Interplay between Autophagy, Exosomes and HIV-1 Associated Neurological Disorders: New Insights for Diagnosis and Therapeutic Applications

Abstract

The autophagy–lysosomal pathway mediates a degradative process critical in the maintenance of cellular homeostasis as well as the preservation of proper organelle function by selective removal of damaged proteins and organelles. In some situations, cells remove unwanted or damaged proteins and RNAs through the release to the extracellular environment of exosomes. Since exosomes can be transferred from one cell to another, secretion of unwanted material to the extracellular environment in exosomes may have an impact, which can be beneficial or detrimental, in neighboring cells. Exosome secretion is under the influence of the autophagic system, and stimulation of autophagy can inhibit exosomal release and vice versa. Neurons are particularly vulnerable to degeneration, especially as the brain ages, and studies indicate that imbalances in genes regulating autophagy are a common feature of many neurodegenerative diseases. Cognitive and motor disease associated with severe dementia and neuronal damage is well-documented in the brains of HIV-infected individuals. Neurodegeneration seen in the brain in HIV-1 infection is associated with dysregulation of neuronal autophagy. In this paradigm, we herein provide an overview on the role of autophagy in HIV-associated neurodegenerative disease, focusing particularly on the effect of autophagy modulation on exosomal release of HIV particles and how this interplay impacts HIV infection in the brain. Specific autophagy–regulating agents are being considered for therapeutic treatment and prevention of a broad range of human diseases. Various therapeutic strategies for modulating specific stages of autophagy and the current state of drug development for this purpose are also evaluated.

Differences in Transcriptional Dynamics Between T-cells and Macrophages as Determined by a Three-State Mathematical Model

“…The degradation/exit rates can encompass multiple potential mechanisms beyond just degradation. This can include the export of viral RNA out of the cell through such cellular secretory pathways as secretory autophagy and extracellular vesicle release 33,35,44,48,49 . Furthermore, to correlate RNA transcription rates with the expression of HIV-1 Tat protein, we utilized densitometry counts of Tat Western blots (Supp.…”

The interplay between exosomes and autophagy – partners in crime

“…Recent studies have uncovered the molecular machinery and regulatory mechanisms shared between exosome biogenesis and macroautophagy, suggesting that the two processes are intimately linked. Emerging evidence from studies of normal development, as well as multiple disease contexts is beginning to reveal a coordinated exosome-macroautophagy response that functions to maintain homeostasis through lysosomal degradation and/or release of cellular cargo (Baixauli et al, 2014;Ojha et al, 2017). Here, we begin with a description of the classic view of exosome biogenesis and macroautophagy.…”

Extracellular Vesicles in Smoking-Mediated HIV Pathogenesis and their Potential Role in Biomarker Discovery and Therapeutic Interventions

“…Among these two, TGF-β1 is reported to be in EVs, however confirming its potential as a biomarker for smoking-mediated HIV progression warrants further investigation [134]. In recent years, more studies with regard to EVs in HAND have revealed that EVs influence the CNS, ultimately deteriorating HAND [21,120,[135][136][137][138]. For example, HIV-induced microRNA-7 and cathepsin B were shown to be transported by EVs to neurons, resulting into neuronal damage [21,135].…”