Sunday, May 18, 2025
5/18/2025
The role of microglial glutaminase in HIV-induced sleep deficits - PROJECT SUMMARY Despite the effectiveness of antiretroviral therapies, virologically suppressed people with HIV (vsPWH) are at a higher risk for comorbidities such as neurocognitive, neuropsychiatric, and sleep disorders. Notably, 50-70% of vsPWH experience symptoms of insomnia, including trouble falling or staying asleep, poor sleep quality, and low daytime energy levels—rates 2.5 times higher than the general population. This exacerbates their health burden significantly. Sleep disorders and inflammation are linked. Sleep disturbances can trigger inflammation, and systemic inflammation may lead to neuroinflammation, disrupting sleep patterns. In vsPWH, elevated CNS inflammatory markers and distinct microglial activation suggest that microglia-mediated neuroinflammation could underlie HIV-related sleep deficits. Nonetheless, the microglial molecular landscape and its role in sleep phenotypes in murine NeuroHIV models remains understudied. Another line of research highlights the importance of microglia in regulating extracellular glutamate in the brain, a neurotransmitter linked to HIV- induced neurocognitive deficits. Glutaminase (GLS1) is the primary enzyme for glutamate synthesis and is upregulated in activated microglia. Using our brain-penetrable GLS1 inhibitor, JHU-083, we have shown that inhibiting microglial GLS1 improves cognitive deficits in disease models of neuroinflammation, including the EcoHIV-infection murine model of HIV. More recently, we found that EcoHIV-infected mice exhibit decreased sleep amount in the early rest period and increased sleep fragmentation, similar to what has been reported in vsPWH, and that JHU-083 could attenuate these deficits. Thus, we hypothesize that increased microglial GLS1 activity contributes to HIV-induced sleep disturbances, and inhibiting microglial GLS1 will alleviate sleep deficits. We will take the following steps to explore this understudied area of research: 1) characterize the sleep phenotypes in two murine NeuroHIV models - HIV-infected hu-BLT-hIL34 mice and EcoHIV-infected C57BL/6J mice using the piezoelectric sleep recording system and EEG; 2) characterize microglia activation, neuronal activity, neuroinflammation, and microglial transcriptome in the two NeuroHIV models and 3) determine whether selective inhibition of microglial GLS1 using a hydroxyl dendrimer-GLS1 inhibitor delivery system will ameliorate HIV-induced sleep deficits and normalizes microglia activation and neuronal activity change, neuroinflammation, and inflammatory/sleep-related microglia molecular signatures. Successful completion of these goals will lay the groundwork for developing novel mechanism-based therapeutics targeting sleep disturbances in vsPWH.
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