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.

Keywords: HIV; autophagy; exosomes; neurodegenerative disorders; therapeutic interventions.

Figure 1

Interaction of different human immunodeficiency virus type 1 (HIV-1) proteins with the autophagy pathway. HIV-1 transcription transactivator (Tat) stimulates autophagy by increasing Bcl-2 associated athanogene 3 (BAG3) levels in human glial cells. On the other hand, Tat interferes with interferon (IFN)-γ-induced autophagy through the suppression of signal transducer and activation of transcription 1 (STAT1) phosphorylation, resulting in the reduced expression of autophagy genes including microtubule-associated protein 1 light chain 3 (LC3B). Interaction of Tat with sequestosome 1 (SQSTM1) leads to the targeting of Tat to lysosomal-mediated degradation via selective autophagy. Tat also interacts with lysosomal associated membrane protein 2A (LAMP2A), suggesting its role in lysosomal fusion in neurons. HIV-1 negative expression factor (Nef) is an anti-autophagic maturation factor which interacts with Beclin-1 resulting in activation of mammalian target of rapamycin (mTOR) and phosphorylation and cytosolic sequestration of transcription factor EB (TFEB), decreasing the biosynthesis of ATG proteins. HIV-1 envelope (Env) induces autophagy after binding to C-X-C chemokine receptor type 4 (CXCR4) on bystander CD4⁺ T cells. HIV viral infectivity factor (Vif) interacts with LC3B on the surface of autophagosomes and can block autophagic flux.