This shared investigator R01 is an extension of 5 P01 NS043985-09. The current work builds on prior successes in developing long-acting nanoformulated antiretroviral therapies (nanoART) to improve drug delivery and therapeutic outcomes for aged virus-infected people. Elucidating the interplay between aging, HIV disease and ART is the overarching project goal. The tools are available to address this interplay which can simplify drug regimens and improve disease outcomes. First, nanoART is available for long- term testing of antiretroviral responses together with central nervous system (CNS) and broad metabolic functions. Second, interdisciplinary bioimaging, behavior, and nanopharmaceutics can evaluate virus, drug, immune, and age-related toxicities. Third, drug pharmacokinetic, pharmacodynamics, drug-drug interactions can be measured by employing PXR humanization (the androstane receptor with replacement of the mouse Cyp3a with human CYP3A4) in rodents. This can be used to evaluate long-term immune and antiviral responses. Fourth, a novel tool designed to improve ART delivery to viral reservoirs was discovered for theranostics (simultaneous diagnostics and therapeutics). This system is called small magnetite ART (or SMART) and permits assay of drug biodistribution by imaging tests. Such outcome measures would improve ART CNS and lymphoid delivery and thus combat persistent HIV-1 infection. A group of investigators with productive histories of working together was assembled. They include neuroscientists (H. Gendelman, Co- PI), immunopathologists (L. Poluektova, Co-PI), aging and cognitive behavior researchers (S. Bonasera), bioimaging experts (M. Boska) those with expertise in neurodegenerative diseases (R. L. Mosley), and experts in nanomedicine and drug delivery (X. Liu). The work is timely and relevant. Although ART has profoundly reduced morbidities and mortality for HIV infection coincident with virus reductions and immune preservation, the prevalence of neurocognitive impairments and drug toxicities remain common. Indeed, the doubling of virus-infected patients > 50 years of age is upon us. New co-morbid conditions now include cerebrovascular disease, non-AIDS malignancies, insulin resistance, hyperlipidemia, dementia, and liver, renal and bone disorders. This demands new model systems for disease studies relevant to current HIV/AIDS trends. Indeed, the work reflects the changing epidemiologic patterns of human disease. [We acknowledge that the prior submission lacked preliminary data and details about our humanized brain model and nanoformulations and response of the animals to treatments. A number of recent publications and significant new preliminary data are now included that addresses each of these concerns in a thorough and reasoned manner.] The tools that are needed to tackle relevant questions in HIV and aging are also available for study.

Public Health Relevance

Combination antiretroviral therapy has reduced the mortality and improved the quality of life of human immunodeficiency virus infected people. As people live longer life's quality is often linked to the toxicities of life-long medicines, as such, the means o best identify and predict untoward effects and make newer more effective drugs or drug formulations remains an important research task. This proposal seeks funds to accomplish this through improved disease monitoring, drug development, and pharmacotoxicology approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
4R01AG043540-04
Application #
9114014
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Mackiewicz, Miroslaw
Project Start
2013-09-30
Project End
2018-05-31
Budget Start
2016-07-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Kevadiya, Bhavesh D; Woldstad, Christopher; Ottemann, Brendan M et al. (2018) Multimodal Theranostic Nanoformulations Permit Magnetic Resonance Bioimaging of Antiretroviral Drug Particle Tissue-Cell Biodistribution. Theranostics 8:256-276
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Sillman, Brady; Woldstad, Christopher; Mcmillan, Joellyn et al. (2018) Neuropathogenesis of human immunodeficiency virus infection. Handb Clin Neurol 152:21-40
Zhou, Tian; Su, Hang; Dash, Prasanta et al. (2018) Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials 151:53-65
Kevadiya, Bhavesh D; Ottemann, Brendan M; Thomas, Midhun Ben et al. (2018) Neurotheranostics as personalized medicines. Adv Drug Deliv Rev :
Zhou, Tian; Lin, Zhiyi; Puligujja, Pavan et al. (2018) Optimizing the preparation and stability of decorated antiretroviral drug nanocrystals. Nanomedicine (Lond) 13:871-885
Kiyota, Tomomi; Machhi, Jatin; Lu, Yaman et al. (2018) Granulocyte-macrophage colony-stimulating factor neuroprotective activities in Alzheimer's disease mice. J Neuroimmunol 319:80-92
McMillan, JoEllyn M; Cobb, Denise A; Lin, Zhiyi et al. (2018) Antiretroviral Drug Metabolism in Humanized PXR-CAR-CYP3A-NOG Mice. J Pharmacol Exp Ther 365:272-280

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