The general objective of this proposal is to study the biochemical and molecular mechanisms governing the HIV-1 life-cycle in neural cells in vitro, and the effects of HIV-1 on neural cell gene expression, as a model for understanding HIV-1 neurotropism and its contribution to AIDS encephalopathy. The proposed studies are based on our recent findings which identified several different features of the HIV-1 life cycle in neural cells (of glial, astroglial, or neuronal origin) compared to T lymphocytes or macrophages. These include efficient fusion of HIV-1 envelope with CD4-negative neural cell membranes, limited viral replication in spite of efficient fusion and entry, transient high-level viral production in CD4-expressing neural cells, and efficient HIV-1 DNA transcription that is partially independent of the Tat/TAR transcriptional system. We hypothesize that these features constitute the basis of HIV-1 neurotropism by allowing the selection of specific viral variants, modulating cellular gene expression during transient high-level HIV-1 DNA transcription, and creating a reservoir of inducible virus in the neural tissue. These direct (albeit non-cytolytic) interactions of macrophage-mediated neuronotoxicity and other effects of HIV-1 infection, to be investigated in other component projects of this Program Project.
The Specific Aims of Project 1 are: 1) To determine how HIV-1 entry determines the outcome of HIV-1 infection in neural cells in vitro; 2) To study the role of env, nef, and vif in HIV-1 neurotropism using primary neurotropic HIV-1's and chimeric neural HIV-1 constructs; 3) To investigate the transient high-level transcription of HIV-1 DNA in neural cells in vitro, including the novel Tat/TAR-independent transcriptional mechanism; 4) To identify cellular genes modulated during HIV-1 infection in vitro and in vivo. The proposed studies will utilize HIV-1 strains and molecular clones, recombinant vectors, cell lines, other reagents, and experience in neural cell biology and molecular virology acquired during the past several years of research on AIDS and HIV-1 in this laboratory. In addition, close collaboration, exchange of information, and reagents with other members in the Program Project will be essential for Aims 1 and 2 (L. Epstein, Project 3; B. Blumberg, Core A;
Aim 3 (H. Gendelman, Project 2), and Aim 4 (L. Sharer, Project 4). We hope that the proposed studies will yield significant new information regarding the mechanism of HIV-1 infection and persistence in human neural cells, adding to the comprehensive investigation of complementary HIV-1 neuropathogenic mechanisms in this Program Project.
| 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 : |
| 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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