HIV-1 Tat-Induced Astrocytic Extracellular Vesicle miR-7 Impairs Synaptic Architecture

Although combination antiretroviral therapy (cART) has improved the health of millions of those living with HIV-1 (Human Immunodeficiency Virus, Type 1), the penetration into the central nervous system (CNS) of many such therapies is limited, thereby resulting in residual neurocognitive impairment c...

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Bibliographic Details
Published in:Journal of neuroimmune pharmacology 2020-09, Vol.15 (3), p.538-553
Main Authors: Hu, Guoku, Niu, Fang, Liao, Ke, Periyasamy, Palsamy, Sil, Susmita, Liu, Jinxu, Dravid, Shashank M., Buch, Shilpa
Format: Article
Language:English
Subjects:
Animals
Antiretroviral drugs
Astrocytes - drug effects
Astrocytes - ultrastructure
Biomedical and Life Sciences
Biomedicine
Cell Adhesion Molecules, Neuronal - metabolism
Cell Biology
Extracellular Vesicles - metabolism
Gene Targeting
HIV
HIV Infections - metabolism
Human immunodeficiency virus
Humans
Immunology
Macaca
MicroRNAs - biosynthesis
MicroRNAs - genetics
MicroRNAs - toxicity
Nerve Tissue Proteins - metabolism
Neurons - metabolism
Neurosciences
Original
Original Article
Pharmacology/Toxicology
Platelet-Derived Growth Factor - metabolism
Simian Acquired Immunodeficiency Syndrome - metabolism
Synapses - drug effects
Synapses - ultrastructure
tat Gene Products, Human Immunodeficiency Virus - toxicity
Up-Regulation
Virology
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Summary:Although combination antiretroviral therapy (cART) has improved the health of millions of those living with HIV-1 (Human Immunodeficiency Virus, Type 1), the penetration into the central nervous system (CNS) of many such therapies is limited, thereby resulting in residual neurocognitive impairment commonly referred to as NeuroHIV. Additionally, while cART has successfully suppressed peripheral viremia, cytotoxicity associated with the presence of viral Transactivator of transcription (Tat) protein in tissues such as the brain, remains a significant concern. Our previous study has demonstrated that both HIV-1 Tat as well as opiates such as morphine, can directly induce synaptic alterations via independent pathways. Herein, we demonstrate that exposure of astrocytes to HIV-1 protein Tat mediates the induction and release of extracellular vesicle (EV) microRNA-7 (miR-7) that is taken up by neurons, leading in turn, to downregulation of neuronal neuroligin 2 (NLGN2) and ultimately to synaptic alterations. More importantly, we report that these impairments could be reversed by pretreatment of neurons with a neurotrophic factor platelet-derived growth factor-CC (PDGF-CC). Graphical Abstract
ISSN:1557-1890
1557-1904
DOI:10.1007/s11481-019-09869-8