Methamphetamine Induces the Release of Proadhesive Extracellular Vesicles and Promotes Syncytia Formation: A Potential Role in HIV-1 Neuropathogenesis.

Subhash Chand,Sowmya V Yelamanchili,Sarah Al-Sharif,Fatah Kashanchi,Austin Gowen,Maria Cowen,Catherine Demarino

doi:10.3390/v14030550

Abstract

Despite the success of combinational antiretroviral therapy (cART), the high pervasiveness of human immunodeficiency virus-1 (HIV)-associated neurocognitive disorders (HAND) poses a significant challenge for society. Methamphetamine (meth) and related amphetamine compounds, which are potent psychostimulants, are among the most commonly used illicit drugs. Intriguingly, HIV-infected individuals who are meth users have a comparatively higher rate of neuropsychological impairment and exhibit a higher viral load in the brain than infected individuals who do not abuse meth. Effectively, all cell types secrete nano-sized lipid membrane vesicles, referred to as extracellular vesicles (EVs) that can function as intercellular communication to modulate the physiology and pathology of the cells. This study shows that meth treatments on chronically HIV-infected promonocytic U1 cells induce the release of EVs that promote cellular clustering and syncytia formation, a phenomenon that facilitates HIV pathogenesis. Our analysis also revealed that meth exposure increased intercellular adhesion molecule-1 (ICAM-1) and HIV-Nef protein expression in both large (10 K) and small (100 K) EVs. Further, when meth EVs are applied to uninfected naïve monocyte-derived macrophages (MDMs), we saw a significant increase in cell clustering and syncytia formation. Furthermore, treatment of MDMs with antibodies against ICAM-1 and its receptor, lymphocyte function-associated antigen 1 (LFA1), substantially blocked syncytia formation, and consequently reduced the number of multinucleated cells. In summary, our findings reveal that meth exacerbates HIV pathogenesis in the brain through release of proadhesive EVs, promoting syncytia formation and thereby aiding in the progression of HIV infection in uninfected cells.

Highlights

Human immunodeficiency virus-1 (HIV)-associated neurocognitive disorders (HAND) are found in nearly one-third of HIV+ patients and pose a significant challenge for society, even with the availability of combinational antiretroviral therapy [1–4]
In order to investigate the extracellular vesicles (EVs) subtype release dynamics after meth treatments, we isolated both the large EVs (10 K) and small EVs (100 K) from cells treated with two doses of meth for 48 h in
Nano tracking particle analysis (NTA) revealed that there was no difference in 10 K EV secretion (Figure 1B); a significant difference was seen with 100 K EVs in all meth treatments (10–250 μM). treated cells released significantly more particles than the untreated controls (Figure 1C)

Summary

Introduction

Human immunodeficiency virus-1 (HIV)-associated neurocognitive disorders (HAND) are found in nearly one-third of HIV+ patients and pose a significant challenge for society, even with the availability of combinational antiretroviral therapy (cART) [1–4]. Methamphetamine (meth), mephedrone, ketamine, and gamma-hydroxybutyrate are the most common recreational drugs associated with chemsex and pose a significant challenge in HIV prevention and treatment [5–7]. These drugs are used to boost, prolong, and intensify sexual experiences [5]. HIV-positive meth users are less likely to adhere to cART and are at high risk of viral load rebound [14–17]. In monkeys infected with simian immunodeficiency virus (SIV), it has been shown that meth treatment significantly increases brain viral load [18]. The impact of meth on HIV infection and disease progression in CNS are yet to be fully elucidated

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