Abstract
HIV-associated neurocognitive disorders (HANDs) are a frequent outcome of HIV infection. Effective treatment of HIV infection has reduced the rate of progression and severity but not the overall prevalence of HANDs, suggesting ongoing pathological process even when viral replication is suppressed. In this study, we investigated how HIV-1 protein Nef secreted in extracellular vesicles (exNef) impairs neuronal functionality. ExNef were rapidly taken up by neural cells in vitro, reducing the abundance of ABC transporter A1 (ABCA1) and thus cholesterol efflux and increasing the abundance and modifying lipid rafts in neuronal plasma membranes. ExNef caused a redistribution of amyloid precursor protein (APP) and Tau to lipid rafts and increased the abundance of these proteins, as well as of Aβ42 ExNef further potentiated phosphorylation of Tau and activation of inflammatory pathways. These changes were accompanied by neuronal functional impairment. Disruption of lipid rafts with cyclodextrin reversed the phenotype. Short-term treatment of C57BL/6 mice with either purified recombinant Nef or exNef similarly resulted in reduced abundance of ABCA1 and elevated abundance of APP in brain tissue. The abundance of ABCA1 in brain tissue of HIV-infected human subjects diagnosed with HAND was lower, and the abundance of lipid rafts was higher compared with HIV-negative individuals. Levels of APP and Tau in brain tissue correlated with the abundance of Nef. Thus, modification of neuronal cholesterol trafficking and of lipid rafts by Nef may contribute to early stages of neurodegeneration and pathogenesis in HAND.
Highlights
HIV-associated neurocognitive disorders (HANDs) include three levels of neurocognitive dysfunction in HIV infection: asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia [1, 2]
The concentration of exNef used in this study was 0.4 ng/ml of Nef, which is lower than the concentration of Nef detected in the blood of anti-retroviral therapy (ART)-treated individuals with undetectable viral load [15, 23]
It was demonstrated in our previous study that the effects of extracellular vesicle (EV) produced by Nefexpressing cells on cholesterol metabolism and lipid rafts are similar to the effects of EVs produced by HIV-infected myeloid cells, whereas EVs from cells infected with DNefHIV did not have such effects [13]
Summary
HIV-associated neurocognitive disorders (HANDs) include three levels of neurocognitive dysfunction in HIV infection: asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia [1, 2]. Nef-containing EVs modify cholesterol metabolism and lipid rafts in neural cells We found that treatment of cells with exNef increased co-localization of both APP and Tau with lipid rafts (Fig. 4, A–D).
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