Novel method to quantify phenotypic markers of HIV-associated neurocognitive disorder in a murine SCID model
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Novel method to quantify phenotypic markers of HIV-associated neurocognitive disorder in a murine SCID model Christina Gavegnano 1,2 & Woldeab Haile 3,4 & Raj Koneru 3,4 & Selwyn J. Hurwitz 1,2 & James J. Kohler 1,2 & William R. Tyor 2,3,4 & Raymond F. Schinazi 1,2 Received: 14 February 2019 / Revised: 18 March 2020 / Accepted: 13 April 2020 # Journal of NeuroVirology, Inc. 2020
Abstract Despite combined antiretroviral therapy (cART), HIV infection in the CNS persists with reported increases in activation of macrophages (MΦ), microglia, and surrounding astrocytes/neurons, conferring HIV-induced inflammation. Chronic inflammation results in HIV-associated neurocognitive disorders (HAND) with reported occurrence of up to half of individuals with HIV infection. The existing HAND mouse model used by laboratories including ours, and the effect of novel agents on its pathology present with labor-intensive and time-consuming limitations since brain sections and immunohistochemistry assays have to be performed and analyzed. A novel flow cytometry-based system to objectively quantify phenotypic effects of HIV using a SCID mouse HAND model was developed which demonstrated that the HIV-infected mice had significant increases in astrogliosis, loss of neuronal dendritic marker, activation of murine microglia, and human macrophage explants compared to uninfected control mice. HIV p24 could also be quantified in the brains of the infected mice. Correlation of these impairments with HIVinduced brain inflammation and previous behavioral abnormalities studies in mice suggests that this model can be used as a fast and relevant throughput methodology to quantify preclinical testing of novel treatments for HAND. Keywords HAND . HIV . Inflammation . Macrophages . Brain
Introduction Of the estimated 37 million people living with HIV-1 infection, HIV-associated neurocognitive disorders (HAND) occur in up to 50%, even with combined antiretroviral therapy (cART) (Anderson et al. 2017; Clifford 2017; Griffin et al. 2015; Jia et al. 2017). Animal models that recapitulate Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13365-020-00842-3) contains supplementary material, which is available to authorized users. * William R. Tyor [email protected] * Raymond F. Schinazi [email protected] 1
Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, Atlanta, GA 30322, USA
2
Emory Center for AIDS Research (CFAR), Emory University, Atlanta, GA 30322, USA
3
Department of Neurology, Emory University School of Medicine, Atlanta, GA 30209, USA
4
Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA
behavioral and phenotypic events that define HAND have proven essential to investigating the correlate mechanism(s) of disease and the development of novel therapeutic strategies (Bennett et al. 2016; Cook-Easterwood et al. 2007; Griffin 3rd et al. 2004; Haile et al. 2016; Sas et al. 2007). To date, animal models have included efforts to isolate resident microglial cells f
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