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Protease inhibitors, saquinavir and darunavir, inhibit oligodendrocyte maturation: Implications for Lysosomal Stress
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In summary, these data add to a growing body of evidence that suggest a role for ART-mediated persistence of HAND. Specifically, these data support a role for ART-mediated persistence of myelin abnormalities observed in HAND individuals. Furthermore, we implicate endolysosome de-acidification as a potential mediating mechanism in DRV or SQV-induced oligodendrocyte maturation defects. In addition to the development of new therapeutics with fewer harmful side effects, we must consider adjunctive therapies designed to alleviate neuronal dysfunction and preservation of myelin formation and maintenance.
When adhered to, ART suppresses viral replication to undetectable levels in the periphery; however, low levels of inflammation and viral reservoirs are known to persist in the CNS. Furthermore, ARVs themselves may directly contribute to HAND pathogenesis, including the white matter abnormalities that are consistently observed.
Our group has previously reported that the ARVs from the protease inhibitor (PI) class, ritonavir and lopinavir, inhibit oligodendrocyte maturation in vitro (e.g. reduction in GalC+ and MBP+ cells), and ritonavir reduced expression levels of myelin proteins (e.g. cyclic nucleoside phosphodiesterase (CNPase) and myelin oligodendrocyte glycoprotein (MOG)) in vivo (JENSEN et al. 2015). At present, the mechanisms mediating these effects are uncertain, though numerous candidates exist including the integrated stress response (ISR), oxidative stress, and organellar stress (AKAY et al. 2012; GANNON et al. 2017; STERN et al. 2018). In particular, lysosomal stress has been implicated in Tat- and gp120-mediated neuronal toxicity (CHEN et al. 2013; BAE et al. 2014; FIELDS et al. 2015) but the role that it may play in ARV-driven oligodendrocyte damage is currently unclear.
Here, we investigated the effects of two PIs, darunavir and saquinavir, on oligodendrocyte differentiation in vitro. We observed concentration-dependent inhibition of oligodendrocyte maturation and myelin protein production with both darunavir and saquinavir. Furthermore, our findings suggest that endolysosomal de-acidification mediates the ability of these ARVs to negatively regulate oligodendrocyte differentiation. Together, these data highlight the influence of proper endolysosome function during oligodendrocyte maturation and suggest that reducing lysosomal pH may provide a valid therapeutic option to prevent oligodendrocyte injury.
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