Star-Shaped Glatiramer Acetate Mitigates Pulmonary Dysfunction and Brain Neuroinflammation in a Murine Model of Cryptococcus-Associated IRIS

<b>Background:</b> <i>Cryptococcus</i>-associated immune reconstitution inflammatory syndrome (C-IRIS) is a life-threatening complication of immune recovery, often triggered by antiretroviral therapy and characterized by Th1-skewed CD4⁺ T cell hyperactivation, neuroinflammation, and pulmonary dysfunction. <b>Methods:</b> Using a validated murine model of unmasking C-IRIS, we assessed the therapeutic potential of star-shaped glatiramer acetate (sGA), a structurally enhanced derivative of the FDA-approved immunomodulator glatiramer acetate (GA). sGA was administered intraperitoneally on days 1 and 3 post-CD4⁺ T cell reconstitution. <b>Results:</b> sGA significantly ameliorated C-IRIS-associated respiratory dysfunction, including increasing breaths per minute by ~35% and improved minute volume, total respiratory cycle time, expiration time, and inspiration time. Survival rate grew to 75% on day 14 for sGA-treated C-IRIS mice. In both the lung and the brain, sGA reduced total CD4⁺ T cells and selectively diminished Th1 cells by 50-60% and Th17 cells by 40-50%. Activated microglia decreased by 45% within the brain, indicating attenuated innate immune activation. Golgi-Cox analysis revealed region-specific neuroprotection: neuronal loss in the prefrontal cortex, lateral hypothalamus, and periaqueductal gray was rescued by 25-40%, whereas hippocampal neurons were relatively preserved, and basolateral amygdala neurons showed no significant recovery. <b>Conclusion:</b> Collectively, our findings suggest that sGA exerts neuroprotection in C-IRIS by limiting peripheral CD4⁺ T cell effector activity and suppressing CNS-resident immune activation. This study supports the use of sGA as a promising preclinical therapeutic candidate for C-IRIS and other Th1-mediated neuroinflammatory conditions.