The proposed studies are based upon the observation that, although human immunodeficiency virus Type 1 (HIV) penetrates the brain early in disease, only in a subset of patients with advanced immunosuppression do inflammatory monocytes enter the brain in large numbers and result in neurological dysfunction. The underlying hypothesis is that brain microvascular endothelial cells (BMVECs) facilitate monocyte entry following direct HIV infection, up-regulation of adhesion molecules, or macrophage-mediated disruption of blood-brain barrier function (BBB). In previous studies the Investigator and his associates demonstrated that pro-inflammatory cytokines and other immunoregulatory molecules produced by macrophages disrupt BBB function and produce up-regulation of adhesion molecules on BMVECs. This provides one mechanism for transendothelial passage of virus and inflammatory cells across the BBB. The Investigator speculates that during advanced immunosuppression, immune competent macrophages can disrupt BBB function and permit passage of monocytes into brain. In addition, he proposes that specific viral strains facilitate neuroimmune activation and attendant monocyte recruitment/binding to endothelial cells, disruption of the BBB, and passage of inflammatory cells into the CNS. In this application the Investigator proposes to assay virus-endothelial cell infection and its relationship to BBB function. The researchers will use monocytes from HIV-infected patients with/without HIV dementia to determine if such cells have facilitated transendothelial migration. They will analyze several putative neurotoxins, as well as other potential agents isolated by RP-HPLC, to determine which factors might facilitate monocyte migration through BMVEC. Their recently-developed SCID mouse model of HIV encephalitis will be used to assess endothelial- and chemokine-mediated monocyte recruitment into the CNS. The combined efforts are designed to determine the viral and immune determinants for BBB dysfunction in AIDS, information that could be helpful in adapting strategies to prevent migration of monocytes into the brain during HIV dementia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
AIDS and Related Research Study Section 7 (ARRG)
Program Officer
Nunn, Michael
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Medical Center
Schools of Medicine
United States
Zip Code
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
McMillan, JoEllyn; Szlachetka, Adam; Slack, Lara et al. (2018) Pharmacokinetics of a Long-Acting Nanoformulated Dolutegravir Prodrug in Rhesus Macaques. Antimicrob Agents Chemother 62:
Sillman, Brady; Woldstad, Christopher; Mcmillan, Joellyn et al. (2018) Neuropathogenesis of human immunodeficiency virus infection. Handb Clin Neurol 152:21-40
Ottemann, Brendan M; Helmink, Austin J; Zhang, Wenting et al. (2018) Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities. Biomaterials 185:174-193
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
McMillan, JoEllyn; Szlachetka, Adam; Zhou, Tian et al. (2018) Pharmacokinetic testing of a first generation cabotegravir prodrug in rhesus macaques. AIDS :

Showing the most recent 10 out of 151 publications