Graduation Date

Spring 5-6-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmacology and Experimental Neuroscience

First Advisor

Larisa Y. Poluektova

Second Advisor

Howard E. Gendelman

Abstract

Extensive research have been conducted to dissect the rapidly evolving mechanism of human immunodeficiency virus (HIV-1) neuropathogenesis, and to investigate the viral reservoirs in the central nervous system (CNS), which is considered as a major barrier for the viral eradication. These efforts have been hindered due to the paucity of relevant animal models of progressive HIV-1 brain infections.

Therefore, we developed a brand new mouse model reconstituted with both a human immune system and human glia (primarily astrocyte and oligodendrocyte lineage) in the brain. We transplanted newborn NOD/SCID/IL2Rγc−/− (NSG) mice with human neural progenitor cells (NPCs) in the lateral ventricle and hematopoietic stem cells (HSCs) in the liver at birth. Human astrocytes repopulated the white matter and periventricular mouse brain regions in an anatomically symmetrical manner, with the highest level of reconstitution in corpus callosum and periventricular region, and relatively low levels in other regions like frontal cortex, striatum and brain stem. Human glial engraftment induced transcriptional changes associated with multiple biological processes, including synaptic transportation, angiogenesis, and axon growth, ion channel activities, compared to non-reconstituted mice, as determined by next generation RNA sequencing.

We then investigated the effects of HIV-1 infection on immune and glial cells pathological and molecular changes. The immune analyses of these HIV-1-infected mice showed increased meningeal and perivascular infiltration by human HLA-DR+ cells and surveillance by activated immune cells in brain tissue. The species-specific transcriptome analysis revealed alterations that were linked to interferon (IFN) type 1 and 2 signaling pathways (STAT1, 2, IRF9, MX1, ISG15, IFI6, CMPK2) and a range of host antiviral responses. Differentially expressed mouse genes in the hippocampus reflected tissue remodeling while down-regulated human genes were linked to altered cell growth, glial cytoskeleton reorganization, oligodendrocyte differentiation and myelin ensheathment (MBP, MOBP, PLP1, MAG and ZNF488). The results overlapped with the disease profile observed by others in human HIV-1 encephalitic brains. Therefore, this new model provided a promising future for study of human-specific viral-immune-glial interactions and discovery of new therapeutic targets for HIV-1 nervous system infection.

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