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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS036126-17
Application #
8606798
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
1996-12-01
Project End
2018-03-31
Budget Start
2013-07-01
Budget End
2014-03-31
Support Year
17
Fiscal Year
2013
Total Cost
$581,431
Indirect Cost
$195,098
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Kelso, Matthew L; Elliott, Bret R; Haverland, Nicole A et al. (2015) Granulocyte-macrophage colony stimulating factor exerts protective and immunomodulatory effects in cortical trauma. J Neuroimmunol 278:162-73
Gendelman, Howard E; Gelbard, Harris A (2014) Adjunctive and long-acting nanoformulated antiretroviral therapies for HIV-associated neurocognitive disorders. Curr Opin HIV AIDS 9:585-90
Guo, Dongwei; Li, Tianyuzi; McMillan, JoEllyn et al. (2014) Small magnetite antiretroviral therapeutic nanoparticle probes for MRI of drug biodistribution. Nanomedicine (Lond) 9:1341-52
Heinrichs-Graham, Elizabeth; Kurz, Max J; Becker, Katherine M et al. (2014) Hypersynchrony despite pathologically reduced beta oscillations in patients with Parkinson's disease: a pharmaco-magnetoencephalography study. J Neurophysiol 112:1739-47
Singh, Dhirender; McMillan, JoEllyn M; Liu, Xin-Ming et al. (2014) Formulation design facilitates magnetic nanoparticle delivery to diseased cells and tissues. Nanomedicine (Lond) 9:469-85
Singh, Dhirender; McMillan, JoEllyn M; Kabanov, Alexander V et al. (2014) Bench-to-bedside translation of magnetic nanoparticles. Nanomedicine (Lond) 9:501-16
Edagwa, Benson J; Zhou, Tian; McMillan, JoEllyn M et al. (2014) Development of HIV reservoir targeted long acting nanoformulated antiretroviral therapies. Curr Med Chem 21:4186-98
Ivanisevic, Julijana; Epstein, Adrian A; Kurczy, Michael E et al. (2014) Brain region mapping using global metabolomics. Chem Biol 21:1575-84
Gendelman, Howard E; Balogh, Lajos P; Bawa, Raj et al. (2014) The 4th Annual Meeting of the American Society for Nanomedicine. J Neuroimmune Pharmacol 9 Suppl 1:S1-3
Guo, Dongwei; Zhang, Gang; Wysocki, Tadeusz A et al. (2014) Endosomal trafficking of nanoformulated antiretroviral therapy facilitates drug particle carriage and HIV clearance. J Virol 88:9504-13

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