This revised competing renewal Program Project application request funds to continue studies on the molecular mechanisms of HIV-1 associated encephalopathy. Our research during the first funding period was marked by establishment of synergistic collaborations among PPG investigators, program-wide access to patient and fetal tissues and primary neural cells permitting studies on neuropathogenesis in natural systems, and complementation among the different disciplines represented by different disciplines represented by individual projects. 57 publication resulted from the first funding period. Significant progress has been made in most of the originally proposed studies with these major findings: we elucidated neurotoxic effects and neuron apoptosis mediated by factors released from HIV-1 infected macrophages, developed a novel animal model for neuropathogenesis, demonstrated restricted HIV-1 infection in astrocytes in vivo and in vitro, isolated and partially cloned primary astrocytotropic HIV-1 from the CNS, and demonstrated deleterious effects of TNFa. HIV-1 infection, and gp120 exposure on glutamate uptake by primary astrocytes. Our research validated the role of HIV-1 infected macrophages in AIDS neuropathogenesis and developed a new concept of direct pathogenic effects of HIV-1 through infection of astrocytes and disruption of their neuroprotective function. These two complementary models of neuropathogenesis will be pursued in parallel in vitro and in vivo studies during next funding period.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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Special Emphasis Panel (ZNS1-SRB-L (02))
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Nunn, Michael
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St. Luke's-Roosevelt Institute for Health Sciences
New York
United States
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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

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