Harnessing albumin as a carrier for the delivery of anti-HIV drugs to the lymphatic system.

The persistence of human immunodeficiency virus (HIV) reservoirs in the lymphatic system remains a major obstacle to a complete cure, largely due to subtherapeutic concentrations of antiretrovirals (ARVs) in lymphatic tissues under current regimens. Developing innovative strategies to enhance ARV delivery to lymphatic tissues could therefore represent a paradigm shift in the pursuit of an HIV cure. Here, we describe a delivery strategy involving an Evans Blue (EB)-based prodrug conjugated with dolutegravir (DTG), a model ARV. This construct is designed to bind albumin with high affinity, facilitating transport to lymph nodes (LNs) via albumin-mediated trans-endothelial transcytosis. EB modification substantially improved the distribution of the conjugated molecule to LNs throughout the body, and the hEB-DTG prodrug increased DTG concentrations in LNs by up to 10-fold, suggesting a promising strategy for eradicating HIV reservoirs. STATEMENT OF SIGNIFICANCE: A major barrier to curing HIV infection is the persistence of viral reservoirs in lymphatic tissues, which current ARV therapies fail to eliminate due to poor drug penetration. To overcome this limitation, we developed a prodrug strategy that harnesses the natural trafficking of albumin to the lymphatic system. In this approach, ARVs are conjugated to EB, a high-affinity albumin-binding dye, to generate EB-ARV prodrugs that hijack albumin's endogenous transport pathways. After intravenous administration, these conjugates rapidly associate with circulating albumin, which mediates their transcytosis across endothelial barriers and directs their accumulation in lymph nodes and other lymphoid tissues. This strategy substantially enhances ARV exposure at the primary sites of viral persistence, representing a promising and potentially transformative approach for eradicating HIV reservoirs and advancing toward a functional cure.