Abstract
In the era of combined antiretroviral therapy (cART), as infected individuals continue to have longer lifespans, there is also an increased prevalence of HIV-associated neurocognitive disorders (HAND). Inflammation is one of the underlying features of HAND, with the role of viral proteins and antiretroviral drugs implicated in this process. Microglia are extremely sensitive to a plethora of stimuli, including viral products and cART. The current study was undertaken to understand the molecular mechanism(s) underlying cART-mediated activation of microglia. Herein we chose a combination of three commonly used drugs, tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and dolutegravir (DTG). We demonstrated that exposure of microglia to this cART cocktail induced lysosomal membrane permeabilization (LMP), which subsequently resulted in impaired lysosomal functioning involving elevated pH and decreased cathepsin D (CTSD) activity. cART exposure of microglia resulted in increased formation of autophagosomes as demonstrated by a time-dependent increase of autophagy markers, with a concomitant defect in the fusion of the lysosomes with the autophagosome. Taken together, our findings suggest a novel mechanism by which cART impairs lysosomal functioning, resulting in dysregulated autophagy and increased neuroinflammation. Interventions aimed at lysosome protection could likely be envisioned as promising therapeutic targets for abrogating cART-mediated microglia activation, which in turn, could thus be considered as adjunctive therapeutics for the treatment of HAND pathogenesis.
Highlights
In the era of combined antiretroviral therapy as infected individuals continue to enjoy longer lifespans, HIV infection has been transformed from a death sentence to a more chronic and manageable disease [1,2,3]
Our findings establish a link between defective autophagy and lysosomal dysfunction, which in turn, contributes to microglial activation in response to combined antiretroviral therapy (cART) exposure and strongly suggest that lysosomal dysfunction plays a critical role in the pathogenesis of HIV-associated neurocognitive disorders (HAND) in HIV-infected individuals on cART, and that lysosome protection could be considered as an adjunctive therapeutic strategy for ameliorating/dampening some of the neurological complications of HAND
The results showed that cART exposure significantly increased autophagosomes. (B) Representative bar graph showing the number of autophagosome the formation of autophagosomes. (B) Representative bar graph showing the number per cell. (C) Representative bar graph showing the number of autolysosome (red of autophagosome per cell. (C) Representative bar graph showing the number of puncta) Rat primary microglial cells (rPMs) were seeded into 12-well platesinto followed cART
Summary
In the era of combined antiretroviral therapy (cART) as infected individuals continue to enjoy longer lifespans, HIV infection has been transformed from a death sentence to a more chronic and manageable disease [1,2,3]. Epidemiological studies have demonstrated “accelerated aging” in HIV+ individuals on cART [4,5] Inflammation, mediated by both viral proteins and cART, has been implicated as a significant underlying factor for the pathogenesis of HAND [6,7]. We chose to use two reverse transcriptase inhibitors (TDF and FTC) as well as an integrase inhibitor (DTG) as the cART cocktail for our current study This combination has been effectively used in the clinical setting [31,32,33,34]. Our findings establish a link between defective autophagy and lysosomal dysfunction, which in turn, contributes to microglial activation in response to cART exposure and strongly suggest that lysosomal dysfunction plays a critical role in the pathogenesis of HAND in HIV-infected individuals on cART, and that lysosome protection could be considered as an adjunctive therapeutic strategy for ameliorating/dampening some of the neurological complications of HAND
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