HIV-1 Tat-Induced Astrocytic Extracellular Vesicle miR-7 Impairs Synaptic Architecture
- PDF / 7,918,145 Bytes
- 16 Pages / 595.276 x 790.866 pts Page_size
- 80 Downloads / 213 Views
ORIGINAL ARTICLE
HIV-1 Tat-Induced Astrocytic Extracellular Vesicle miR-7 Impairs Synaptic Architecture Guoku Hu 1 & Fang Niu 1 & Ke Liao 1 & Palsamy Periyasamy 1 & Susmita Sil 1 & Jinxu Liu 2 & Shashank M. Dravid 2 & Shilpa Buch 1 Received: 24 December 2018 / Accepted: 28 July 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract 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). Keywords HIV-1 tat . Extracellular vesicles . miRNA . Neuroligin . PDGF . Synapse
Introduction The clinical outlook for patients with HIV-1 (Human Immunodeficiency Virus, Type 1) has improved dramatically as an increasingly effective combination antiretroviral therapy (cART) options have become readily available (Maschke et al. 2000; Sacktor et al. 2002; Gray et al. 2003; McArthur et al. 2003). Paradoxically, however, increased survival rates resulting from therapy usage have resulted in an undesirable increase in the prevalence of minor neurocognitive impairment collectively referred to as NeuroHIV. Complications of Guoku Hu and Fang Niu contributed equally to this work. * Guoku Hu [email protected] * Shilpa Buch [email protected] 1
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
2
Department of Pharmacology, Creighton University, Omaha, NE, USA
the central nervous system (CNS) represent a substantial health burden in HIV-1 infected individuals because of the privileged immune status of the brain coupled with the limited accessibility of some ART regimens to penetrate the CNS (Ellis et al. 2007). Despite ART-mediated near complete suppression of virus replication, NeuroHIV still exists in almost 40% of infected patients (Simioni et al. 2010). Viral protein transactivator of transcription (Tat) that was first identified as a neurotoxin by Nath et al. (Nath et al. 1996) has been shown to exert diverse cytotoxic effects including, bu
Data Loading...
