Effects Of Lymphocyte Trafficking on Antiretroviral Drug Distribution within the Lymph Node

Abstract

The lymph node (LN) lobule is physically isolated by selective transport barriers, including high endothelial venules and sinusoidal endothelium, that restrict free diffusion of many antiretroviral (ARV) drugs used to treat HIV, especially non-lipophilic compounds. Recent spatial pharmacokinetic analyses have suggested that passive diffusion alone cannot explain observed ARV concentrations in lymphoid tissues, raising the possibility that lymphocytes may act as incidental drug carriers. To investigate the relative contributions of free and cell-mediated drug trafficking, we conducted murine experiments in which drug was delivered intravenously to a murine model, with lymphocyte entry into the lobule blocked by a functional antibody. The experimental results show that blocking lymphocyte entry into the LN increases raw intracellular drug concentration within the LN for tenofovir and efavirenz, but not raltegravir. To understand the mechanism behind this observation, we developed a computational transport model. The model consists of a mechanistic physiologically based pharmacokinetic framework with four compartments: plasma, peripheral blood mononuclear cells, LN extracellular fluid, and LN intracellular space, while dynamically accounting for changes in LN extracellular fluid volume driven by lymphocyte trafficking. Our simulations predicted that blocking lymphocyte trafficking increases extracellular fluid volume and, counterintuitively, elevates intracellular drug concentration within the LN, with the effect size depending on the drug's intracellular equilibration kinetics. Raltegravir, which equilibrates rapidly between extracellular and intracellular compartments, is insensitive to this mechanism, a model prediction confirmed by the experimental null result. In conclusion, our study identifies extracellular fluid volume dynamics within the lymph node as a previously unrecognized, drug class-dependent modulator of intranodal ARV distribution. This mechanism operates independently of barrier-level penetration and has direct implications for drug efficacy in patients with altered immune trafficking.