The overall goal of this revised renewal Project 1 application is to continue studies initiated in the first funding period to investigate the mechanism of astrocytotropic HIV-1 infection and its effects on human astrocyte function. During the first funding period we identified astrocytotropic HIV-1 strains (A-HIV-1), which preferentially infect astrocytes rather than T cells or macrophages. We have initiated molecular analysis of the env region of A-HIV-1 and determined several parameters of their interactions with astrocytes. Recently, we have shown that HIV-1 and purified gp120 cause inhibition of glutamate uptake by primary astrocytes; the inhibition is long lasting and, at least in part involves regulation of astrocyte gene expression resulting in loss of functional glutamate transporters. We hypothesize that A-HIV-1 strains contribute directly to AIDS cells, and causing lasting disruption of neuroprotective astrocyte functions such as L-glutamate uptake. The main concerns of the Reviewers were insufficient consideration of adult brain tissues and small sample size. We expanded our research plan and revised the application accordingly.
The Specific Aims of this revised application are: 1) identification of A-HIV-1 in brain tissue of pediatric and adult patients; 2) Molecular and functional characterization of A-HIV-1 strains; 3) Studies on the mechanism of L-glutamate uptake inhibition in human astrocytes infected with A-HIV-1 or exposed to gp120; 4) Expression and co-localization of HIV-1 and neuropathogenic effects induced by A-HIV-1 infected astrocytes and A-HIV-1 envelope in an animal model. The proposed studies will link efforts within this Program Project to determine the molecular structure and in vitro and in vivo functions and effects of neurotropic HIV-1 in order to test direct virological causes of dementia. Glutamate transporter and HIV-1 co-localization will be studied with L. Sharer (Core B), mechanism of transporter modulation by HIV-1 and Tat protein with P. Fisher (Project 3) and pathogenicity of A-HIV-1 infected astrocytes with H. Gendelman and J. Limoges (Project 2 and Core 1). Full molecular and functional characterization of A-HIV-1 may provide leads to future antiviral strategies to combat AIDS dementia.
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| McMillan, JoEllyn; Szlachetka, Adam; Slack, Lara et al. (2018) Pharmacokinetics of a Long-Acting Nanoformulated Dolutegravir Prodrug in Rhesus Macaques. Antimicrob Agents Chemother 62: |
| 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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