Drug toxicities, patient compliance and limited penetrance into viral reservoirs (notably the central nervous system (CNS), gut and lymphatic organs) have diminished long-term antiretroviral therapy (ART) efficacy for HIV infection. Eliminating residual infection despite ART affected suppression of plasma viremia is our project goal. Novel strategies are sought for improved ART delivery to mononuclear phagocytes (MP: monocytes, perivascular and tissue macrophages and microglia) to bring drugs to tissue viral reservoirs. During the past R01 NS36126 funding cycle, now in its 17th year, we pioneered the development of long-acting injectable nanoformulated ART (nanoART) with superior biodistribution and pharmacokinetics over native drugs. Monthly nanoART injection, to subcellular sites of viral replication is possible We posit that this """"""""Trojan Horse"""""""" MP carriage of the drug formulations can facilitate long-lived storage depots, in liver and spleen, resulting in reduced viral mutation and sustained plasma ART levels. Our drug formulations can readily cross the blood- brain barrier (BBB), from monocytes to endothelial cells, and enable drug transfer to and from an infected CNS. The current proposal seeks to perfect nanoART technology and as such move it to human use. First, we seek to maximize viral clearance (measured reduction of integrated viral DNA) by developing a range of antiretroviral nanoformulated drugs used alone or in combination. These include ritonavir boosted atazanavir, maraviroc, lamivudine, dolutegravir and efavirenz. Second, synthesis of polymer drug packaging with attachments of specific ligand coating will direct the drug to specific virus'target cells, tissues and subcellular regions to optimize antiretroviral activities. We posit that such cell-targeted nanoART will facilitate cell entry, intracellular trafficking and drug secretion. Third, we will probe the """"""""best"""""""" directed formulations in rodents using a newly discovered small magnetite ART (SMART) platform. This will readily permit evaluation of broad numbers of coating ligands. Fourth, we will evaluate the functional consequences to the cell as it is linked to intracellular particle trafficking and stability. Fifth SMART formulations that pass evaluation will be synthesized by crystalline particles and evaluated for drug pharmacokinetics (uptake, release, plasma, and tissue distribution). This will include measures of BBB penetrance and tissue drug levels in brain, spleen, lymph nodes, and liver. Histologic and imaging assays will evaluate potential drug toxicities. Last, the most promising drug polymer formulations will be tested for antiretroviral efficacy, immune and neuroprotection in a humanized mouse model of HIV infection and neuroAIDS. The overall premise is to develop the necessary """"""""state of the art"""""""" tools to improve nanoART induced viral reduction in its CNS and other viral reservoirs.

Public Health Relevance

Human immunodeficiency virus (HIV) replicates in reservoirs that include the central nervous system, gut and lymphoid tissues despite antiretroviral therapy. Reducing the viral reservoir would facilitate clearance of residual virus and improve disease outcomes. To this end we will design novel nanoformulated therapeutic strategies aimed at reductions in HIV from its hidden sanctuaries.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
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University of Nebraska Medical Center
Schools of Medicine
United States
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Embury, Christine M; Dyavarshetty, Bhagyalaxmi; Lu, Yaman et al. (2017) Cathepsin B Improves ß-Amyloidosis and Learning and Memory in Models of Alzheimer's Disease. J Neuroimmune Pharmacol 12:340-352
Edagwa, Benson; McMillan, JoEllyn; Sillman, Brady et al. (2017) Long-acting slow effective release antiretroviral therapy. Expert Opin Drug Deliv 14:1281-1291
Guo, Dongwei; Zhou, Tian; Araínga, Mariluz et al. (2017) Creation of a Long-Acting Nanoformulated 2',3'-Dideoxy-3'-Thiacytidine. J Acquir Immune Defic Syndr 74:e75-e83
Heinrichs-Graham, Elizabeth; Santamaria, Pamela M; Gendelman, Howard E et al. (2017) The cortical signature of symptom laterality in Parkinson's disease. Neuroimage Clin 14:433-440
Kevadiya, Bhavesh D; Bade, Aditya N; Woldstad, Christopher et al. (2017) Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging. Acta Biomater 49:507-520
Araínga, Mariluz; Edagwa, Benson; Mosley, R Lee et al. (2017) A mature macrophage is a principal HIV-1 cellular reservoir in humanized mice after treatment with long acting antiretroviral therapy. Retrovirology 14:17
Gnanadhas, Divya Prakash; Dash, Prasanta K; Sillman, Brady et al. (2017) Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs. J Clin Invest 127:857-873
Shahnaz, Gul; Edagwa, Benson J; McMillan, JoEllyn et al. (2017) Development of mannose-anchored thiolated amphotericin B nanocarriers for treatment of visceral leishmaniasis. Nanomedicine (Lond) 12:99-115
Ivanisevic, Julijana; Stauch, Kelly L; Petrascheck, Michael et al. (2016) Metabolic drift in the aging brain. Aging (Albany NY) 8:1000-20
Sajja, Balasrinivasa R; Bade, Aditya N; Zhou, Biyun et al. (2016) Generation and Disease Model Relevance of a Manganese Enhanced Magnetic Resonance Imaging-Based NOD/scid-IL-2R?c(null) Mouse Brain Atlas. J Neuroimmune Pharmacol 11:133-41

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