HIV-1 Nef Contributes to Myelin Impairment and Neuroinflammation in the Murine Central Nervous System.
Open Access DepositedHuman immunodeficiency virus (HIV) associated neurocognitive disorders (HAND) are a spectrum of cognitive impairments that continue to affect approximately half of all HIV-positive individuals despite effective viral suppression via antiretroviral therapy (ART). White matter pathologies have persisted in the ART era, and the degree of white matter damage correlates with the degree of neurocognitive impairment in patients with HAND. The HIV-1 protein Nef has been implicated in HAND pathogenesis, but the role of Nef in oligodendrocyte damage and myelin impairment is relatively understudied. Thus, this thesis sought to address this major research gap. Cells can be impaired by both endogenously produced Nef in infected cells and by Nef-containing extracellular vesicles (Nef EVs). Therefore, I explored the role of Nef in the central nervous system (CNS) via two murine models: 1) mice injected with Nef EVs, and CNS cells and tissue treated with Nef EVs, and 2) mice injected with EcoHIV, a chimeric murine HIV. Using in vivo, ex vivo, and in vitro approaches, I showed that acute application of Nef EVs disrupted myelin sheaths and damaged oligodendrocytes in the murine CNS. Intracranial injection of Nef EVs reduced myelin basic protein (MBP) staining and decreased the number of CC1+ oligodendrocytes in the corpus callosum. Similarly, cerebellar slice cultures treated with Nef EVs displayed decreased MBP expression and increased unmyelinated axons. Both primary mixed brain cultures and enriched oligodendrocyte precursor cell cultures treated with Nef EVs displayed decreased number of O4+ cells, indicating oligodendrocyte damage by Nef EVs. These results suggest that Nef EV-mediated damage to oligodendrocytes and myelin maintenance may be a component of HAND pathogenesis. I utilized a novel nef-deficient EcoHIV construct, termed EcoHIVΔNef, to examine the chronic effects of Nef in intracranially injected mice. Similar to EcoHIV-infected mice, mice infected with EcoHIVΔNef displayed stable infection up to 16 weeks post injection. Compared to mice infected with EcoHIVΔNef, EcoHIV-infected mice displayed increased infiltration of IBA1+ microglia and upregulated pro-inflammatory cytokines that was associated with a trend towards decreased MBP staining and GFAP fluorescence intensity in the corpus callosum as well as decreased MAP2 fluorescence intensity in the hippocampal CA1 region. These results suggest that chronic Nef mediated inflammation may contribute to demyelination, astrocyte impairment, and neuronal injury in EcoHIV-infected mice. These studies may help explain how Nef contributes to neuropathology in HAND.
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