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Differential effects of integrase strand transfer inhibitors, elvitegravir and raltegravir, on oligodendrocyte maturation: A role for the integrated stress response
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Download the PDF here
February 2021
Lindsay M. Roth 1,2 | Bassam Zidane 1,2,3 | Lindsay Festa 1,2 | Raj Putatunda1 |
Micah Romer1 | Hubert Monnerie1 | Kelly L. Jordan-Sciutto2 | Judith B. Grinspan1
Abstract
Regardless of adherence to combined antiretroviral therapy, white matter and myelin pathologies persist in patients with HIV-associated neurocognitive disorders, a spectrum of cognitive, motor, and behavioral impairments. We hypothesized that antiretroviral therapy alters the maturation of oligodendrocytes which synthesize myelin. We tested whether specific frontline integrase strand transfer inhibitors would alter oligodendrocyte differentiation and myelination. To model the effect of antiretrovirals on oligodendrocytes, we stimulated primary rat oligodendrocyte precursor cells to differentiate into mature oligodendrocytes in vitro in the presence of therapeutically relevant concentrations of elvitegravir or raltegravir and then assessed differentiation with lineage specific markers. To examine the effect of antiretrovirals on myelination, we treated mice with the demyelinating compound cuprizone, for 5 weeks. This was followed by 3 weeks of recovery in absence of cuprizone, during which time some mice received a daily intrajugular injection of elvitegravir. Brains were harvested, sectioned and processed by immunohistochemistry to examine oligodendrocyte maturation and myelination. Elvitegravir inhibited oligodendrocyte differentiation in vitro in a concentration-dependent manner, while raltegravir had no effect. Following cuprizone demyelination, administration of elvitegravir to adult mice reduced remyelination compared with control animals. Elvitegravir treatment activated the integrated stress response in oligodendrocytes in vitro, an effect which was completely blocked by pretreatment with the integrated stress response inhibitor Trans-ISRIB, preventing elvitegravir-mediated inhibition of oligodendrocyte maturation.
In summary, our data add to a growing body of evidence suggesting the involvement of cART in the persistence of white matter abnormalities in HAND individuals. We also provide evidence that the ISR pathway mediates, at least in part, the EVG-induced inhibition of oligodendrocyte maturation. In light of this, it is important to consider adjunctive therapies designed not only to alleviate neuronal dysfunctions but also to preserve myelin formation and maintenance.
"We previously reported that ARV compounds from the protease inhibitor class ritonavir, lopinavir, saquinavir and darunavir, inhibited oligodendrocyte maturation, in vitro, while ritonavir also inhibited myelin protein production, in vivo (Festa et al., 2019; Jensen et al., 2015).
In the present study, we tested a new class of ARV compounds, integrase strand transfer inhibitors (INSTIs), which inhibit the function of the HIV integrase enzyme which integrates the reverse transcribed viral DNA into the host cell genome (Arts & Hazuda, 2012; Deeks, 2014). All current frontline cART regimens include one INSTI, making these compounds clinically relevant to study (AIDSinfo, 2019; WHO, 2016). We demonstrate that elvitegravir (EVG), but not raltegravir (RAL), decreased oligodendrocyte maturation, in vitro, and inhibited remyelination following cuprizone-mediated demyelination, in vivo (Matsushima & Morell, 2001). Finally, we show that the ISR mediates the effects of EVG in our in vitro oligodendrocyte maturation model. Our results suggest that EVG could contribute to myelin abnormalities seen in HAND patients and provides further evidence to suggest the ISR could be therapeutically relevant to these patients."
Here is a larger version of the other screenshot you circulated, Jules, in case it's helpful. For context, everyone, this is from a lecture by Judith Grinspan from Penn today. The data support that nearly all of the ART drugs can inhibit oligodendrocyte maturation, which could account for the white matter abnormalities that are common in PWH and are associated with cognitive impairment. Dr. Grinspan presented substantial additional data on this understudied area.
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