Extracellular vesicles (EVs) play an important role in neuronal survival and immune surveillance of the central nervous system (CNS) by mediating the intercellular communication between neurons and other brain cells. Our early in vitro and in vivo studies showed that opioids (morphine and heroin) and/or HIV could inhibit the expression of a number of the intracellular and circulating HIV restriction microRNAs (miRNAs). Recently, we demonstrated that EVs could shuttle antiviral signals from immune-activated brain microvascular endothelial cells (BMVEC) to macrophages, resulting in HIV inhibition. In addition, we showed that plasma EVs from HIV-infected subjects enriched several miRNAs that have neurotoxic effect (miR-21 and let-7) or target tight junction proteins (miR-17 and miR-20a). We thus hypothesize that opioids and/or HIV impair the blood-brain barrier (BBB) integrity and exert neurotoxicity via EVs-mediated intercellular transmission of miRNAs. We propose two specific aims to address this hypothesis:
Specific Aim 1. To determine the impact of EVs-mediated miRNAs on BBB innate immunity against HIV and neuronal injury in the context of opioid use;
Specific Aim 2. To mechanistically study the role of BMVEC- and plasma-derived EVs in the BBB innate antiviral immunity and neuronal injury, we will generate bioengineered exosomes that contain the specific miRNAs. We will then determine the 3? UTR targets of these miRNAs and whether these miRNAs are involved in the modulation of immune activation and inflammation in BMVEC and neuronal cells. The findings from this project will provide scientific evidence of EVs-mediated BBB innate immunity against HIV and a novel mechanism for opioid and/or HIV-mediated neuronal injury.
The proposed studies will reveal the novel mechanisms by which opioids and/or HIV impair the BBB innate immunity and induce neuronal injury through modulating EVs-mediated intercellular transmission of immunoregulatory miRNAs.
| Ma, Tong-Cui; Le Guo; Zhou, Run-Hong et al. (2018) Soybean-derived Bowman-Birk inhibitor (BBI) blocks HIV entry into macrophages. Virology 513:91-97 |
| Liu, J B; Li, J L; Zhuang, K et al. (2018) Epigallocatechin-3-gallate local pre-exposure application prevents SHIV rectal infection of macaques. Mucosal Immunol 11:1230-1238 |
| Zhou, Runhong; Wang, Xu; Liu, Hang et al. (2018) GalNAc-Specific Soybean Lectin Inhibits HIV Infection of Macrophages through Induction of Antiviral Factors. J Virol 92: |
| Zhou, Run-Hong; Guo, Le; Liu, Jin-Biao et al. (2017) Epigallocatechin Gallate Inhibits Macaque SEVI-Mediated Enhancement of SIV or SHIV Infection. J Acquir Immune Defic Syndr 75:232-240 |
