The proposed Program Project is designed to determine the molecular basis of HIV-1 associated encephalopathy. The Program utilizes several novel experimental models and techniques to elucidate the interaction of HIV-1 with human neural tissue. These include new systems to study highly permissive and non-permissive HIV-1 replication in neural cells in vitro, a model for neuronotoxin induction involving HIV-1 infected macrophages, an explant model of developing human brain, and two polymerase chain reaction-based systems for testing HIV-1 involvement directly (ex vivo) in brain section of HIV-1 infected children. Throughout this Program, we intend to test two distinct, but complementary routes to HIV-1 associated neuropathogenesis: through direct effects of HIV-1 replication in neural cells and through indirect effects of HIV-1 infected macrophages on neural cells. Although they come from four different institutions, the Project and Core Leaders in this Program have a history of increasingly intense collaborations with each other that made this comprehensive Program possible. The major goals of the individual Projects are as follows: Project 1. To determine the molecular interactions engendering efficient HIV-1 replication in neural cells and their dysfunction. Project 2. To determine the molecular mechanisms through which HIV-1 infected macrophages and their products induce glial cell synthesis of neuronotoxins. Project 3. To employ (cultured neural cells) and explant model of fetal brain and to investigate the impact of HIV-1 replication, its cellular origin, and its tropism on neuropathogenesis. Project 4. To localize HIV-1 infection, its gene expression, and cellular gene modulation by in situ hybridization/PCR in brain sections from children who died of AIDS. Core 9001. To determine env, nef, vif sequences unique to brain tissue and construct chimeric viruses carrying them. Together these studies will use the detailed molecular mechanisms revealed in culture systems directly to probe analogous interactions in developing tissue and ex vivo to determine the basis for HIV-1 associated encephalopathy and its control.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (SRC (13))
Program Officer
Kerza-Kwiatecki, a P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
St. Luke's-Roosevelt Institute for Health Sciences
New York
United States
Zip Code
Schutt, Charles R; Gendelman, Howard E; Mosley, R Lee (2018) Tolerogenic bone marrow-derived dendritic cells induce neuroprotective regulatory T cells in a model of Parkinson's disease. Mol Neurodegener 13:26
Sillman, Brady; Bade, Aditya N; Dash, Prasanta K et al. (2018) Creation of a long-acting nanoformulated dolutegravir. Nat Commun 9:443
Thomas, Midhun B; Gnanadhas, Divya Prakash; Dash, Prasanta K et al. (2018) Modulating cellular autophagy for controlled antiretroviral drug release. Nanomedicine (Lond) 13:2139-2154
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
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 :
McMillan, JoEllyn; Szlachetka, Adam; Zhou, Tian et al. (2018) Pharmacokinetic testing of a first generation cabotegravir prodrug in rhesus macaques. AIDS :
AraĆ­nga, 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

Showing the most recent 10 out of 270 publications