Abstract
Damage to the cerebral vascular endothelium is a critical initiating event in the development of HIV-1-associated neurocognitive disorders. To study the role of mitochondria in cerebral endothelial dysfunction, we investigated how exosomes, isolated from both cell lines with integrated provirus and HIV-1 infected primary cells (HIV-exosomes), accelerate the dysfunction of primary human brain microvascular endothelial cells (HBMVECs) by inducing mitochondrial hyperfusion, and reducing the expression of phosphorylated endothelial nitric oxide synthase (p-eNOS). The quantitative analysis of the extracellular vesicles (EVs) indicates that the isolated EVs were predominantly exosomes. It was further supported by the detection of exosomal markers, and the absence of large EV-related protein in the isolated EVs. The exosomes were readily taken up by primary HBMVECs. HIV-exosomes induce cellular and mitochondrial superoxide production but reduce mitochondrial membrane potential in HBMVECs. HIV-exosomes increase mitochondrial hyperfusion, possibly due to loss of phosphorylated dynamin-related protein 1 (p-DRP1). HIV-exosomes, containing the HIV-Tat protein, and viral Tat protein reduce the expression of p-DRP1 and p-eNOS, and accelerate brain endothelial dysfunction. Finally, exosomes isolated from HIV-1 infected primary human peripheral blood mononuclear cells (hPBMCs) produce more exosomes than uninfected controls and reduce both p-DRP1 and p-eNOS expressions in primary HBMVECs. Our novel findings reveal the significant role of HIV-exosomes on dysregulation of mitochondrial function, which induces adverse changes in the function of the brain microvascular endothelium.
Highlights
Thirty years after the beginning of the acquired immune deficiency syndrome (AIDS) epidemic, the introduction of combined antiretroviral therapy has moved the management of human immunodeficiency virus-1 (HIV-1) infection toward the suppression of viral load
We show that HIV-exosomes induce mitochondrial hyperfusion due to loss of phosphorylated dynamin-related protein 1 (p-DRP1) and the reduced expression of phosphorylated endothelial nitric oxide synthase (p-eNOS) in human brain microvascular endothelial cells (HBMVECs)
We observed that HIVexosomes or HIV+human peripheral blood mononuclear cells (hPBMCs) Exo induced mitochondrial hyperfusion due to the loss of p-DRP1 and the reduced expression of p-eNOS in HBMVECs
Summary
Thirty years after the beginning of the acquired immune deficiency syndrome (AIDS) epidemic, the introduction of combined antiretroviral therapy (cART) has moved the management of human immunodeficiency virus-1 (HIV-1) infection toward the suppression of viral load. Recent literature indicates that a large proportion of extracellular vesicles (EVs) released by HIV-1 infected cells contain HIV-1 Env [15], gp120 [16], HIV-1 Gag [16], the Nef protein [17,18,19,20], trans-activation response elements [21, 22], and EV-associated cytokines [23]. Since their discovery, EVs have been shown to be an important means of communication between cell types [24]. Little is known about the effect of exosomes released by replication defective, latent, HIV-1 infected cells on primary HBMVECs
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