Lymph node as Cerberus: the study and simulation of HIV drug exclusion

Abstract

Combination Antiretroviral Therapy (cART) has effectively suppressed HIV replication in most infected individuals over the past two decades. However, cART cannot eradicate the virus, requiring patients to maintain lifelong adherence to the drug regimen to prevent viral rebound. Recent studies have revealed heterogeneous distribution of cART drugs in certain tissues, particularly lymphatic organs such as lymph nodes. Our previous work demonstrates that drug exclusion from these sites can create pharmacological sanctuaries within lymph nodes, potentially hindering HIV treatment efficacy. Understanding the mechanisms of drug exclusion in lymph nodes is crucial for developing more effective therapies for HIV and other diseases, including cancer. This dissertation presents a novel approach to solving pharmacokinetic (PK) reaction-diffusion equations on an anatomically accurate three-dimensional (3D) murine lymph node using the Finite Volume Method (FVM) for several cART drugs. This marks the first instance of PK dynamics being solved on the exact geometry of an anatomically reconstructed lymph node. Our modeling tool enables comprehensive sensitivity analyses to determine the relationship between between drug transport characteristics and lymph node penetration. Ultimately, this research provides a powerful framework for enhancing drug design, potentially leading to more effective treatments for HIV and related conditions.