Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice

Abstract

BackgroundHost-species specificity of the human immunodeficiency virus (HIV) limits pathobiologic, diagnostic and therapeutic research investigations to humans and non-human primates. The emergence of humanized mice as a model for viral infection of the nervous system has overcome such restrictions enabling research for HIV-associated end organ disease including behavioral, cognitive and neuropathologic deficits reflective of neuroAIDS. Chronic HIV-1 infection of NOD/scid-IL-2Rgcnull mice transplanted with human CD34+ hematopoietic stem cells (CD34-NSG) leads to persistent viremia, profound CD4+ T lymphocyte loss and infection of human monocyte-macrophages in the meninges and perivascular spaces. Murine cells are not infected with virus.MethodsChanges in mouse behavior were measured, starting at 8 weeks after viral infection. These were recorded coordinate with magnetic resonance spectroscopy metabolites including N-acetylaspartate (NAA), creatine and choline. Diffusion tensor magnetic resonance imaging (DTI) was recorded against multispectral immunohistochemical staining for neuronal markers that included microtubule associated protein-2 (MAP2), neurofilament (NF) and synaptophysin (SYN); for astrocyte glial fibrillary acidic protein (GFAP); and for microglial ionized calcium binding adaptor molecule 1 (Iba-1). Oligodendrocyte numbers and integrity were measured for myelin associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG) antigens.ResultsBehavioral abnormalities were readily observed in HIV-1 infected mice. Longitudinal open field activity tests demonstrated lack of habituation indicating potential for memory loss and persistent anxiety in HIV-1 infected mice compared to uninfected controls. End-point NAA and creatine in the cerebral cortex increased with decreased MAG. NAA and glutamate decreased with decreased SYN and MAG. Robust inflammation reflected GFAP and Iba-1 staining intensities. DTI metrics were coordinate with deregulation of NF, Iba-1, MOG and MAG levels in the whisker barrel and MAP2, NF, MAG, MOG and SYN in the corpus callosum.ConclusionsThe findings are consistent with some of the clinical, biochemical and pathobiologic features of human HIV-1 nervous system infections. This model will prove useful towards investigating the mechanisms of HIV-1 induced neuropathology and in developing novel biomarkers and therapeutic strategies for disease.Electronic supplementary materialThe online version of this article (doi:10.1186/1750-1326-9-58) contains supplementary material, which is available to authorized users.

Characterization of neuropathology in the HIV-1 transgenic rat at different ages

“…Our results also do not concur with the neuropathology seen in humanized HIV-1 mice which included robust inflammation reflected in GFAP and Iba-1 staining intensities (Boska, Dash, 2014, Dash, Gorantla, 2011, Epstein, Narayanasamy, 2013, Gorantla, Makarov, 2010). This however can be explained by the inherent differences between the two animal models as far as pathophysiology: the HIV humanized mouse is an immunodeficient model (NOD/scid-IL-2Rgamma(c)(null) mice) reconstituted with human hematopoietic CD34(+) stem cells and infected with HIV, thus reflecting human HIV-1 infection more closely, with persistent viremia, profound CD4+ T lymphocyte loss and infection of human monocyte-macrophages in the meninges/perivascular spaces of the rodent brain (Boska, Dash, 2014, Epstein, Narayanasamy, 2013).…”

“…Engineering rodents that are permissive for HIV infection is technically demanding and only a few centers in the country have mastered the production and utilization of HIV-susceptible humanized mice (Akkina, 2013, Berges and Rowan, 2011, Boska et al, 2014, Dash et al, 2012, Dash et al, 2011, Epstein et al, 2013, Gorantla et al, 2010, Zhang and Su, 2012). Despite the usefulness of the latter, they remain technically complicated to produce and sustain (Akkina, 2013, Zhang and Su, 2012), and for our purposes of developing molecular imaging biomarkers, the small brain size of the humanized mouse poses a limitation especially when lower resolution techniques such as PET imaging are used.…”

“…This however can be explained by the inherent differences between the two animal models as far as pathophysiology: the HIV humanized mouse is an immunodeficient model (NOD/scid-IL-2Rgamma(c)(null) mice) reconstituted with human hematopoietic CD34(+) stem cells and infected with HIV, thus reflecting human HIV-1 infection more closely, with persistent viremia, profound CD4+ T lymphocyte loss and infection of human monocyte-macrophages in the meninges/perivascular spaces of the rodent brain (Boska, Dash, 2014, Epstein, Narayanasamy, 2013). The Tg rat on the other hand reflects chronic viral protein toxicity (Midde et al, 2011, Peng, Vigorito, 2010, Royal, Zhang, 2012, Vigorito et al, 2015, Wayman et al, 2015), and is closer pathologically to optimally-treated HIV+ patients than actively infected patients, as described below.…”

Migration of CD8+ T Cells into the Central Nervous System Gives Rise to Highly Potent Anti-HIV CD4dimCD8bright T Cells in a Wnt Signaling–Dependent Manner

“…HIV infected mice had 2,063 HIV RNA copies/mL at two weeks post-infection and 67,400 HIV RNA copies/mL at three weeks post-infection. These data are consistent with previously published work (33–34). Two and three weeks post-HIV infection, the brains were harvested and T cells isolated by percoll gradient centrifugation.…”

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

“…These human cells localize predominantly in the meninges and perivascular spaces and, to a lesser extent, in brain parenchyma 205,207 . Despite low viral burdens, chronically HIV-infected NSG-hCD34 + mice show several important characteristics of HAND, including activation of resident microglia and astrocytes in some brain regions, limited brain pathology in some mice, elevated markers of neuroinflammation, and evidence of neuronal injury and neurodegeneration, assessed with brain metabolite analysis and immunofluorescence staining 205–207 . Some of these changes were reversed by nanoparticle-based CART 208 .…”