Our initial (1985) neuropathologic/virologic studies on AIDS encephalopathy in children identified the brain as a primary site of persistent HIV-1 infection. The brain is a reservoir for large amounts of HIV-1 unintegrated DNA (UVD) and is the major site of multinucleated (syncytial) cell formation. In vitro passage of HIV-1 selects for replication efficiency in the target cells employed, but excludes HIV-1 strain variants important for neuropathology. In particular, most laboratory strains of HIV-1 are lymphocyte-tropic, whereas much recent evidence points to a link between macrophage-tropic strains and neurovirulence. Studies from our groups have implicated neuroinvasion or neurovirulence in AIDS with specific regions of the HIV-1 env gp120 (CD4 binding, V3 and """"""""efficiency"""""""" domains), and with the regulatory genes nef and vif.
Our Specific Aims are: 1. To amplify and clone these HIV-1 gene sequences directly from post-mortem brain and selected tissues of children. 2. To determine the nucleotide sequence of these HIV-1 genes and characterize differences between individuals, between different tissues of the same individual (including PBMC), and between tissue-derived and cultured HIV- 1 isolates. 3. To construct chimeric HIV-1 DNAs using lymphocyte- trophic, macrophage-trophic, or glial-trophic HIV-1 clones with selected neuropathologic gene sequences. These recombinant constructs will be used to test HIV-1 replication, syncytium formation and cytokine induction in neural tissue (Project 1), and neurotoxicity (Projects 2 and 3) in both in vitro and in vivo assay systems.
| 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 : |
| 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 |
| Araínga, 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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