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Antiretroviral-Mediated Microglial Activation Involves Dysregulated Autophagy and Lysosomal Dysfunction
Ashutosh Tripathi1, Annadurai Thangaraj2, Ernest T Chivero3
1Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA. ashutosh.tripathi@unmc.edu.
Cells
|October 2, 2019
Summary
Combined antiretroviral therapy (cART) can activate microglia, leading to neuroinflammation in HIV-associated neurocognitive disorders (HAND). This study reveals cART impairs lysosomal function, disrupting autophagy and offering potential therapeutic targets for HAND.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Increased lifespan of HIV-infected individuals on combined antiretroviral therapy (cART) correlates with a higher prevalence of HIV-associated neurocognitive disorders (HAND).
- Neuroinflammation, driven by microglia activation, is a key feature of HAND, with viral proteins and cART implicated in this process.
Purpose of the Study:
- To elucidate the molecular mechanisms behind cART-induced microglia activation.
- To investigate the impact of a specific cART combination (TDF, FTC, DTG) on microglial function.
Main Methods:
- Exposure of primary microglia to a cART drug combination (TDF, FTC, DTG).
- Assessment of lysosomal membrane permeabilization (LMP), lysosomal pH, cathepsin D (CTSD) activity, and autophagosome formation/lysosome fusion.
Main Results:
- cART exposure induced lysosomal membrane permeabilization (LMP) in microglia.
- Impaired lysosomal function was observed, characterized by elevated pH and reduced CTSD activity.
- cART led to increased autophagosome formation but defective autophagosome-lysosome fusion, indicating dysregulated autophagy.
Conclusions:
- cART impairs microglial lysosomal function, leading to dysregulated autophagy and neuroinflammation, contributing to HAND pathogenesis.
- Targeting lysosome protection may offer a novel therapeutic strategy for mitigating cART-mediated microglia activation and treating HAND.
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