We propose to design and develop pharmacologically relevant and clinically significant drug delivery strategies using novel nanocarrier and drug regimens that target CNS HIV reservoirs. Due to the inability of antiretroviral drugs (ARVs) to cross the blood-brain-barrier (BBB) and ARV-induced neurotoxicity, the current ARV regimens are incapable of treating HIV-associated CNS dysfunction, including HIV-associated neurocognitive disorders (HAND). Our drug delivery strategies are designed for enhanced BBB permeability, facilitating drug passage across the BBB and effectively suppressing the virus in CNS reservoirs, especially in macrophages and microglia, with minimal/tolerable neurotoxicity. We seek to develop a novel “biological nanoparticle” delivery system using “extracellular vesicles (EVs)”, which are known to cross the BBB and largely accumulate in microglia. For drug loading, we will use elvitegravir (EVG), an integrase inhibitor, along with its pharmacoenhancer, cobicistat (COBI), which are a member of the least toxic class of ARVs and used as first line of therapy. We will combine EVG with a chemodietary agent, which has been proven to be effective in treating many CNS diseases and in reducing inflammation and oxidative stress, the hallmark of HIV pathogenesis. Our central hypothesis is that dual loading of EVG-COBI and chemodietary agent within EVs, will bypass efflux transporters, cross the BBB, target macrophages and microglia, and deliver EVG and chemodietary agent to these cells, leading to HIV suppression. We will test the hypothesis by: Aim 1: Developing EV-drug formulations and determining their efficacy in macrophages and microglia using an in vitro BBB model, and Aim 2: Determining pharmacokinetic, tissue distribution, and safety profile of EV-drug formulations in an animal model. We expect to achieve novel nano-formulations of EVG-COBI and chemodietary agent in EVs that cross the BBB and target macrophages and microglia. Through our future studies, these regimens are eventually expected to improve HIV treatment outcomes in the CNS and reduce prevalence of HAND and other neurological disorders.

A critical barrier to progress in improving HIV treatment outcomes in HIV CNS reservoirs, macrophages and microglia, is the lack of optimal concentration of antiretroviral drugs in these cells. Our goal is to improve HIV treatment outcomes by improving the optimal concentration of antiretroviral regimes in CNS reservoirs by targeted delivery. The impact of this project includes improving therapeutic interventions using extracellular vesicles mediated drug delivery that would reduce/eliminate the virus from the CNS reservoirs and repurpose the drugs for combating HIV.