Dr. Norman Haughey
Tulane University/Johns Hopkins University School of Medicine
RESCHEDULED
“Perturbations of energy metabolism with HIV infection and antiretroviral therapy are associated with cognitive impairments that can be improved by transient shifts in brain energy substrate preference”
Despite successful viral suppression with antiretroviral therapy (ART), people with HIV (PWH) continue to experience persistent immune dysfunctions that contribute to damage across multiple organ systems, including the brain. Our recent studies show that ART only partially restores immunometabolic reprogramming in PWH and identify oxylipins as potential mediators of immune dysregulation and energy metabolism. In humanized NSG mice, HIV infection elevated plasma levels of linoleic acid (LA) metabolites and a resolvin. In the frontal cortex, levels of prostaglandin E2 (PGE2) were significantly increased, while docosahexaenoic acid (DHA), PGE3, and a LA metabolite were decreased. Although ART reduced plasma HIV loads to undetectable levels after ten weeks, it further disrupted both plasma and brain oxylipin metabolism, as evidenced by reduced DHA, arachidonic acid (AA), and LA levels, alongside increased concentrations of their metabolic products, including PGE2 and leukotrienes (LTB4). These findings indicate that HIV infection induces lasting alterations in oxylipin metabolism that are not fully corrected by ART. Additionally, iPSC-derived human microglia infected with HIVBal released elevated amounts of PGE2, TBX2, and LTB4, while accumulating lactate and α-ketoglutarate, suggesting an upregulation of glycolysis and glutaminolysis compared to uninfected controls. Similar metabolic shifts were observed in U937 cells exposed to PGE2 or LTB4, showing enhanced glycolysis and disrupted fatty acid oxidation. Collectively, these results suggest that oxylipins play a significant role in modulating bioenergetic adaptations in immune cells, including microglia, astrocytes and monocytes.
Thinking that modulating energy substrate utilization could be protective in the setting of HIV and ART we conducted a randomized, double-blind, placebo-controlled study to examine the effects of intranasal insulin (INI) versus placebo on cognitive function in 21 non-diabetic PWH with mild-to-moderate CI. INI improved global dementia score over time compared with placebo. Improvements with INI were apparent on the Hopkins Verbal Learning Test, Rey delayed recall, and the Trail Making Test-Part A. Partial least square discernment analysis of plasma metabolites generated a clear treatment group separation after 24 weeks of INI that was driven by decreased tryptophan, arachidonic acid, glycine, serine, sphingolipid and phospholipid metabolism, with increased bioenergetic and antioxidant defenses. INI increased the mI/total creatine ratio in parietal gray matter. INI did not modify plasma cytokines or neurofilament light protein. In tissue culture experiments we discovered that insulin acts directly on astrocytes to promote the uptake of glucose and fatty acids while shifting their substrate preference through a sequential shift in expression of genes associated with fatty acid uptake, synthesis, transport and metabolism. Under these conditions, fatty acids are converted into TCA cycle intermediates to satisfy astrocyte energy demands, allowing pyruvate derived from glucose to be directed toward the production of lactate; a preferred fuel for neurons. This shift in astrocyte energy substrate preference is required for insulin to enhance long-term potentiation in the Schaffer collateral. Together these findings suggest that transient shifts in energy substrate utilization may protect the brain by reducing the production of inflammatory eicosanoids and enhancing lactate production to fuel neurons.