixation probability of an advantageous mutant, with weakened selection occurring if CTL responses are of intermediate strength. (ii) Compartmental structure is predicted to reduce the rate mutant generation, which becomes more pronounced for stronger CTL responses. (iii) Compartmental structure is predicted to slow down the overall rate of mutant invasion, with the effect becoming more pronounced for stronger CTL responses. Altogether, this work shows that in vivo virus evolution proceeds slower in models with compartmental structure compared to models that assume equivalent virus load in the absence of compartmental structure, especially for strong CTL-mediated virus control. This has implications for understanding the rate of disease progression.